MyocardialProtectionEDITED BY

Tomas A. Salerno, MDProfessor and Chief

Division of Cardiothoracic Surgery

University of Miami

Jackson Memorial Hospital

Miami, Florida

and

Marco Ricci, MDAssistant Professor of Surgery

Division of Cardiothoracic Surgery

Staff Surgeon, Section of Pediatric Cardiac Surgery

University of Miami

Jackson Memorial Hospital

Miami, Florida

Futura, an imprint of Blackwell Publishing

Myocardial Protection

This book is dedicated to our wives

Michelle Ricci and

Helen Salerno

MyocardialProtectionEDITED BY

Tomas A. Salerno, MDProfessor and Chief

Division of Cardiothoracic Surgery

University of Miami

Jackson Memorial Hospital

Miami, Florida

and

Marco Ricci, MDAssistant Professor of Surgery

Division of Cardiothoracic Surgery

Staff Surgeon, Section of Pediatric Cardiac Surgery

University of Miami

Jackson Memorial Hospital

Miami, Florida

Futura, an imprint of Blackwell Publishing

© 2004 by Futura, an imprint of Blackwell Publishing

Blackwell Publishing, Inc./Futura Division, 3 West Main Street, Elmsford, New York 10523, USA

Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA

Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK

Blackwell Science Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

All rights reserved. No part of this publication may be reproduced in any form or by any

electronic or mechanical means, including information storage and retrieval systems, without

permission in writing from the publisher, except by a reviewer who may quote brief passages in

a review.

03 04 05 06 5 4 3 2 1

ISBN: 1-4051-1643-9

Library of Congress Cataloging-in-Publication Data

Myocardial protection / edited by Tomas A. Salerno and Marco

Ricci. a 1st ed.

p. ; cm.

Includes bibliographical references and index.

ISBN 1-4051-1643-9

1. HeartaSurgeryaComplicationsaPrevention. 2. Myocardium.

3. Cardiac arrest, Induced. 4. Myocardial reperfusion. 5. Re-perfusion

injuryaPrevention. I. Salerno, Tomas A. II. Ricci,

Marco, M.D.

[DNLM: 1. Cardiovascular Surgical Proceduresamethods.

WG 168 M9958 2004]

RD598.M915 2004

617.4′1adc21

2003009294

A catalogue record for this title is available from the British Library

Acquisitions: Steven Korn

Production: Julie Elliott

Typesetter: Graphicraft Ltd, Hong Kong

Printed and bound in Great Britain by CPI Bath, Bath

For further information on Blackwell Publishing, visit our website:

www.futuraco.com

www.blackwellpublishing.com

Notice: The indications and dosages of all drugs in this book have been recommended in the

medical literature and conform to the practices of the general community. The medications

described do not necessarily have specific approval by the Food and Drug Administration for

use in the diseases and dosages for which they are recommended. The package insert for each

drug should be consulted for use and dosage as approved by the FDA. Because standards for

usage change, it is advisable to keep abreast of revised recommendations, particularly those

concerning new drugs.

List of Contributors, vii

Foreword, xi

W. Gerard Rainer, MD

Preface, xii

1 The History of Myocardial Protection, 1

Anthony L. Panos, MD, MSc, FRCSC, FACS

2 The Duality of Cardiac Surgery: Mechanical and

Metabolic Objective, 13

Gerald D. Buckberg, MD

3 Modification of Ischemia-Reperfusion-Induced

Injury by Cardioprotective Interventions, 18

Ming Zhang, MD, Tamer Sallam, BS, BA, Yan-Jun

Xu, PhD, and Naranjan S. Dhalla, PhD, MD

(Hon), DSc (Hon)

4 Anesthetic Preconditioning: A New Horizon in

Myocardial Protection, 33

Nader D. Nader, MD, PhD, FCCP

5 Myocardial Protection During Acute Myocardial

Infarction and Angioplasty, 43

Alexandre C. Ferreira, MD, FACC and Eduardo

deMarchena, MD, FACC

6 Intermittent Aortic Cross-Clamping for

Myocardial Protection, 53

Fabio Biscegli Jatene, MD, PhD, Paulo M.

Pêgo-Fernandes, MD, PhD, and Alexandre

Ciappina Hueb, MD

7 Intermittent Warm Blood Cardioplegia: The

Biochemical Background, 59

Ganghong Tian, MD, PhD, Tomas A. Salerno, MD,

and Roxanne Deslauriers, PhD

8 Warm Heart Surgery, 70

Hassan Tehrani, MB, BCh, Atiq Rehman, MD,

Pierluca Lombardi, MD, Mohan Thanikachalam,

MD, and Tomas Salerno, MD

9 Intermittent Antegrade Warm Blood

Cardioplegia, 75

Antonio Maria Calafiore, MD, Giuseppe Vitolla,

MD, and Angela Iacò, MD

10 Antegrade, Retrograde, or Both?, 82

Frank G. Scholl, MD and Davis C. Drinkwater, MD

11 Miniplegia: Biological Basis, Surgical Techniques,

and Clinical Results, 88

Giuseppe D’Ancona, MD, Hratch Karamanoukian,

MD, Luigi Martinelli, MD, Michael O. Sigler, MD,

and Tomas A. Salerno, MD

12 Substrate Enhancement in Cardioplegia, 94

Shafie Fazel, MD, Marc P. Pelletier, MD, and

Bernard S. Goldman, MD

13 Is There a Place for On-Pump, Beating Heart

Coronary Artery Bypass Grafting Surgery? The

Pros and Cons, 119

Simon Fortier, MD, Roland G. Demaria, MD,

PhD, FETCS, and Louis P. Perrault, MD, PhD,

FRCSC, FACS

14 Myocardial Protection in Beating Heart Coronary

Artery Surgery, 126

Vinod H. Thourani, MD and John D. Puskas,

MD, MSc

15 Beating Heart Coronary Artery Bypass Grafting:

Intraoperative Strategies to Avoid Myocardial

Ischemia, 134

Kushagra Katariya, MD, Michael O. Sigler, MD

and Tomas A. Salerno, MD

16 Beating Heart Coronary Artery Bypass in Patients

with Acute Myocardial Infarction: A New Strategy

to Protect the Myocardium, 144

Jan F. Gummert, MD, PhD, Michael A. Borger,

MD, PhD, Ardawan Rastan, MD, and Friedrich W.

Mohr, MD, PhD

Contents

v

vi Contents

17 Beating Heart Coronary Artery Bypass with

Continuous Perfusion Through the Coronary

Sinus, 152

Harinder Singh Bedi, MCh, FIACS

18 On-Pump Beating Heart Surgery for Dilated

Cardiomyopathy and Myocardial Protection, 160

Tadashi Isomura, MD and Hisayoshi Suma, MD

19 Myocardial Protection with Beta-Blockers in

Valvular Surgery, 167

Nawwar Al Attar, FRCS, MSc, FETCS, Marcio

Scorsin, MD, PhD, and Arrigo Lessana, MD, FETCS

20 Myocardial Protection in Minimally Invasive

Valvular Surgery, 174

René Prêtre, MD and Marko I. Turina, MD

21 Intermittent Warm Blood Cardioplegia in Aortic

Valve Surgery: An Update, 181

M. Saadah Suleiman, PhD, Raimondo Ascione,

MD, and Gianni D. Angelini, MD, FRCS

22 Myocardial Protection in Surgery of the

Aortic Root, 189

Stephen Westaby, PhD, MS, FETCS

23 Myocardial Protection in Major Aortic

Surgery, 193

Marc A. Schepens, MD, PhD and Andrea Nocchi,

MD

24 Recent Advances in Myocardial Protection for

Coronary Reoperations, 196

Jan T. Christenson, MA, MD, PhD, PD, FETCS and

Afksendiyos Kalangos, MD, PhD, PD, FETCS

25 Myocardial Protection During Minimally Invasive

Cardiac Surgery, 203

Saqib Masroor, MD, MHS and Kushagra Katariya,

MD

26 Current Concepts in Pediatric Myocardial

Protection, 207

Bradley S. Allen, MD

27 Myocardial Preconditioning in the Experimental

Model: A New Strategy to Improve Myocardial

Protection, 230

Eliot R. Rosenkranz, MD, Jun Feng, MD, PhD,

and Hong-Ling Li, MD, MSc

28 New Concepts in Myocardial Protection in

Pediatric Cardiac Surgery, 264

Bindu Bittira, MD, MSc, Dominique Shum-Tim,

MD, MSc, and Christo I. Tchervenkov, MD

29 Extracardiac Fontan: The Importance of Avoiding

Cardioplegic Arrest, 275

Carlo F. Marcelletti, MD and Raúl F. Abella,

MD

30 Preservative Cardioplegic Solutions in Cardiac

Transplantation: Recent Advances, 282

Romualdo J. Segurola Jr., MD and Rosemary F.

Kelly, MD

31 Myocardial Preservation in Clinical Cardiac

Transplantation: An Update, 292

Louis B. Louis IV, MD, Xiao-Shi Qi, MD, PhD,

and Si M. Pham, MD, FACS

32 Myocardial Protection During Left Ventricular

Assist Device Implantation, 301

Aftab R. Kherani, MD, Mehmet C. Oz, MD, and

Yoshifumi Naka, MD, PhD

33 Gene Therapy for Myocardial Protection, 304

Said F. Yassin, MD and Christopher G. McGregor,

MD

34 Aortic and Mitral Valve Surgery on the Beating

Heart, 311

Marco Ricci, MD, Pierluca Lombardi, MD, Michael

O. Sigler, MD, Giuseppe D’Ancona, MD and

Tomas A. Salerno, MD

Index, 321

Raúl F. Abella, MDConsultant in Cardiac Surgery, Division of PediatricCardiovascular Surgery, Ospedale Civico di Palermo,Palermo, Sicily, Italy

Nawwar Al Attar, FRCS,MSc, FETCSCardiac Surgeon, Department of Cardiac Surgery, Centre Cardiologique du Nord, St. Denis, France

Bradley S. Allen, MDChief, Division of Pediatric Cardiac Surgery, University ofTexas, Houston; Memorial Hermann Children’s Hospital,Houston Texas, USA

Gianni D. Angelini, MD, FRCSBristol Heart Institute, University of Bristol, Bristol, United Kingdom

Raimondo Ascione, MDBristol Heart Institute, University of Bristol, Bristol, United Kingdom

Harinder Singh Bedi, MCh, FIACSChief Cardiac Surgeon and Chairman, CardiovascularSurgery, Metro Heart Institute, Noida, New Delhi, India

Bindu Bittira, MD, MScChief Resident, Thoracic Surgery, Division ofCardiothoracic Surgery, The Montreal General Hospital,McGill University, Montreal, Quebec, Canada

Michael A. Borger, MD, PhDLeipzig Heart Center, University of Leipzig, Leipzig,Germany

Gerald D. Buckberg, MDDivision of Thoracic and Cardiovascular Surgery, University of California, Los Angeles, Los Angeles, CA, USA

Antonio Maria Calafiore, MDProfessor and Chief, Department of Cardiac Surgery, “G. D’Annunzio” Chieti University, Chieti, Italy

Jan T. Christenson, MA, MD, PhD, PD, FETCSChief of Clinic, Department of Surgery, Clinic forCardiovascular Surgery, University Hospital of Geneva,Geneva, Switzerland

Giuseppe D’Ancona, MDHospital San Martino Genova, University of GenovaMedical School, Genova, Italy

Eduardo deMarchena, MD, FACCProfessor of Medicine and Surgery, Chief, InterventionalCardiology, University of Miami School of Medicine,Miami, FL, USA

Roland G. Demaria, MD, PhD, FETCSDepartment of Surgery and Research Center, MontrealHeart Institute, Montreal, Quebec, Canada

Roxanne Deslauriers, PhDDirector of Research, Institute for Biodiagnostics, NationalResearch Council, Winnipeg, Manitoba, Canada

Naranjan S. Dhalla, PhD, MD (Hon), DSc (Hon)Distinguished Professor and Director, Institute ofCardiovascular Sciences, St. Boniface General HospitalResearch Centre, Winnipeg, Manitoba, Canada

Davis C. Drinkwater, MDDepartment of Cardiothoracic Surgery, VanderbiltUniversity Medical Center, Nashville, TN, USA

Shafie Fazel, MDResident, Division of Cardiac Surgery, University ofToronto, Toronto, Ontario, Canada

Alexandre C. Ferreira, MD, FACCAssistant Professor of Medicine, Coordinator,Interventional Training Program, University of MiamiSchool of Medicine, Miami, FL

Simon Fortier, MDDepartment of Surgery and Research Center, MontrealHeart Institute, Montreal, Quebec, Canada

List of Contributors

vii

viii List of Contributors

Bernard S. Goldman, MDSurgeon, Division of Cardiovascular Surgery, Sunnybrookand Women’s College Health Sciences Centre, Toronto;Professor, Department of Surgery, University of Toronto,Toronto, Ontario, Canada; Editor-in-Chief, Journal ofCardiac Surgery

Jan F. Gummert, MD, PhDLeipzig Heart Center, University of Leipzig, Leipzig,Germany

Alexandre Ciappina Hueb, MDDepartment of Thoracic and Cardiovascular Surgery, Heart Institute, University of São Paulo, São Paulo, Brazil

Angela Iacò, MDStaff Surgeon, Department of Cardiac Surgery, “G.D’Annunzio” Chieti University, Chieti, Italy

Tadashi Isomura, MDDirector, Cardiovascular Surgery, Hayama Heart Center,Hayama, Kanagawa, Japan

Fabio Biscegli Jatene, MD, PhDDepartment of Thoracic and Cardiovascular Surgery, Heart Institute, University of São Paulo, São Paulo, Brazil

Afksendiyos Kalangos, MD, PhD, PD, FETCSChief of Service, Department of Surgery, Clinic forCardiovascular Surgery, University Hospital of Geneva,Geneva, Switzerland

Hratch Karamanoukian, MDCenter for Less Invasive and Robotic Heart Surgery, KaleidaHealth, Buffalo, NY, USA

Kushagra Katariya, MDDivision of Cardiothoracic Surgery, University of Miami,Jackson Memorial Hospital, Miami, FL, USA

Rosemary F. Kelly, MDAssistant Professor of Surgery, University of Minnesota,Cardiovascular and Thoracic Surgery, Minneapolis, MN,USA

Aftab R. Kherani, MDResident in General Surgery, Duke University MedicalCenter, Durham, NC; Research Fellow, Division ofCardiothoracic Surgery, Columbia University, College ofPhysicians and Surgeons, New York, NY, USA

Arrigo Lessana, MD, FETCSChief of Surgery, Department of Cardiac Surgery, CentreCardiologique du Nord, St. Denis, France

Pierluca Lombardi, MDFellow in Cardiothoracic Surgery, Division ofCardiothoracic Surgery, Daughtry Family Department ofSurgery, University of Miami, Miami, FL, USA

Louis B. Louis IV, MDDivision of Cardiothoracic Surgery, University of MiamiSchool of Medicine, Miami, FL, USA

Carlo F. Marcelletti, MDCardiovascular Surgeon-in-Chief, Division of PediatricCardiovascular Surgery, Ospedale Civico di Palermo,Palermo, Sicily, Italy

Luigi Martinelli, MDHospital San Martino Genova, University of GenovaMedical School, Genova, Italy

Saqib Masroor, MD, MHSDivision of Thoracic and Cardiovascular Surgery, Universityof Miami, Jackson Memorial Hospital, Miami, FL, USA

Christopher G. McGregor, MDMayo Clinic Foundation, Rochester, MN, USA

Friedrich W. Mohr, MD, PhDLeipzig Heart Center, University of Leipzig, Leipzig,Germany

Nader D. Nader, MD, PhD, FCCPAssociate Professor of Anesthesiology, Surgery, Pathology,and Anatomical Sciences, State University of New York atBuffalo; Chief, Perioperative Care and Anesthesia, UpstateVA Healthcare System, Buffalo, NY, USA

Yoshifumi Naka, MD, PhDHerbert Irving Assistant Professor of Surgery, Director,Mechanical Circulatory Support, Columbia University,College of Physicians and Surgeons, New York, NY, USA

Andrea Nocchi, MDCardiothoracic Surgeon, Department of Cardiac Surgery,Ospedale Carlo Poma, Mantova, Italy

Mehmet C. Oz, MDAssociate Professor of Surgery, Director, The CardiovascularInstitute, Columbia University, College of Physicians andSurgeons, New York, NY, USA

Anthony L. Panos, MD, MSc, FRCSC,FACSDivision of Cardiothoracic Surgery, William S. MiddletonVA Medical Center; Associate Professor, University ofWisconsin at Madison, Madison, WI, USA

Paulo M. Pêgo-Fernandes, MD, PhDDepartment of Thoracic and Cardiovascular Surgery, HeartInstitute, University of São Paulo, São Paulo, Brazil

List of Contributors ix

Marc P. Pelletier, MDSurgeon, Division of Cardiovascular Surgery, Sunnybrookand Women’s College Health Sciences Centre, Toronto;Assistant Professor, Department of Surgery, University ofToronto, Toronto, Ontario, Canada

Louis P. Perrault, MD, PhD, FRCSC, FACSDepartment of Surgery and Research Center, MontrealHeart Institute, Montreal, Quebec, Canada

Si M. Pham, MD, FACSDirector, Section of Cardiopulmonary Transplantation,Division of Cardiothoracic Surgery, University of MiamiSchool of Medicine, Miami, FL

René Prêtre, MDCardiovascular Surgery, University Hospital Zürich, Zürich,Switzerland

John D. Puskas, MD, MScAssociate Professor of Surgery, Carlyle Fraser Heart Center,Division of Cardiothoracic Surgery, Department of Surgery,Emory University School of Medicine, Atlanta, GA, USA

Xiao-Shi Qi, MD, PhDDivision of Cardiothoracic Surgery, University of MiamiSchool of Medicine, Miami, FL, USA

W. Gerard Rainer, MDDistinguished Clinical Professor of Surgery, University ofColorado Health Sciences Center; Past President andHistorian, Society of Thoracic Surgeons

Ardawan Rastan, MDLeipzig Heart Center, University of Leipzig, Leipzig,Germany

Atiq Rehman, MDFellow in Cardiothoracic Surgery, Division ofCardiothoracic Surgery, Daughtry Family Department ofSurgery, University of Miami, Miami, FL, USA

Marco Ricci, MDAssistant Professor of Surgery, Division of CardiothoracicSurgery, University of Miami, Jackson Memorial Hospital,Miami, FL, USA

Eliot R. Rosenkranz, MDDirector, Section of Pediatric Cardiac Surgery, AssociateProfessor of Surgery, University of Miami, JacksonMemorial Hospital, Miami, FL, USA

Tomas A. Salerno, MDProfessor and Chief, Division of Cardiothoracic SurgeryUniversity of Miami, Jackson Memorial Hospital, Miami, FL, USA

Tamer Sallam, BS, BAResearch Fellow, Institute of Cardiovascular Sciences, St.Boniface General Hospital Research Centre, Winnipeg,Manitoba, Canada

Marc A. Schepens, MD, PhDDepartment of Cardiothoracic Surgery, St. AntoniusHospital, Nieuwegein, The Netherlands

Frank G. Scholl, MDDepartment of Cardiothoracic Surgery, VanderbiltUniversity Medical Center, Nashville, TN, USA

Marcio Scorsin, MD, PhDCardiac Surgeon, Department of Cardiac Surgery, CentreCardiologique du Nord, St. Denis, France

Romualdo J. Segurola Jr., MDCardiovascular and Thoracic Surgery, University ofMinnesota, Minneapolis, MN, USA

Michael O. Sigler, MDDepartment of Surgery, University of Miami, JacksonMemorial Hospital, Miami, FL, USA

Dominique Shum-Tim, MD, MScStaff Surgeon, The Montreal Children’s Hospital; StaffSurgeon, The Montreal General Hospital; AssistantProfessor of Surgery, McGill University, Montreal, Quebec,Canada

M. Saadah Suleiman, PhDBristol Heart Institute, University of Bristol, Bristol, UnitedKingdom

Hisayoshi Suma, MDHonored Director, Cardiovascular Surgery, Hayama HeartCenter, Hayama, Kanagawa, Japan

Christo I. Tchervenkov, MDDirector, Cardiovascular Surgery, The Montreal Children’sHospital, Montreal, Quebec, Canada

Hassan Tehrani, MB, BChFellow in Cardiothoracic Surgery, Division ofCardiothoracic Surgery, Daughtry Family Department ofSurgery, University of Miami, Miami, FL, USA

Mohan Thanikachalam, MDFellow in Cardiothoracic Surgery, Division ofCardiothoracic Surgery, Daughtry Family Department ofSurgery, University of Miami, Miami, FL, USA

Vinod H. Thourani, MDResident in Cardiothoracic Surgery, Carlyle Fraser HeartCenter, Division of Cardiothoracic Surgery, Department ofSurgery, Emory University School of Medicine, Atlanta, GA,USA

x List of Contributors

Ganghong Tian, MD, PhDAssociate Research Officer, Institute for Biodiagnostics,National Research Council, Winnipeg, Manitoba, Canada

Marko I. Turina, MDCardiovascular Surgery, University Hospital Zürich, Zürich,Switzerland

Giuseppe Vitolla, MDStaff Surgeon, Department of Cardiac Surgery,“G. D’Annunzio” Chieti University, Chieti, Italy

Stephen Westaby, PhD, MS, FETCSOxford Heart Centre, John Radcliffe Hospital, Oxford,United Kingdom

Yan-Jun Xu, PhDResearch Scientist, Institute of Cardiovascular Sciences, St.Boniface General Hospital Research Centre, Winnipeg,Manitoba, Canada

Said F. Yassin, MDDivision of Cardiothoracic Surgery, University of MiamiSchool of Medicine, Miami, FL, USA

Ming Zhang, MDResearch Fellow, Institute of Cardiovascular Sciences, St.Boniface General Hospital Research Centre, Winnipeg,Manitoba, Canada

When open heart surgery became a possibility one-

half century ago, it seems that considerable atten-

tion was directed toward protection of the body as a

whole (perhaps it was assumed that this would take

care of the needs of the heart as well). Hypothermia,

partial perfusion, intermittent aortic cross-clamping

and a variety of other techniques were thought to

suffice until careful observers noted occurrence of

such events as “stone heart,” subendocardial ischemia,

and other manifestations of inadequate myocardial

protection. This dramatically demonstrated that the

heart could not be treated as just any other organ or

part of the body. Its function is so different because of

its intricate neuromuscular structure that investiga-

tions were begun (and continue until the present) to

define the cellular metabolic needs of the heart and to

develop ways to meet those needs so that, hopefully,

minimal cardiac function will be lost following correc-

tion of the underlying abnormality.

Salerno and Ricci have admirably filled a needed

niche by pulling together various approaches and

modalities for myocardial protection applicable to

many different scenariosathe chapter titles speak for

themselves in exhibiting the array of situations dis-

cussed in detail along with au courant data regarding

various methods of protection based upon pioneer-

ing investigations by contributors such as Kirklin,

Buckberg, and others.

This volume is an absolute necessity for cardiac sur-

geons in training and in practice and is so designed to

be an invaluable teaching tool and reference into the

foreseeable future.

W. Gerard Rainer, MD

Distinguished Clinical Professor of Surgery

University of Colorado Health Sciences Center

Past President and Historian, Society

of Thoracic Surgeons

Foreword

xi

Cardiac surgery has undergone major changes in the

recent past. With changes came new knowledge, tech-

nology and progress, all aimed at providing better

care to our patients. Fundamentally, however, cardiac

surgery “is myocardial protection,” the realization

that no matter how perfect the reparative surgery,

myocardial function has to be preserved for a short

and long-term successful outcome. The pace of tech-

nological advancements has accelerated over the last

five years, allowing surgeons to perform cardiac surgery

differently and more comfortably. For each proced-

ure, there is the need for different technology, such as

devices, valves, suture materials, stabilizers, shunts,

blowers, and others. One factor, however, has remained

constant, i.e. the need for individualization for a

specific method of myocardial protection tailored to

each operation.

It is in this spirit that the editors of this book felt the

need to put together a collection of manuscripts writ-

ten by experts in the different fields of myocardial pro-

tection. The idea is to give the reader an up-to-date

view of how myocardial protective strategies are being

utilized by surgeons performing different procedures.

Although it was recognized that the past plays a major

role in current methods of myocardial protection, the

book was intentionally aimed at the present and the

future.

The editors are grateful to all the authors and

co-authors who wrote this modern book. Their tasks

were time consuming, aside from their daily work as

clinicians and scientists. It is a tribute to them that the

publishers were able to print a textbook that is up to

date with current knowledge regarding myocardial

protection.

Tomas A. Salerno, MD

Marco Ricci, MD

Preface

xii

Introduction

The history of myocardial protection is a rich and

varied story that encompasses the work of basic scient-

ists and clinicians working in different countries over

many years. It is an excellent example of clinical prob-

lems stimulating basic research and then translating

that knowledge back “from the bench to the bedside.”

Many surgeons are aware of the famous quotation by

the great 19th century surgeon Theodore Billroth, that

“any surgeon who operates upon the heart, should

lose the respect of his colleagues.” At the time that

Billroth made that statement, cardiac surgery was

indeed very hazardous because knowledge and tech-

niques were not available to make it safe. The ensuing

years saw a growth in knowledge and new technology

that led to the development of modern cardiac surgery

as we currently practice it.

Myocardial protection was a key part of these

developments that allowed safe cardiac surgery to

be performed. The term myocardial protection en-

compasses more than just cardioplegia, and can be

said to include things such as the perioperative man-

agement of patients with medical treatment (such

as beta-blockers, etc.), or support devices (such as

intraaortic balloon pumps), better anesthetic agents,

and better hemodynamic management. All of these

treatments contribute to making cardiac surgery

safer, and to get a sick patient through a major opera-

tion. However, for the purposes of our discussion we

will focus more on the development of cardioplegia.

This is a very large field of research and has been

reviewed in several books [1–5] and review articles

[6]. In one chapter we will only be able to go over

some of the important highlights, and give a general

outline of the work that has brought us to where we

are today.

Early cardiac physiology

The whole of biologic and medical sciences flowered

at the end of the 19th century, as exemplified by the

microbiologic discoveries of Pasteur, Koch’s postul-

ates, and Claude Bernard’s emphasis on homeostasis

as a principle, to maintain the “internal milieu” [7].

There were also great advances in physiology, espe-

cially cardiac physiology and the understanding of

muscle mechanics by Otto Frank [8–10], and Starling

[11].

The pioneering work of Sydney Ringer on the

effects of electrolytes on the regulation of the heart

beat [12–15] is summarized by Toledo-Pereyra [16].

Physiologists in the late 19th century thought about

control of cardiac function in terms of myogenic ver-

sus neurogenic theories. It was in this atmosphere that

Ringer conducted his elegant experiments and showed

the effects of various ions on the heartbeat. Ringer’s

work was initally not appreciated in Europe, but was

followed by American physiologists, who extended it

[17–21]. As early as 1935, Zwikster and Boyd had

shown that the heart could be reversibly arrested using

potassium [22]. However, surgeons did not appreciate

this physiological research, and the clinical applica-

tion of this knowledge would occur 20 years later.

Cardiovascular physiology continued to expand

through the early years of the 20th century, but was

carried on largely by zoologists, and physiologists

working on problems of basic science. For example,

there were studies of the thebesian vein system that

would later become especially important to the

1 CHAPTER 1

The history of myocardialprotection

Anthony L. Panos, MD, MSc, FRCSC, FACS

1

2 CHAPTER 1

technique of retrograde cardioplegia [23–31]. Others

studied the electrophysiology [21,32] of the heart,

the physiology of coronary blood flow [33–38], myo-

cardial energetics [31,39–41], and the relationships

between coronary blood flow and cardiac mechanics

[42–44]. All of this important basic science work was

crucial to later clinical applications.

Early operationsCclosed

Surgeons returned from the second world war after

exposure to military surgery, and had developed an

interest in the treatment of traumatic chest wounds

[45]. This renewed interest in cardiac surgery led to a

great expansion of the specialty in the 1950s. Cardiac

surgery developed later than other surgical specialties,

largely due to the technical difficulties of operating on

the heart. The surgeon could not support the circula-

tion while working on the heart, and this limited the

kinds of surgery that could be done upon the heart. As

a result, the early operations for cardiac disease con-

sisted mostly of extracardiac procedures, such as the

ligation of a patent ductus arteriosus by Gross and

Hubbard [46], and the revolutionary work of Blalock

and Taussig to create palliative shunts for the treat-

ment of cyanotic congenital heart disease [47].

There were other early attempts to operate on

the surface of the heart. These operations included

methods to treat ischemic heart disease by increas-

ing the blood flow to the myocardium by creating

noncoronary collateral blood supply to the heart.

Pericardial adhesions were created, for example, by

means of pericardial irritation, or by covering the

heart with omentum after epicardial and pericardial

abrasion [48–50]. Some investigators studied the

effects of coronary sinus ligation in animal models

in an effort to impede venous outflow and thereby

improve coronary artery perfusion of myocardium

[27–29,51]. Dr Claude Beck developed an operation

to “revascularize” the heart using the cardiac venous

system [48–50]. The Beck operation created a venous

bypass to the epicardial veins of the heart and sub-

sequent ligation of the coronary sinus [52–56]. It is

remarkable how much Beck achieved with the limited

technology available to him, and how prescient his

work was, predicting that surgery would become

important in the treatment of angina pectoris.

There were also some closed operations performed,

such as mitral commissurotomy for the treatment

of mitral valve stenosis [57–59] or pulmonary valve

stenosis [60]. There were a variety of ingenious opera-

tions done through artificial “wells,” for example, to

allow closure of an atrial septal defect “underwater”

[61].

All of these operations reflected the limits of the

technology of their time. Most were very ingenious,

and in many ways ahead of their time. However, in the

final analysis they all required the ability to support

the circulation to make the breakthroughs that they

were seeking.

Early operationsCopen

Experimental work using inflow occlusion to allow

work within the heart (i.e. “open” operations) found

that brain injury occurred when the cerebral blood

flow was interrupted. The irreversible brain injury

occurred with interruptions of about 4 min duration.

Bigelow first proposed the use of hypothermia dur-

ing cardiac surgery in 1950 [62]. This led Bigelow,

Swan, Boerema, and others to investigate the use

of hypothermia in cardiac surgery [39,62–71]. This

laboratory work was then taken into the clinical world

and the first intracardiac repairs using systemic

hypothermia were reported [67,69,70,72]. However,

it is important to note that in these early papers the

original intention for the use of hypothermia was to

protect primarily the brain, and not the heart.

In 1950 Bigelow found that in experimental models

the total body oxygen consumption decreased with

temperature, and this included myocardial metabol-

ism [62,63]. This data was later expanded and became

the rationale for the use of hypothermia as a technique

to protect the heart.

The crucial technology of artificial circulatory sup-

port was developed, principally by the perseverance of

Dr John Gibbon [73–75]. The “heart-lung machine”

of Gibbon could support the circulation, and this

development really allowed cardiac surgery to be done

[76]. Surgeons could at last safely support the patient’s

circulation while working within the heart. However,

in order to provide the body’s oxygen requirements,

high flow rates were needed. This was initially a dif-

ficult problem, and stressed the available technology

of early oxygenators. Investigators reassessed Bigelow’s

earlier findings for total body oxygen consumption

and temperature dependence. They found that by

adding hypothermia, the total body requirements for

History of myocardial protection 3

oxygen were greatly decreased in patients. Therefore,

the total flow rates needed to provide the body’s

oxygen requirements could also be decreased greatly.

Cardioplegia

The first use of “elective cardiac arrest” was by Melrose

in 1955, who also coined the term “cardioplegia” for

the technique [77]. Melrose used a solution con-

taining potassium to remove the transmembrane

electrical potential and hence to stop the cardiac im-

pulse and arrest the heart in diastole. However, once

again, the paper by Melrose makes it clear that his

initial impetus to devise the technique was to reduce

the foaming that occurred with the cardiopulmonary

machines he was using, in order to reduce air emboli,

and not to protect the heart.

Also, during the 1950s there was the first use of

alternate routes of cardioplegia administration and

various temperatures [78–80]. Gott et al. used retro-

grade perfusion of the heart via the coronary sinus

using warm blood with Melrose solution, both experi-

mentally and clinically [78,79]. Lillehei’s group also

used retrograde perfusion of the coronary sinus with

blood during aortic valve surgery [80].

Gradually as experience with the technique increased

[81], the long-term effects of Melrose solution became

known. Surgeons found that there was late vascular

and myocardial injury in these patients [82–88]. As a

result, surgeons abandoned the technique.

Some surgeons used direct ostial cannulation of the

coronary ostia in order to perfuse the heart during

surgery. However, reports of ostial stenoses discour-

aged most surgeons from using this technique [89,90].

In the late 1950s and early 1960s Shumway

and Lower reported their work using hypothermic

methods to protect the heart [91]. The use of

hypothermia became widespread, and combined with

intermittent ischemia became the dominant method

of myocardial management during cardiac surgery in

the USA during the 1960s. Despite the problems with

Melrose solution, some surgeons in Europe continued

to use and develop cardioplegia [92]. Bretschneider

and others continued to develop the methods of car-

dioplegia based on an “intracellular” electrolyte solu-

tion, which reduced transmembrane gradients, and

arrested the heart [93–95]. Others, such as Hoelscher,

studied the effects of magnesium-procainamide

as compared to potassium citrate cardioplegia, and

found that there was no ultrastructural damage

with the magnesium-procainamide method [96,97].

Bretschneider also developed the idea of buffering of

the cardioplegic solution as an important principle of

myocardial protection [92,94]. This continuing work

on cardioplegia in Europe was important to the even-

tual resurgence of interest in America in the 1970s.

Reassessment of myocardialdamage

In the 1960s surgeons reviewing the complications

of cardiac surgery did not consider that the complica-

tions were due to the surgery itself. Slowly data accu-

mulated that questioned this prevailing concept. In

1967, Taber’s group reported that there was myocar-

dial necrosis following cardiac surgery [98]. He found

that patchy necrosis affected as much as 30% of the

myocardium. In a paper by Najafi’s group, the authors

found that there was subendocardial necrosis seen in

patients who underwent valve surgery, with normal

coronary arteries [99]. In the setting of double valve

operations Cooley et al. first described the condition

of “stone heart” [100]. This was seen when the

ischemic time was prolonged, and the hearts went

into a state of ischemic contracture.

Other investigators also found that patients under-

going valve surgery, who had otherwise normal coron-

ary arteries, had perioperative myocardial infarction

[101,102]. Storstein et al. studied the mechanisms

of these infarctions [103]. In other studies, patients

undergoing atrial septal defect repair had enzyme

evidence of myocardial infarction [104]. This gradu-

ally led surgeons to once again question whether the

intraoperative myocardial protection was effectively

protecting the heart, and whether they could improve

their techniques.

Reintroduction of cardioplegiaSome investigators, such as Tyers, identified the

problems with Melrose solution as toxicity due to

inappropriately high ionic concentrations, rather than

due to the idea of electromechanical arrest in and

of itself [105,106]. In 1973 Gay and Ebert pioneered

the reintroduction of cardioplegia using crystalloid

solutions with much lower concentrations of KCl,

which were just sufficient to give electromechanical

arrest [107]. In 1974 Hearse’s group reported their

experimental work with a potassium chloride solution

4 CHAPTER 1

[108]. In 1976 another paper extended this work

[109]. These experimental papers led to the develop-

ment of cardioplegic solutions for clinical use, such as

the St Thomas’ solution [108–112], which was first

used clinically in 1976 [110].

A great deal of work ensued on the various com-

ponents of cardioplegia solutions, on what should be

included in the solutions, and in what concentrations.

Many papers were written on the proper use and con-

centrations of buffers, Mg2+, Ca2+, acid–base balance,

local anesthetics, and even oxygen.

Some investigators wanted to deliver oxygen during

the arrest period and introduced oxygen into the car-

dioplegia solutions to “oxygenate” them [113,114].

There was even interest in the use of artificial solutions

such as fluorocarbons for cardioplegia because of their

oxygen-carrying capacity [115–118].

Blood cardioplegia

The interest in delivering oxygen and buffering the

cardioplegia solution led investigators to question

whether the best buffer and oxygen-carrying could be

achieved by blood itself. Dr Gerald Buckberg’s group

working at UCLA did a large amount of experimental

work that led to the development of blood cardio-

plegia in the late 1970s [119]. Other surgeons were

also interested in the technique [120–122], its use

spread, and it became widely adopted as a cardioplegic

method during the 1980s.

Nevertheless, there are many proponents of

crystalloid cardioplegia [113,114,123], and other

methods of myocardial protection such as fibrillatory

arrest [124,125], who continue to use their methods

with good results.

Dr Buckberg’s group continued to work on

myocardial protection and developed several very

important techniques. Their work asked whether we

could use cardioplegia not merely to prevent damage,

but also to act as a form of treatment, and to reverse

injury to the myocardium.

They reported the use of warm blood cardioplegia

given to induce cardiac arrest and replenish high-

energy phosphates in energy-depleted hearts before

giving cold cardioplegia [126]. This is important in

chronically ill patients, and also those suffering from

acute ischemia [127].

This led to investigations altering the conditions

of reperfusion (pressure, temperature, etc.) at the

end of the arrest period. The use of terminal warm

cardioplegia, the so-called terminal “hot-shot,” was

confirmed experimentally [128] and clinically [129] to

be advantageous to myocardial metabolism.

Buckberg’s group also investigated the use of amino

acids in the cardioplegia to provide substrates for

Kreb’s cycle [130]. This method of substrate enhance-

ment has been shown to be beneficial clinically, reduc-

ing the need for inotropic support or the use of the

intraaortic balloon pump [131–133]. This work also

led to the development of “secondary” blood cardio-

plegia to resuscitate poorly functioning injured hearts

at the end of the operation with a further period of

warm cardioplegic arrest [134,135].

Continuous cardioplegia

Salerno’s group at the University of Toronto was

interested in myocardial protection, both experiment-

ally and clinically. They questioned whether surgeons

could avoid ischemia altogether [136]. Several investi-

gators had used continuous cold blood cardioplegia,

in patients undergoing valve surgery [137], in acute

postinfarction mitral regurgitation [138], and in

patients with ventricular hypertrophy [139].

The use of continuous blood cardioplegia was done

in an effort to provide oxygen and substrate through-

out the operation. This eventually led to questions

about the ability to deliver oxygen at lower tempera-

tures. It was well known that the oxygen–hemoglobin

dissociation curve was shifted to the right by hypo-

thermia, and interfered with unloading of oxygen at

the cellular level. The question was “Did we need

hypothermia”? If we used a warm induction dose of

cardioplegia, cold in the middle, and a “hot-shot” at

the end, did we really need the cold in the middle? Ali

has summarized the theoretical background and

rationale of the technique [140,141].

After Salerno reintroduced the use of continu-

ous normothermic blood cardioplegia [142], initial

experimental [143] and clinical [144–146] work led to

renewed interest in the technique. It led to the devel-

opment of new technology in order to use the tech-

nique to advantage. Visualization could be difficult, so

a variety of “blowers” were developed to aid the sur-

geon [147,148]. Some investigators developed the use

of equipment to monitor the adequacy of perfusion

during the operation. Other groups explored the

physiological limits of the technique. Could the flow

be interrupted, and if so, for how long? This was stud-

ied experimentally [149,150] and clinically [151–154].

History of myocardial protection 5

There was initially some concern about the issue

of neurologic protection [155]. However, other in-

vestigators found that the neurologic threat was not

seen in their studies [156–160]. A great deal of work

ensued concerning the use of normothermic tech-

niques. This was summarized in a monograph [5].

After the initial flush of enthusiasm, the technique has

found its niche, and shown that myocardial protection

can be achieved with methods other than hypother-

mia, which had become so deeply entrenched.

Retrograde cardioplegia

There was a resurgence of interest in coronary sinus

retroperfusion of the heart in the early 1980s, led by

Gundry, Chitwood, Menasché, Fabiani, Carpentier,

Fuentes, and Chiu, among others. Coronary sinus per-

fusion was used initially with crystalloid cardioplegia,

and then with blood cardioplegia, and both were used

“cold.” However, the need to deliver cardioplegia in

a near continuous fashion for the normothermic

techniques of warm heart surgery led some surgeons

to reexamine the retrograde route of administration

[161,162]. It had been used by surgeons sporadic-

ally over the years [163–169], but became much more

wide-spread after the upsurge in interest in normo-

thermic techniques.

Thebesius first described the anatomy of the coro-

nary veins in 1708 [170], and this was studied further

by Abernathy in 1798 and Langer in 1880. This led to

the work by Pratt in 1898, in which the feline heart

was supported with retrograde perfusion alone for

up to 1 h [23]. In 1928 Wearn showed that coronary

veins communicate with thebesian veins [24–26], and

in 1929 Grant found that effluent drained into both

ventricles. Katz showed great variability in venous

anatomy in 1938 [38]. In the same year, Gregg showed

that there was increased backflow through the coron-

ary arteries when the coronary sinus was ligated [27].

In 1943 Roberts performed dye injection of the coron-

ary sinus, and found filling of the coronary arteries

[171,172]. This suggested that the heart could be

nourished via retrograde perfusion, and may be useful

in the treatment of myocardial ischemia.

Dr Claude Beck tested these hypotheses in 1945.

Beck was an early proponent of coronary sinus inter-

vention [48,52–55,173–175]. He found a decrease

in the size of an experimental myocardial infarction

with ligation of the coronary veins to that area. This

led to the “Beck operation,” in which a bypass was

performed from the aorta to the coronary sinus. This

was modified by the ligation of the coronary sinus

to facilitate retroperfusion of the myocardium (the

Beck II operation). By 1954 Beck had performed the

operation on 43 patients and symptoms of angina

were improved in 88% [176]. However, it was a

difficult operation to perform using the technology

then available. The difficulty of the operation, early

surgical failures, and deaths led to the abandonment

of the procedure.

In 1956 the pioneering work in cardiac surgery

from the University of Minnesota extended to the

investigation of cardiac perfusion and cardioplegia.

Gott and Lillehei first used retrograde continuous

normothermic blood cardioplegia in a dog model

[78] using potassium citrate blood cardioplegia as

described by Melrose. They also went on to use the

technique clinically in valve surgery [79,80]. However,

as outlined above, other technical developments

superceded this technique.

Work continued on retroperfusion in experimental

models. In 1967 Hammond et al. found that retro-

perfusion provided some myocardial protection dur-

ing coronary artery ligation in dogs [177]. In 1973

Lolley et al. found that retroperfusion with substrate

enhancement gave better protection during nor-

mothermic ischemic arrest [178]. The technique of

retroperfusion of the heart was picked up again clinic-

ally in the following decade.

There were several studies done to assess the

adequacy of retrograde coronary sinus perfusion for

protection of the heart, and it was especially important

with the normothermic blood cardioplegia technique

because of the question of right ventricle protection

[163,179–182]. Most surgeons today have had some

experience with the retrograde route of cardioplegia

administration, and many would advocate its use

in redo surgery or valvular surgery. Some surgeons,

such as Buckberg and Salerno, have also advocated the

use of simultaneous antegrade and retrograde delivery

of cardioplegia to better perfuse all capillary beds

[181,183–185].

Other subgroups of patients

The growth of cardiac surgery led investigators to try

to improve myocardial protection in various sub-

groups of patients. In particular, some subgroups

have a higher mortality rate, such as patients at the

extremes of age, both the very young and the very old.

6 CHAPTER 1

There has been research in optimizing the methods of

myocardial protection in these more extreme groups.

Patients undergoing the repair of congenital heart

defects often have multiple abnormalities, not just

cardiac ones. In addition, there is some evidence that

the myocardium of these patients may be different

from normal on a cellular level. Pediatric heart sur-

geons have carried out work to improve the protection

of the heart during repair of congenital lesions in

immature and newborn children [186–196].

The population in western countries is increas-

ingly aging. Cardiac surgeons are operating on older

patients, with more comorbidities. This group of

patients also poses special challenges for myocardial

protection. Several investigators have studied the

changes associated with aging, and the effects on

myocardial protection [197–201]. The “senescent”

myocardium changes as it ages, and several studies

suggest we may get better myocardial protection in

this age group by altering the cardioplegia ingredients,

or by changing our strategy.

There was also an enthusiasm for alternative

methods of achieving cardiac arrest that use potassium

channel “openers” to remove the transmembrane

potential [202–206]. Further work needs to be done

before we better understand the role of this technique.

Summary

One could consider that the whole field of myocardial

protection has gone almost full circle as the emphasis

has returned to the avoidance of ischemia. The other

chapters in this book will address each topic more

fully, but one might view the return of beating heart

surgery as the best way to avoid ischemia altogether.

This is certainly a promising area for research, both

with regards to myocardial protection and neurolog-

ical functioning. We may see a change in emphasis as

we adopt the new paradigm of “off-pump” surgery,

but we will still need the basic concepts of myocardial

protection, even in that setting. We will also need to

use methods of circulatory support and myocardial

protection for “open” procedures, such as valve

surgery or intracardiac repairs of congenital defects,

for the foreseeable future. There will still be a need for

myocardial protection.

The topic of myocardial protection is very large. In

this chapter we have given only an overview. It is a

story that continues to evolve, and is not yet com-

pleted. The history of this topic was written, and con-

tinues to be written, by the contributors to this book.

References

1 Chitwood WR. Myocardial Preservation: clinical applica-tions. Philadelphia: Hanley & Belfus, 1988.

2 Chiu RCJ, eds. Cardioplegia. Current concepts and controversies. Austin TX: RG Landes, 1993.

3 Engelman RM, Levitsky S eds. A Textbook ofCardioplegia for Difficult Clinical Problems. MountKisco, NY: Futura Publishing, 1992.

4 Roberts AJ, ed. Myocardial Protection in Cardiac Surgery.New York: Marcel Dekker, 1987.

5 Salerno TA, eds. Warm Heart Surgery. London: Arnold,1995.

6 Krukenkamp IB, Levitsky S. Myocardial protection:modern studies [key references]. Ann Thorac Surg 1996;61: 1581–2.

7 Bernard C. Experimental Medicine. New Brunswick:Transaction Publishers, 1991.

8 Frank O. Zur dynamik des herzmuskels. Z Biol 1895; 32:370–447.

9 Frank O. Die grundform des arteriellen pulses. Z Biol1899; 37: 483–526.

10 Frank O. On the dynamics of cardiac muscle. Am Heart J1959; 58: 282–317.

11 Starling EH. The Linacre Lecture on the Law of the Heart.London: Longmans, Green, and Co, 1918.

12 Ringer S. Concerning the influence exerted by each ofthe constituents of the blood on the contraction of theventricle. J Physiol Lond 1880–2; 3: 380–93.

13 Ringer S. A further contribution regarding the influenceof different constituents of the blood on the contractionof the heart. J Physiol Lond 1883; 4: 29–42.

14 Ringer S. A third contribution regarding the influence of the inorganic constituents of the blood on the ven-tricular contraction. J Physiol Lond 1883; 4: 222–5.

15 Ringer S, Buxton D. Upon the similarity and dissimilar-ity of the behavior of cardiac and skeletal muscle whenbrought into relation with solutions containing sodium,calcium, and potassium salts. J Physiol Lond 1887; 8:288–95.

16 Toledo-Pereyra LH. A study of the historical origins ofcardioplegia. PhD thesis. Minneapolis: University ofMinnesota, 1984.

17 Baetjer AM, MacDonald CH. The relation of thesodium, potassium and calcium ions to the heart rhyth-micity. Am J Physiol 1931–2; 99: 666.

18 Greene CW. On the relation of inorganic salts of bloodto the automatic activity of a strip of ventricular muscle.Am J Physiol 1898–9; 2: 82–126.

19 Howell WH. On the relation of the blood to the auto-maticity and sequence of the heartbeat. Am J Physiol1898–9; 2: 47–81.

20 Lingle DJ. The action of certain ions on ventricular muscle. Am J Physiol 1900; 4: 265–82.

History of myocardial protection 7

21 Wiggers CJ. Studies in the consecutive phases of the cardiac cycle. Am J Physiol 1921; 56: 415–59.

22 Zwikster GH, Boyd JE. Reversible loss of the all or noneresponse in cold blooded hearts treated with excesspotassium. Am J Physiol 1935; 113: 356–67.

23 Pratt FH. The nutrition of the heart through the vesselsof Thebesius and the coronary veins. Am J Physiol 1898;1: 86–103.

24 Wearn JT. Extent of capillary bed of heart. J Exp Med1928; 47: 273–92.

25 Wearn JT. Role of thebesian vessels in circulation ofheart. J Exp Med 1928; 47: 293–316.

26 Wearn JT. Thebesian vessels of heart and their relationto angina pectoris and coronary thrombosis. New Engl JMed 1928; 198: 726–7.

27 Gregg DE, Dewald D. The intermittent effects of occlu-sion of the coronary veins on the dynamics of the coronary circulation. Am J Physiol 1938; 124: 144.

28 Gregg DE, Dewald D. Immediate effects of coronarysinus ligation on dynamics of coronary circulation. ProcSoc Exp Biol Med 1938; 39: 202–4.

29 Gregg DE. Immediate effects of occlusion of coronaryveins on collateral blood flow in coronary arteries. Am JPhysiol 1938; 124: 435–43.

30 Gregg DE. Immediate effects of occlusion of coronaryveins on dynamics of coronary circulation. Am J Physiol1938; 124: 444–56.

31 Gregg DE. Effect of coronary perfusion pressure orcoronary flow on oxygen usage of the myocardium. CircRes 1963; 8: 497–500.

32 Hooker DR. On recovery of heart in electric shock. AmJ Physiol 1929; 91: 305.

33 Katz LN, Lindner E. Action of excess Na, Ca and K oncoronary vessels. Am J Physiol 1938; 124: 155–60.

34 Katz LN, Mendlowitz M, Kaplan HA. Action of digitalison isolated heart. Am Heart J 1938; 16: 149–58.

35 Katz LN et al. Effects of various drugs on coronary circulation of denervated isolated heart of dog and cat;observations on epinephrine, acetylcholine, acetyl-β-methylcholine, nitroglycerine, sodium nitrite, pitressinand histamine. Arch Int Pharmacodyn Ther 1938; 59:399–415.

36 Katz LN, Mendlowitz M. Heart failure analyzed in isolated heart circuit. Am J Physiol 1938; 122: 262–73.

37 Katz LN, Jochim K, Bohning A. Effect of extravascularsupport of ventricles on flow in coronary vessels. AmJ Physiol 1938; 122: 236–51.

38 Katz LN, Jochim K, Weinstein W. Distribution of cor-onary blood flow. Am J Physiol 1938; 122: 252–61.

39 Reissman KR, Van Citters RL. Oxygen consumptionand mechanical efficiency of the hypothermic heart. J Appl Physiol 1956; 9: 427–30.

40 McKeever W, Gregg DE, Canney P. Oxygen uptake of the nonworking left ventricle. Circ Res 1958; 6: 612–23.

41 Kahler RL, Braunwald E, Kelminson LL, Kedes L,Chidsey CA. Effect of alterations of coronary blood flowon the oxygen consumption of the nonworking heart.Circ Res 1963; 13: 501–9.

42 Ross J, Jr, Klocke F, Kaiser G, Braunwald E. Effect ofalterations of coronary blood flow on the oxygen con-sumption of the working heart. Circ Res 1963; 13:510 –13.

43 Sarnoff SJ, Gilmore JP, Skinner NS, Jr, Wallace AG,Mitchell JH. Relation between coronary blood flow andmyocardial oxygen consumption. Circ Res 1963; 13:514–21.

44 Weisberg H, Katz LN, Boyd E. Influence of coronaryflow upon oxygen consumption and cardiac perform-ance. Circ Res 1963; 13: 522–8.

45 Harken DE. Foreign bodies in, and in relation to, thoracic blood vessels and heart. I. Techniques forapproaching and removing foreign bodies from cham-bers of the heart. Surg Gynecol Obstet 1946; 83: 117–25.

46 Gross RE, Hubbard JP. Surgical ligation of patent duc-tus arteriosus: report of first successful case. JAMA 1939;112: 729–31.

47 Blalock A, Taussig HB. The surgical treatment of malformations of the heart in which there is pulmon-ary stenosis or pulmonary atresia. JAMA 1945; 128:189–202.

48 Beck CS, Griswold RA. Pericardiectomy in the treat-ment of the Pick syndrome: experimental and clinicalobservations. Arch Surg 1930; 21: 1064–113.

49 Hudson CL, Moritz AR, Wearn JT. The extracardiacanastomoses of the coronary arteries. J Exp Med 1932;56: 919–26.

50 Moritz AR, Hudson CL, Orgain S. Augmentation ofthe extracardiac anastomoses of the coronary arteriesthrough pericardial adhesions. J Exp Med 1932; 56:927–32.

51 Gross L, Blum L, Silverman G. Experimental attempts toincrease the blood supply to the dog’s heart by means ofcoronary sinus occlusion. J Exp Med 1937; 65: 91–108.

52 Beck CS. The surgical approach to diseases of the heart.Trans Coll Phys Philadelphia 1939.

53 Beck CS. The coronary operation. Am Heart J 1941; 22:539–44.

54 Beck CS. Revascularization of the heart. Ann Surg 1948;128: 854.

55 Beck CS, Stanton E, Batinchok W, Leiter E.Revascularization of the heart by graft of systemicartery. JAMA 1948; 137: 436–42.

56 Beck CS, Hahn RS. Revascularization of the heart.Circulation 1952; 5: 801.

57 Cutler EC, Levine SA. Cardiotomy and valvulotomy formitral stenosis. Experimental observations and clinicalnotes concerning an operated case with recovery. BostonMed Surg J 1923; 188: 1023–7.

58 Souttar HS. The surgical treatment of mitral stenosis. Br Med J 1925: 603–6.

59 Harken DE, Dexter L, Ellis LB, Farrand RE, Dickson JF.The surgery of mitral stenosis III. Finger-fracture valvu-loplasty. Ann Surg 1951; 134: 722.

60 Brock RC. Pulmonary Valvotomy for the Relief ofCongenital Pulmonary Stenosis. Report of three cases. Br Med J 1948: 1121–6.

8 CHAPTER 1

61 Gross RE, Watkins E, Pomeranz AA, Goldsmith EI. Amethod for surgical closure of interauricular septaldefects. Surg Gynecol Obstet 1953; 96: 1–24.

62 Bigelow WG, Lindsay WK, Greenwood WF. Hypo-thermia its possible role in cardiac surgery. An investi-gation of factors governing survival in dogs at low bodytemperatures. Ann Surg 1950; 132: 849–66.

63 Bigelow WG, Lindsay WK, Harrison RC, Gordon RA,Greenwood WF. Oxygen transport and utilization indogs at low body temperature. Am J Physiol 1950; 160:125–37.

64 Bigelow WG, Callaghan JC, Hopps JA. Generalhypothermia for experimental intracardiac surgery.Ann Surg 1950; 132: 531–40.

65 Boerema I, Wildschut A, Schmidt WJH, Broekhuysen L.Experimental researches into hypothermia as an aid inthe surgery of the heart. Arch Chir (Neerl) 1951; 3:25–34.

66 Cookson BA, Neptune WB, Bailey CP. Hypothermia asa means of performing intracardiac surgery under directvision. Dis Chest 1952; 22: 245–60.

67 Swan H, Zeavin I, Blount SG, Jr, Virtue RW. Surgery bydirect vision in the open heart during hypothermia.JAMA 1953; 153: 1081–5.

68 Swan H, Zeavin I, Holmes JH, Montgomery V. Cessa-tion of circulation in general hypothermia. I. Physiologicchanges and their control. Ann Surg 1953; 138: 360–76.

69 Bigelow WG, Mustard WT, Evans JG. Some physiolog-ical concepts of hypothermia and their application tocardiac surgery. J Thorac Cardiovasc Surg 1954; 28: 463.

70 Swan H, Zeavin I. Cessation of circulation in generalhypothermia: techniques of intracardiac surgery underdirect vision. Ann Surg 1954; 139: 385.

71 Andjus RK, Smith AN. Reanimation of adult rats frombody temperatures between 0 and +2°C. J Physiol 1955;128: 446.

72 Lewis FJ, Taufic M. Closure of atrial septal defects withthe aid of hypothermia: experimental accomplishmentsand the report of one successful case. Surgery 1953; 33:52–9.

73 Gibbon JH. Artificial maintenance of circulation duringexperimental occlusion of pulmonary artery. Arch Surg1937; 34: 1105–31.

74 Gibbon JH. Application of mechanical heart and lungapparatus to cardiac surgery. Minn Med 1954; 37:171–85.

75 Miller BJ, Gibbon JH, Gibbon MH. Recent advances inthe development of a mechanical heart and lung appara-tus. Ann Surg 1951; 134: 694.

76 Melrose DG. A history of cardiopulmonary bypass. In:Taylor KM, ed. Cardiopulmonary Bypass: principles andmanagement. Baltimore: Williams & Wilkins, 1986:1–12.

77 Melrose DG, Dreyer B, Bentall HH, Baker JBE. Electivecardiac arrest. Lancet 1955; ii: 21–2.

78 Gott VL, Gonzalez JL, Paneth M et al. Cardiac retroper-fusion with induced asystole for open surgery upon theaortic valve or coronary arteries. Proc Soc Exp Biol Med1957; 94: 689–92.

79 Gott VL, Gonzalez JL, Zuhdi MN, Varco RL, LilleheiCW. Retrograde perfusion of the coronary sinus fordirect vision aortic surgery. Surg Gynecol Obstet 1957;104: 319–28.

80 Lillehei CW, DeWall RA, Gott VL, Varco RL. The directvision correction of calcific aortic stenosis by means of apump-oxygenator and retrograde coronary sinus perfu-sion. Dis Chest 1956; 30: 123–32.

81 Gerbode F, Melrose DG. The use of potassium arrest inopen cardiac surgery. Am J Surg 1958; 96: 221–7.

82 Allen P, Lillehei CW. Use of induced cardiac arrest inopen-heart surgery. Minn Med 1957; 40: 672.

83 Bjork VO, Fors B. Induced cardiac arrest. J ThoracCardiovasc Surg 1961; 41: 387–94.

84 MacFarland JA, Thomas LB, Gilbert JW, Morrow AG.Myocardial necrosis following elective cardiac arrestinduced with potassium citrate. J Thorac CardiovascSurg 1960; 40: 200–8.

85 Nunn DD, Belisle CA, Lee WH. A comparative study ofaortic occlusion alone and of potassium citrate arrestduring cardiopulmonary bypass. Surgery 1959; 45: 848.

86 Waldhausen JA, Braunwald NS, Bloodwell RD,Cornwell WP, Morrow AG. Left ventricular functionfollowing elective cardiac arrest. J Thorac CardiovascSurg 1960; 39: 799–807.

87 Willman VL, Cooper T, Zafiracopoulos P, Hanlon CR.Depression of ventricular function following electivecardiac arrest with potassium citrate. Surgery 1959; 46:792–6.

88 Hoelscher B, Just OH, Merker HF. Studies by electronmicroscopy on various forms of induced cardiac arrestin dog and rabbit. Surgery 1961; 49: 492–9.

89 Midell AI, Deboer A, Bermudez G. Post perfusion coronary ostial stenosis. J Thorac Cardiovasc Surg 1976;72: 80–5.

90 Pennington DG, Dencer B, Beshiti H et al. Coronaryartery stenosis following aortic valve replacement andintermittent intracoronary cardioplegia. Ann ThoracSurg 1982; 33: 576–84.

91 Shumway NE, Lower RR. Hypothermia for extendedperiods of anoxic arrest. Surg Forum 1959; 10: 563.

92 Gebhard MM, Bretschneider HJ, Gersing E, SchnabelPA. Bretschneider’s histidine-buffered cardioplegic solu-tion. Concept, application and efficiency. In: RobertsAJ, ed. Myocardial Protection in Cardiac Surgery. NewYork: Marcel Dekker, 1987: 95–119.

93 Bretschneider HJ. Uberlenszeit und, Weiderbelebungszeitdes, Herzens bei Normo- und Hypothermie. Verh DtschGes Kreisl-Forsch 1964; 30: 11–34.

94 Bretschneider J, Hubner G, Knoll D et al. Myocardialresistance and tolerance to ischemia: Physiological andbiochemical basis. J Cardiovasc Surg 1975; 16: 241–60.

95 Sondergaard T, Berg E, Staffeldt I, Szcezepanski K.Cardioplegia cardiac arrest in aortic surgery. JCardiovasc Surg 1975; 16: 228–90.

96 Hoelscher B. Studies by electron microscopy on the effects of magnesium chloride-procainamide orpotassium citrate on the myocardium in induced car-diac arrest. J Cardiovasc Surg 1967; 8: 163–6.

History of myocardial protection 9

97 Hoelscher B. Studies by electron microscopy on variousforms of induced cardiac arrest in dog and rabbit.Surgery 1967; 49: 492–9.

98 Morales AR, Fine G, Taber RE. Cardiac surgery andmyocardial necrosis. Arch Pathol 1967; 83: 71–9.

99 Henson DE, Najafi H, Callaghan R et al. Myocardiallesions following open heart surgery. Arch Pathol 1969;88: 423–30.

100 Cooley DA, Reul GJ, Wikasch DC. Ischemic contractureof the heart: “stone heart.” Am J Cardiol 1972; 29: 575–7.

101 Hultgren HN, Miyagawa M, Buch W, Angell WW.Ischemic myocardial injury during cardiopulmonarybypass surgery. Am Heart J 1973; 85: 167–76.

102 Rossiter SJ, Hultgren HN, Kosek JC, Wuerflein RD,Angell WW. Ischemic myocardial injury with aorticvalve replacement and coronary bypass. Arch Surg 1974;109: 652–8.

103 Storstein O, Efskind L, Torgersen O. The mechanism ofmyocardial infarction following prosthetic aortic valvereplacement. Acta Med Scand 1973; 193: 103–8.

104 Hairston P, Parker EF, Arrants JE, Bradham RR, LeeWH, Jr. The adult atrial septal defect: results of surgicalrepair. Ann Surg 1974; 179: 799–804.

105 Tyers GFO, Todd GJ, Neibauer IM, Manley NJ,Waldhausen JA. The mechanism of myocardial damagefollowing potassium citrate (Melrose) cardioplegia.Surgery 1975; 78: 45–53.

106 Todd GJ, Tyers GFO. Potassium induced arrest of theheart: effect of low potassium concentrations. SurgForum 1975; 26: 255–6.

107 Gay WA, Ebert PA. Functional metabolic, and morpho-logic effects of potassium-induced cardioplegia. Surgery1973; 74: 284–90.

108 Hearse DJ, Stewart DA, Chain EB. Recovery from car-diac bypass and elective cardiac arrest. Circ Res 1974; 35:448–57.

109 Hearse DJ, Stewart DA, Braimbridge MV. Cellular pro-tection during myocardial ischaemia: the developmentand characterization of a procedure for the induction of reversible ischaemic arrest. Circulation 1976; 54:193–202.

110 Braimbridge MV, Chayen J, Bitensky L et al. Cold car-dioplegia or continuous coronary perfusion? J ThoracCardiovasc Surg 1977; 74: 900–6.

111 Hearse DJ, Stewart DA, Braimbridge MV. Hypothermicarrest and potassium arrest: metabolic and myocardialprotection during elective cardiac arrest. Circ Res 1975;36: 481–9.

112 Ledingham SJN, Braimbridge MV, Hearse DJ. The StThomas’ Hospital cardioplegic solution: a comparisonof the efficacy of the two formulations. J ThoracCardiovasc Surg 1987; 93: 240–6.

113 Guyton RA, Dorsey LMA, Craver JN et al. Improvedmyocardial recovery after cardioplegic arrest with anoxygenated crystalloid solution. J Thorac CardiovascSurg 1985; 89: 877–87.

114 Guyton RA. Oxygenated crystalloid cardioplegia. SemThorac Cardiovasc Surg 1993; 5: 114–21.

115 Moores WY. The role of blood substitutes in myocardialprotection. In: Roberts AJ, ed. Myocardial Protection inCardiac Surgery. New York: Marcel Dekker, 1987: 475–93.

116 Novick RJ, Stefaniszyn HJ, Michel RP, Burdon FD,Salerno TA. Protection of the hypertrophied pigmyocardium. A comparison of crystalloid, blood, andFluosol-DA cardioplegia during prolonged aorticclamping. J Thorac Cardiovasc Surg 1985; 89: 547–66.

117 Stefaniszyn HJ, Novick RJ, Michel RP, Salerno TA.Reaction of subcutaneous tissues to injection of Fluosol-DA, 20%. Can J Surg 1984; 27: 176–8.

118 Stefaniszyn HJ, Wynands JE, Salerno TA. InitialCanadian experience with artificial blood (Fluosol-DA-20%) in severely anemic patients. J Cardiovasc Surg1985; 26: 337–42.

119 Follette DM, Mulder DG, Maloney JV, Jr, Buckberg GD.Advantages of blood cardioplegia over continuouscoronary perfusion and intermittent ischemia. J ThoracCardiovasc Surg 1978; 76: 604–19.

120 Barner HB, Laks H, Codd JE et al. Cold blood as thevehicle for potassium cardioplegia. Ann Thorac Surg1979; 28: 509–16.

121 Barner HB, Kaiser GC, Tyras DH et al. Cold blood as thevehicle for hypothermic potassium cardioplegia. AnnThorac Surg 1980; 29: 224–30.

122 Engelman RM, Rousou JH, Dobbs W, Pals MA, LongoF. The superiority of blood cardioplegia in myocardialpreservation. Circulation 1980; 62 (Suppl I): 62–6.

123 Hendry PJ, Masters RG, Haspect A. Is there a place forcold crystalloid cardioplegia in the 1990s? Ann ThoracSurg 1994; 58: 1690–4.

124 Akins CW. Noncardioplegic myocardial preservationfor coronary revascularization. J Thorac Cardiovasc Surg1984; 88: 174–81.

125 Akins CW. Hypothermic fibrillatory arrest for coronaryartery bypass grafting. J Cardiac Surg 1992; 7: 342–7.

126 Rosenkranz ER, Vinten-Johansen J, Buckberg GD et al.Benefits of normothermic induction of cardioplegia inenergy-depleted hearts, with maintenance of arrest bymultidose cold blood cardioplegic infusions. J ThoracCardiovasc Surg 1982; 84: 667–77.

127 Rosenkranz ER, Buckberg GD, Mulder DG, Laks H.Warm-glutamate blood cardioplegia induction ininotropic, intra-aortic balloon dependent coronarypatients in cardiogenic shock. Initial experience andoperative strategy. J Thorac Cardiovasc Surg 1983; 86:507–18.

128 Follette D, Steed D, Foglia R, Fey K, Buckberg GD.Reduction of post ischemic myocardial damage bymaintaining arrest during initial reperfusion. SurgForum 1977; 28: 281–3.

129 Teoh KH, Christakis GT, Weisel RD et al. Acceleratedmyocardial metabolic recovery with warm blood car-dioplegia. J Thorac Cardiovasc Surg 1986; 91: 888–95.

130 Rosenkranz ER, Okamoto F, Buckberg GD et al. Safetyof prolonged aortic clamping with blood cardioplegia.Aspartate enrichment of glutamate blood cardioplegiain energy depleted hearts after ischemic and reperfusioninjury. J Thorac Cardiovasc Surg 1986; 91: 428–35.

10 CHAPTER 1

131 Allen BS, Buckberg GD, Schwaiger M et al. Studies of controlled reperfusion after ischemia. XVI. Earlyrecovery of regional wall motion in patients followingsurgical revascularization after eight hours of acutecoronary occlusion. J Thorac Cardiovasc Surg 1986; 92:636–48.

132 Laks H, Rosenkranz ER, Buckberg GD. Surgical treat-ment of cardiogenic shock after myocardial infarction.Circulation 1986; 74 (Suppl 3): 16–22.

133 Rosenkranz ER, Buckberg GD, Laks H, Mulder DG.Warm induction of cardioplegia with glutamate-enriched blood in coronary patients with cardiogenicshock who are dependent on inotropic drugs and intra-aortic balloon support. J Thorac Cardiovasc Surg 1983;86: 507–18.

134 Lazar HL, Buckberg GD, Manganaro AM, Becker H.Myocardial energy replenishment and reversal ofischemic damage by substrate enhancement of sec-ondary blood cardioplegia with amino acids duringreperfusion. J Thorac Cardiovasc Surg 1980; 80: 350–9.

135 Lazar HL, Buckberg GD, Manganaro AM, Becker H,Maloney JV, Jr Reversal of ischemic damage with aminoacid substrate enhancement during reperfusion. Surgery1980; 88: 702–9.

136 Cusimano RJ, Ashe KA, Salerno PR, Lichtenstein SV,Salerno TA. Oxygenated solutions in myocardial pre-servation. Cardiac Surg 1988; 2: 167–80.

137 Bomfim V, Kaijser L, Bendz R, Sylven C, Olen C.Myocardial protection during aortic valve replacement.Cardiac metabolism and enzyme release following con-tinuous blood cardioplegia. Scand J Thorac CardiovascSurg 1981; 15: 141–7.

138 Panos A, Christakis GT, Lichtenstein SV et al. Operationfor acute postinfarction mitral insufficiency using con-tinuous oxygenated blood cardioplegia. Ann ThoracSurg 1989; 48: 816–19.

139 Khuri SF, Warner KG, Josa M et al. The superiority ofcontinuous cold blood cardioplegia in the metabolicprotection of the hypertrophied human heart. J ThoracCardiovasc Surg 1988; 95: 442–54.

140 Ali IS, Al-Nowaiser O, Deslauriers R et al. Continu-ous normothermic blood cardioplegia. Sem ThoracCardiovasc Surg 1993; 5: 141–50.

141 Ali IS, Panos AL. Origins and conceptual framework ofwarm heart surgery. In: Salerno TA, ed. Warm HeartSurgery. London: Arnold, 1995: 16–25.

142 Salerno TA. Continuous blood cardioplegia. option forthe future or return to the past? J Mol Cell Cardiol 1990;22 (Suppl V): S49.

143 Panos A, Kingsley SJ, Hong AP, Salerno TA,Lichtenstein SV. Continuous warm blood cardioplegia.Surg Forum 1990; 41: 233–5.

144 Panos A, Ashe K, El-Dalati H et al. Heart surgery withlong cross-clamp times. Clin Invest Med 1989; 12 (5Suppl): C55.

145 Panos A, Ashe K, El-Dalati H et al. Clinical comparisonof continuous warm (37°C) versus continuous cold(10°C) blood cardioplegia in CABG surgery. Clin InvestMed 1989; 12 (5 Suppl): C55.

146 Panos A, Abel J, Slutsky AS, Salerno TA, LichtensteinSV. Warm aerobic arrest: a new approach to myocardialprotection. J Mol Cell Cardiol 1990; 22 (Suppl V): S31.

147 Maddaus M, Ali IS, Birnbaum PL, Panos AL, SalernoTA. Coronary artery surgery without cardiopulmonarybypass. Usefulness of the surgical blower-humidifier.J Cardiac Surg 1992; 7: 348–50.

148 Teoh KHT, Panos AL, Harmantas AA, Lichtenstein SV,Salerno TA. Optimal visualization of coronary arteryanastomoses by gas jet. Ann Thorac Surg 1991; 52: 564.

149 Tian G, Xiang B, Butler KW et al. A 31-P nuclear mag-netic resonance study of intermittent warm blood car-dioplegia. J Thorac Cardiovasc Surg 1995; 108: 1155–63.

150 Misare BD, Krukenkamp IB, Caldarone CA, Levitsky S.Can continuous warm blood cardioplegia be safelyinterrupted. Surg Forum 1992; 43: 208–10.

151 Ali IM, Kinley CE. The safety of intermittent warmblood cardioplegia. Eur J Cardiothorac Surg 1994; 8:554–6.

152 Doyle D, Dagenais F, Poirier N, Normandin D, CartierP. La cardioplegie sanguine «chaude» intermittente.Ann Chir 1992; 46: 800–4.

153 Calafiore AM, Teodori G, Mezzetti A et al. Intermittentantegrade warm blood cardioplegia. Ann Thorac Surg1995; 59: 398–402.

154 Calafiore AM, Mezzetti A. Intermittent antegrade normothermic blood cardioplegia. In: Salerno TA, ed.Warm Heart Surgery. London: Arnold, 1995: 77–89.

155 Martin TD, Craver JM, Gott JP et al. Prospective, ran-domized trial of retrograde warm blood cardioplegia:myocardial benefit and neurologic threat. Ann ThoracSurg 1994; 57: 298–304.

156 Warm Heart Investigators. Randomised trial of nor-mothermic versus hypothermic coronary bypasssurgery. Lancet 1994; 343 (8897): 559–63.

157 Wong BI, McLean RF, Naylor CD et al. Central-nervous-system dysfunction after warm or hypothermiccardiopulmonary bypass. Lancet 1992; 339 (8806):1383–4.

158 Singh AK, Bert AA, Feng WC. Neurological complica-tions during myocardial revascularization using warm-body, cold-heart surgery. Eur J Cardiothorac Surg 1994;8: 259–64.

159 Singh AK, Feng WC, Bert AA, Rotenberg FA. Warmbody, cold heart surgery: clinical experience in 2817patients. Eur J Cardiothorac Surg 1994; 7: 225–30.

160 Laursen H, Waaben J, Gefke K et al. Brain histology,blood–brain barrier and brain water after normother-mic and hypothermic cardiopulmonary bypass in pigs.Eur J Cardiothorac Surg 1989; 3: 539–43.

161 Rashid A, Fabri BM, Jackson M et al. A prospective ran-domised study of continuous warm versus intermittentcold blood cardioplegia for coronary artery surgery:preliminary report. Eur J Cardiothorac Surg 1994; 8:265–9.

162 Salerno TA, Houck JP, Barrozo CAM et al. Retrogradecontinuous warm blood cardioplegia: a new concept in myocardial protection. Ann Thorac Surg 1991; 51:245–7.

History of myocardial protection 11

163 Menasché P, Kural S, Fauchet M et al. Retrograde coronary sinus perfusion: a safe alternative for ensuring cardioplegic delivery in aortic valve surgery. Ann ThoracSurg 1982; 34: 647–58.

164 Fabiani JN, Romano M, Chapelon C et al. La car-dioplegie retrograde: etude experimentale et clinique.[Retrograde cardioplegia. experimental and clinicalstudy.] Ann Chir 1984; 38: 513–16.

165 Gundry SR, Kirsh MM. A comparison of retrograde car-dioplegia versus antegrade cardioplegia in the presenceof coronary artery obstruction. Ann Thorac Surg 1984;38: 124–7.

166 Gundry SR, Sequiera A, Razzouk AM, McLaughlin JS,Bailey LL. Facile retrograde cardioplegia. transatrialcannulation of the coronary sinus. Ann Thorac Surg1990; 50: 882–6.

167 Fabiani JN, Deloche A, Swanson J, Carpentier A.Retrograde cardioplegia through the right atrium. AnnThorac Surg 1986; 41: 101–2.

168 Guiraudon GM, Campbell CS, McLellan DG et al.Retrograde coronary sinus versus aortic root perfusionwith cold cardioplegia. Randomized study of levels ofcardiac enzymes in 40 patients. Circulation 1986; 74(Suppl III): 105–15.

169 Chitwood WR, Jr. Myocardial protection by retrogradecardioplegia: coronary sinus and right atrial methods.Cardiac Surg 1988; 2: 197–218.

170 Langer L. Die foramina Thebesii im herzen des menschen. Sitzungsb D K Akad Wissensch Math-Naturw1880; 82 (3 Abth): 25–39.

171 Roberts JT. Experimental studies on the nourishment ofthe left ventricle by the luminal (Thebesial) vessels. FedProc 1943; 2: 90.

172 Roberts JT, Browne RS, Roberts G. Nourishment of themyocardium by way of the coronary sinus. Fed Proc1943; 2: 90.

173 Beck CS. The development of a new blood supply to theheart by operation. Ann Surg 1935; 102: 801–13.

174 Beck CS. A new blood supply to the heart by operation[editorial]. Surg Gynecol Obstet 1935; 61: 407–10.

175 Beck CS. Further data on the establishment of a newblood supply to the heart by operation. J Thorac Surg1936; 5: 604–11.

176 Beck CS, Leighninger DS. Operations for coronaryartery disease. JAMA 1954; 156: 1226–33.

177 Hammond GL, Davies AL, Austen WG. Retrogradecoronary sinus perfusion. A method of myocardial pro-tection in the dog during left coronary artery occlusion.Ann Surg 1967; 166: 39–47.

178 Lolley DM, Hewitt RL, Drapanas T. Retroperfusion of the heart with a solution of glucose, insulin, andpotassium during anoxic arrest. J Thorac CardiovascSurg 1974; 67: 364–70.

179 Gundry SR, Wang N, Bannon D et al. Retrograde continuous warm blood cardioplegia: maintenance ofmyocardial homeostasis in humans. Ann Thorac Surg1993; 55: 358–61.

180 Menasché P, Fleury JP, Droc L et al. Metabolic and func-tional evidence that retrograde warm blood cardioplegia

does not injure the right ventricle in human beings.Circulation 1994; 90: II310–15.

181 Partington MT, Acar C, Buckberg GD, Julia PL. Studiesof retrograde cardioplegia. II. Advantages of antegrade/retrograde cardioplegia to optimize distribution injeopardized myocardium. J Thorac Cardiovasc Surg1989; 97: 613–22.

182 Stirling MC, McClanahan TB, Schott RJ et al. Dis-tribution of cardioplegic solution infused antegradelyand retrogradely in normal canine hearts. J ThoracCardiovasc Surg 1989; 98: 1066–76.

183 Ihnken K, Morita K, Buckberg GD et al. The safety ofsimultaneous arterial and coronary sinus perfusion:experimental background and initial clinical results. J Cardiac Surg 1994; 9: 15–25.

184 Hoffenberg EF, YeJ, Sun J, Ghomeshi HR, Salerno TA,Deslauriers R. Antegrade and retrograde continuouswarm blood cardioplegia: a 31P magnetic resonancestudy. Ann Thorac Surg 1995; 60: 1203–9.

185 Tian G, Shen J, Sun J et al. Does simultaneous antegrade/retrograde cardioplegia improve myocardial perfusion in the areas at risk? A magnetic resonance per-fusion imaging study in isolated pig hearts. J ThoracCardiovasc Surg 1998; 115: 913–24.

186 del Nido PJ. Myocardial protection and cardiopulmonary bypass in neonates and infants. Ann ThoracSurg 1997; 64: 878–9.

187 Takeuchi K, Nagashima M, Itoh K et al. Improving glucose metabolism and/or sarcoplasmic reticulumCa2+-ATPase function is warranted for immature pres-sure overload hypertrophied myocardium. Jpn Circ J2001; 65: 1064–70.

188 Gundry SR. Retrograde cardioplegia in infants and chil-dren. In: Mohl, W, ed. Coronary Sinus Interventions in Cardiac Surgery. Austin TX: RG Landes, 1994: 67–70.

189 Hammon JW, Jr. Myocardial protection in the imma-ture heart. Ann Thorac Surg 1995; 60: 839–42.

190 McMahon WS, Gillette PC, Hinton RB et al. Devel-opmental differences in myocyte contractile responseafter cardioplegic arrest. J Thorac Cardiovasc Surg 1996;111: 1257–66.

191 Rebeyka IM, Hanan SA, Borges MR et al. Rapid coolingcontracture of the myocardium. The adverse effect ofprearrest cardiac hypothermia. J Thorac Cardiovasc Surg1990; 100: 240–9.

192 Williams WG, Rebeyka IM, Tibshirani RJ et al. Warminduction blood cardioplegia in the infant. A techniqueto avoid rapid cooling myocardial contracture. J ThoracCardiovasc Surg 1990; 100: 896–901.

193 Jessen ME, Abd-Elfattah AS, Wechsler AS. Neonatalmyocardial oxygen consumption during ventricularfibrillation, hypothermia, and potassium arrest. AnnThorac Surg 1996; 61: 82–7.

194 Abd-Elfattah AS, Ding M, Wechsler AS. Myocardialstunning and preconditioning: age, species, and modelrelated differences: role of AMP-5′-nucleotidase inmyocardial injury and protection. J Card Surg 1993;8 (2 Suppl): 257–61.

12 CHAPTER 1

195 Rebeyka IM, Yeh T, Jr, Hanan SA et al. Altered contractile response in neonatal myocardium to citrate-phosphate-dextrose infusion. Circulation 1990; 82 (5Suppl): IV367–IV370.

196 Mask WK, Abd-Elfattah AS, Jessen M et al. Embryonicversus adult myocardium: adenine nucleotide degrada-tion during ischemia. Ann Thorac Surg 1989; 48: 109–12.

197 Blanche C, Khan SS, Chaux A et al. Cardiac reoperationsin octogenarians. analysis of outcomes. Ann Thorac Surg1999; 67: 93–8.

198 Burns PG, Krukenkamp IB, Caldarone CA et al. Is the preconditioning response conserved in senescentmyocardium? Ann Thorac Surg 1996; 61: 925–9.

199 Caldarone CA, Krukenkamp IB, Burns PG et al. Bloodcardioplegia in the senescent heart. J Thorac CardiovascSurg 1995; 109:269–74.

200 Panos AL, Khan SJ, Del Rizzo DF et al. Results of cardiacsurgery in the elderly using normothermic techniques.Cardiol Elderly 1995; 3: 189–92.

201 Amrani M, Chester AH, Jayakumar J, Yacoub MH.Aging reduces postischemic recovery of coronary

endothelial function. J Thorac Cardiovasc Surg 1996;111: 238–45.

202 Cason BA, Gordon HJ, Avery IVEG, Hickey RF. Therole of ATP sensitive potassium channels in myocardialprotection. J Card Surg 1995; 10 (4 Suppl): 441–4.

203 Cohen NM, Wise RM, Wechsler AS, Damiano RJ, Jr Elective cardiac arrest with a hyperpolarizing adenosine triphosphate-sensitive, potassium channelopener. A novel form of myocardial protection?J Thorac Cardiovasc Surg 1993; 106: 317–28.

204 Cohen NM, Damiano RJ, Jr, Wechsler AS. Is there analternative to potassium arrest? Ann Thorac Surg 1995;60: 858–63.

205 Maskal SL, Cohen NM, Hsia PW, Wechsler AS,Damiano RJ, Jr. Hyperpolarized cardiac arrest with a potassium-channel opener, aprikalim. J ThoracCardiovasc Surg 1995; 110 (4 Part 1): 1083–95.

206 Menasché P, Mouas C, Grousset C. Is potassium channel opening an effective form of precondition-ing before cardioplegia? Ann Thorac Surg 1996; 61:1764–8.

There are dual objectives at operation, and the two

fundamental components are technical success and

absence of iatrogenic injury due to inadequate myo-

cardial protection. We have entered a new millen-

nium, and the spectrum of surgical procedures used to

correct abnormal structure is expanding. Intervals of

aortic clamping need to be longer, so that we make the

correct diagnosis and implement a more natural cor-

rection (i.e. mitral valve repair, Ross procedure, aortic

reconstruction with stentless valves, homografts).

In addition, our patients’ vulnerability to injury

has increased, so we need to improve our methods of

protection as well as learn new operative techniques.

This chapter deals both with the evolution of current

methods and the recognition of newer methods of

protection, so that the dual relationship between pro-

tection and procedures is not separated.

Technical success and the avoidance of intra-

operative damage are our dual surgical objectives. The

early and late success of a cardiac surgical procedure

is related to how well the operation corrected the

mechanical problem, and how carefully myocardial

protection avoided the secondary dysfunctional effects

of aortic clamping for technical repair. There is no

separation between these two central events. The

mechanically perfect heart cannot undergo early or

late survival if operative damage from protection is

severe. An example is the development of “stone”

heart after 30 min of normothermic aortic clamping

for aortic stenosis, or late dilatation from evolving scar

from intraoperative ischemic damage. Conversely,

the normal myocardium on bypass, with preserved

structural and biochemical integrity, cannot maintain

cardiac output if there is a technical operative error,

such as a closed coronary anastomosis or iatrogenic

valvar insufficiency.

The need for these vital elements to be in harmony

is well known, yet there are important differences in

the cardiac surgical approaches to these two funda-

mental determinants of outcome. On one level, the

meticulous pursuit of mechanical perfection is unend-

ing; for example, through cardiac vision (i.e. eye

glasses, 2-5–3-5 loops, 4-5 loops, 6-0 loops, the micro-

scope, and finally robotic magnification away from the

direct operative field). Surgical suture techniques,

starting at 5-0 prolene, progress to 10-0 to secure a

perfect anastomosis or repair. Major interventional

changes in mitral valve repair are developed to avoid

replacement, and novel mechanical methods are

introduced to return the ventricle in a normal ellipt-

ical cardiac position. This structural goal is the tech-

nical belief of cardiac surgery and the pursuit of

excellent technology will never end.

Focal examples of this drive come from the ongoing

search for perfection, through learning the Ross pro-

cedure for aortic valve replacement and repeated visits

to valvuloplasty clinics to enlarge our concepts of

valve repair to avoid mechanical replacement. The

undercurrent theme is that sufficient time must be

spent during aortic clamping, in an unhurried way

to: (i) inspect the functional anatomy; and then

(ii) accomplish a novel technical repair. There is an

enlarging body of surgeons wanting to utilize these

creative technical approaches, but the numbers of

clinical centers dealing with these more difficult

valvular problems is limited. The surgical restriction,

despite an available cadre of patients, is underlying

concern about producing extended intraoperative

2 CHAPTER 2

The duality of cardiac surgery:mechanical and metabolic objective

Gerald D. Buckberg, MD

13

14 CHAPTER 2

damage during the prolonged aortic clamping times

required for novel technical success.

On a second level, these more extensive procedures

are often withheld from patients with underlying

impairment of ventricular function due to: (i) recog-

nized increased vulnerability to damage in hearts with

hypertrophy and/or coronary disease; (ii) limited

functional reserve if protection is marginal; and/or

(iii) use of a shorter procedure (i.e. using an artificial

valve) to avoid the prolonged intra-aortic clamping

needed to be used for correcting the lesion in a more

natural way.

The performance of evolving operative techniques

is halted in many centers by the conceptual barrier

that “prolonged aortic clamping will cause progressive

tissue damage” when the new task is undertaken,

because of the knowledge that repair “burns extra

minutes” into our efforts to achieve mechanical

success. The barrier is the uncertainty of the value of

current techniques of myocardial protection during

prolonged aortic clamping in patients with advanced

cardiac disease when there is diminished preoperative

function. Unfortunately, unbridled progress to learn

new techniques is unaccompanied, in many centers,

with a similarly more intensive understanding, look-

ing for reasons why more damage is invoked if the

interval of clamping is prolonged. A fundamental rea-

son is that techniques of improved protection have

made slower educational progress during our ongoing

pursuit of the evolution of improved technique.

I will cite several examples of evolving methods of

protection, to bring into focus this disparity between

mechanical and metabolic excellence. So that all

surgeons can have the freedom to use their technical

skills to the full, this disparity should be dissolved.

The first method of protection is hypothermia,

provided by cold perfusate and surface cooling based

upon findings by Shumway in 1959 to limit damage

from normothermia. To some, this became the his-

toric “end stop” of myocardial protective strategies.

This may reflect the “iceberg age,” and restricted focus

upon this method alone has arrested progress toward

a full understanding of the mechanics of ischemic

damage, and how to reverse these changes. Our

progress becomes cushioned by the classic statement

“we have good results, why change”? The reason to

change methods of protection is obvious, unless

current protective methods provide complete avoid-

ance of massive inotropic support, assist devices, or

transplantation, following technically successful repair.

Hopefully, a “rigid” concept that cold is everything

“will not veil” any further development of our know-

ledge in cardiac protection.

Our capacity to stop metabolic demands quickly,

and simultaneously limit progressive extension of

damage over time, has been enhanced by cardioplegic

techniques that retard metabolism, and are now used

almost universally. Hypothermia is a vital component,

but reflects an addition, rather the unifying force

that becomes the only solution. Further progress has

developed by general agreement that blood contains

natural benefits over conceptual crystalloid tech-

niques, red blood cells are a fundamental component

of most cardioplegic solutions. Those who externally

create a crystalloid component and exclude blood

must now address the well-proven benefits of restor-

ing the blood vehicle that normally nourishes the

nonbypassed heart that must function when bypass

is discontinued. In addition, strategic methods to

distribute solution, both antegrade, retrograde, and

simultaneously antegrade/retrograde, have been

developed, and are used commonly throughout the

world. More importantly, new methods to prevent

ischemic damage (i.e. buffering, hypocalcemia, oxy-

gen radical scavengers, reducing complement) under

more favorable conditions have been added. How-

ever, few centers are now involved with the surgical

adoption of these new protective techniques. Many

use methods that were developed 20 years ago. The

injury could be limited if we addressed the newer

metabolic and delivery changes that have been initi-

ated. Consequently, there has been a mechanical

leap in technical skills, but only “microsteps” taken

in advancing and using efforts for protection.

The recognition that temperature and cardiologic

vehicle do not insure adequate distribution has

allowed the evolution of retrograde delivery. These

methods of retroperfusion are used in greater than

60% of patients in the United States and somewhat

less worldwide. However, this is not a universal vehicle

for cardioplegic delivery, despite evidence that differ-

ent areas of diseased hearts are perfused by antegrade

and retrograde techniques. This is very important

because of the limited capacity of retrograde methods

to consistently protect the right ventricle, and is espe-

cially important in reoperative coronary procedures.

The ready clinical demonstration that different

regions are perfused by retrograde perfusion (i.e.

Duality of cardiac surgery 15

coronary sinus effluent during antegrade perfusions

starting blue and becoming red, then with retrograde

perfusion, aortic effluent starting blue and then

becoming red), indicates that different areas are per-

fused during the period of aortic clamping. This shows

that some regions were imperfectly perfused using

one technique only. Clinical evidence has gradually

attained general acceptance that these antegrade and

retrograde delivery methodologies should be com-

bined. These changes are further limited by those who

have not yet “made this step of transatrial cannula-

tion.” To many, a slight prolongation of operation

to open the right atrium and directly cannulate the

coronary sinus provides a sufficient reason to limit

pursuing retrograde methodology. Little attention is

given to the prolonged inotropic and metabolic

support that is needed when this potential 5-min sup-

plement is excluded. Some accept the prolonged

intensive care unit and increased hospital stay, and

mortality is due to the nature of the disease rather

than the potential consequence of not using this

methodology. The value in morbidity of consecutive

hospital cases and reduced cost was shown nicely in a

study by Loop several years ago at the Cleveland Clinic

[1].

The aforementioned applications of cold blood

cardioplegia and retrograde perfusion are simply the

start of the advanced techniques of myocardial protec-

tion, as many centers have made physiologic variances

in the cardioplegic temperature while using blood

cardioplegic protection. Evidence is clear that the

jeopardized heart has increased vulnerability to dam-

age, and that this injury can be modified, both experi-

mentally, and clinically, by a warm controlled blood

cardioplegic reperfusion, especially if there is amino

acid enrichment [2–4]. Despite this knowledge,

there is much slower adaptation to using proven con-

cepts of controlled reperfusion before releasing the

aortic clamp. Warm reperfusion is used in less than

50% of centers, with fewer participants in Europe.

Furthermore, it should be recognized that ongoing

ischemia during aortic clamping is not needed when

the procedure is ongoing and direct heart visualiza-

tion is unimpaired (i.e. doing proximal anastomosis,

placing sutures from the valve ring to the valve, and

closing the aorta or atrium) as the procedure pro-

gresses. During these times, continuous cold blood

perfusion is available, yet is not commonly used. The

result is that ischemia is prolonged unnecessarily. The

potential injury could be limited if there was under-

standing of the availability of reperfusion, especially

retrograde, when operative vision does not become

impaired by ongoing perfusion while the aorta is

clamped.

The “blending” of methods of protection can be

used to avoid the arbitrary “alternative position

stance,” where there is an unnecessary introduction of

a surgically imposed contrast between “warm versus

cold, antegrade versus retrograde, intermittent versus

continuous,” which now becomes an “integrated

method.” This integrated approach takes advantage

of the benefits of each method, rather than pitting

one method against the other. The result is that

each patient receives warm induction, cold blood

cardioplegia, and a warm reperfusate, with delivery

antegrade, retrograde, and sometimes simultane-

ously antegrade and retrograde, in either an inter-

mittent delivery, and in a continuous way if vision is

not impaired by perfusion. The cold arrested heart

remains stopped by hypothermia, so that the blood

delivery can be with either a cardioplegia solution,

or with cold regular blood, or a nonpotassium-

containing solution with the cardioplegic constituents

[5,6]. The benefits of this combined approach were

shown, recently, in more than 1500 patients with

advanced heart disease, and even more extensively

in an alternate subset of patients with valve complex

mitral valve disease [5] or Ross procedures with dam-

aged ventricles, where ischemic times were greater

than 180–250 min without inotropic support [7].

Further supplemental steps like white blood cell

filtration, oxygen radical scavenger addition, magne-

sium supplementation, low Po2 to limit reoxygenation

damage, short-acting calcium antagonists to reduce

and prevent calcium-related injury, adding sodium

hydrogen ion exchangers, and other evolving regions

are at the frontier of better techniques to protect the

heart. These concepts have been developed, yet there

is a slower pathway among surgeons towards incor-

porating these procedures into the operation. Some

think change is “living with the university.” That is

simply the wrong idea. We must advance in our learn-

ing of myocardial protection modalities, in the same

way as we progress with mechanical matters to pro-

vide our patients with many of the benefits of each

aspect that should be in the armamentarium of the

cardiac surgeon, just as in the natural evolution of

mechanical methods of repair.

16 CHAPTER 2

The concepts of myocardial protection developed

in adults are directly applicable to the pediatric

population, where vulnerability to damage is highest

because of preoperative ischemia and cyanosis. These

approaches are similar to adult methods, but are

rarely employed. The increasing tendency to avoid

cardiopulmonary bypass to reduce the inflammatory

reaction to extracorporeal circulation has led to cor-

onary artery bypass graft (CABG) without bypass. It is

clear that the precursor to regional stunning (that we

know globally as the low-output syndrome) is brief

occlusion for 10–15 min with normal blood reperfu-

sion. This established technique of damage is applied

to patients with coronary artery disease, but there is

less damage in them because of collateral flow from

stenotic lesions. Methods to protect the regional seg-

ment in patients undergoing CABG without bypass

must be addressed and included, to avoid stunning of

both the endothelium and the myocyte.

The method of surgery on the beating heart, which

is useful without bypass, is also applicable in patients

on extracorporeal circulation. The beating heart with

regional ischemia has been used in CABG procedures,

since bypass reduces global oxygen demand, and the

nonischemic areas remain perfused which potentially

limits their injury. A marked advantage of surgery on

the beating heart has been achieved during ventricular

restoration, where the beating heart is opened and

continually perfused as its volume is reduced. This

method has been useful both experimentally, and clin-

ically [8–10]. The principle of using the beating heart

is not new, as this method has been used during surg-

ical treatment of ventricular arrythmias [11]. It is also

well known, from Kirklin’s studies of aortic stenosis,

that continuous perfusion of the beating vented heart

can cause marked subendocardial ischemia if there

is left ventricular hypertrophy [12]. The goal in select-

ing a method of protection is to make the choice

after learning how and why the method has been

developed, and understanding how to benefit from its

advantages, and avoid inappropriate use by recogniz-

ing the disadvantages. The choice for protection is

precisely similar to the selection of a structural tech-

nique for surgical repair of an underlying cardiac

lesion.

The underlying principle in this dual bilateral pro-

gram is for each of us to recognize that each effort

(mechanical and metabolic) is of equal importance.

Failure in either modality is not a surgical problem,

but rather a problem for the patients and the existing

cost of caring for those who have delayed recovery

despite a technically successful procedure.

Improved myocardial protection is not a phase

of surgical development, but rather is intrinsic to

improved surgical care. The virtual absence of papers

at surgical meetings about myocardial protection may

indicate that the problem of myocardial protection

has not been solved. Despite this, there are reports

of patients needing intra-aortic balloons and mech-

anical assist devices when protection has been inad-

equate. The search for technical improvement must

be accompanied by ongoing learning about cardio-

protective methods that avoid completely the need

to use machines to correct cardiac performance after

the heart has been mechanically restored to its more

normal architecture. We should strive to increase

our knowledge about protection, as it must become

an essential component of the surgical correction of

cardiac defects. Protection and technical adequacy

cannot be separated, as our deep understanding of

how to correct the cardiac lesion must be matched by a

recognition of how to avoid damage as we satisfy our

dual goals.

References

1 Loop FD, Higgins TL, Panda R, Pearce G, Estafanous FG.Myocardial protection during cardiac operations. J Thorac Cardiovasc Surg 1992; 104: 608–18.

2 Allen BS, Buckberg GD, Fontan F et al. Superiorityof controlled surgical reperfusion vs. PTCA in acutecoronary occlusion. J Thorac Cardiovasc Surg 1993;105: 864–84.

3 Rosenkranz ER, Okamoto F, Buckberg GD et al. Safety ofprolonged aortic clamping with blood cardioplegia. III.Aspartate enrichment of glutamate-blood cardioplegia inenergy-depleted hearts after ischemic and reperfusioninjury. J Thorac Cardiovasc Surg 1986; 91: 428–35.

4 Allen BS, Rosenkranz ER, Buckberg GD et al. Studies onprolonged regional ischemia. VI. Myocardial infarctionwith LV power failure: a medical/surgical emergencyrequiring urgent revascularization with maximal protec-tion of remote muscle. J Thorac Cardiovasc Surg 1989; 98:691–703.

5 Buckberg GD, Beyersdorf F, Allen B, Robertson JM.Collective review: Integrated myocardial management.Background and initial application. J Card Surg 1995; 10:68–89.

6 Kronon MT, Allen BS, Halldorsson A et al. Delivery of anonpotassium modified maintenance solution to enhancemyocardial protection in stressed neonatal hearts: a newapproach. J Thorac Cardiovasc Surg 2002; 123: 119–129.