M. Obladen P. Koehne
Interventions for Persisting Ductus Arteriosus in the Preterm Infant
M. Obladen (Editor) P. Koehne (Editor)
Interventions for Persisting
Ductus Arteriosus in the Preterm Infant
With 51 Figures and 7 Tables
123
Prof. Dr. Michael Obladen
Director, Department of Neonatology, Charité Universitätsmedizin Berlin,
Campus Virchow/Campus Benjamin Franklin, Augustenburger Platz 1, 13353 Berlin [email protected]
Dr. Petra Koehne
Head Physician, Department of Neonatology, Charité Universitätsmedizin Berlin,
Campus Virchow,
Augustenburger Platz 1, 13353 Berlin [email protected]
ISBN 3-540-24511-1
Springer Medizin Verlag Heidelberg
Cataloging-in-Publication Data applied for
A catalog record for this book is available from the Library of Congress.
Bibliographic information published by Die Deutsche Bibliothek
Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografi e;
detailed bibliographic data is available in the Internet at <http://dnb.ddb.de>.
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on micro- fi lm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer Medizin Verlag. Violations are liable for prosecution under the German Copyright Law.
Springer Medizin Verlag.
A member of Springer Science+Business Media springer.de
© Springer Medizin Verlag Heidelberg 2005 Printed in The Netherlands
The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
Product liability: The publisher cannot guarantee the accuracy of any information about dosage and application thereof contained in this book. In every individual case the user must check such information by consulting the relevant literature.
SPIN 11384281
Cover Design: deblik, Berlin, Germany
Typesetting: TypoStudio Tobias Schaedla, Heidelberg, Germany Printed on acid free paper 18/3160/yb – 5 4 3 2 1 0
Preface
»Nature knows in advance that the fetal lung, an organ in development and without movement, does not have the same needs as the mature, breathing lung. Nature has there- fore connected the pulmonary artery with the aorta.« This was written by Galen in the second century after Christ <opera omnia IV:243>, confirmed by Giulio Cesare Aranzio
<de humano foetu> in 1564 and later falsely attributed to Leonardo Botallo who became famous by this error. By connecting the pulmonary artery with the aorta, nature had not foreseen that in Europe most infants born at 25–27 weeks gestation would survive at the beginning of the 21st century. Over the past few years we have witnessed a remarkably rapid evolution in the professional level of neonatology and in the survival of immature infants.
Sadly, many of these survivors later have neurodevelopmental handicaps, and presently there is not too much the neonatologist can do to prevent them. Avoiding ventilation, pneumothorax, and hypocarbia are the best choice. Closure of the ductus is another option, but many uncertainties exist concerning indication, approach, best time, and side effects.
These issues were discussed in a European workshop in Fulda, Germany, on April 4 and 5, 2004. Not only the speakers but most participants were experts either in neonatology or in pediatric cardiology, and this small book contains the abstracts of the workshop, which, as we hope, will help to define the level of evidence and to develop standards of interven- tion for persisting ductus arteriosus in Europe. With survival of more and more immature infants, adequate dealing with the ductus will become a challenge for every perinatal center.
We are deeply indebted to the many talented and dedicated contributors, we thank the staff of Springer publishers for good advice and for help in editing this volume, and we thank Dr. Barbara Donnerstag and Mr. Eberhard Kroll from Orphan Europe, not only for spon- soring this meeting but also for developing evidence based therapies for specific and small patient groups in whom little money can be earned.
Berlin, December 2004 Michael Obladen, MD
Petra Koehne, MD V
Part I: Basics
1 Developmental Anatomy of the Ductus
Arteriosus . . . 2
Regina Bökenkamp Introduction . . . 2
Embryogenesis . . . 2
Ductal Maturation . . . 2
Patent Ductus Arteriosus in Premature Infants . . . 4
Persistent Ductus Arteriosus (PDA) . . . 4
Summary . . . 4
References . . . 4
2 Regulation of Smooth Muscle Contraction . . . . 6
Ingo Morano References . . . 10
3 Prostaglandin Metabolism and Effects of Inhibitors . . . 12
Karsten Schrör References . . . 14
4 Postnatal Circulatory Adaptation . . . 15
Michael Hofbeck References . . . 18
5 Epidemiology of Persisting Ductus in Preterm Infants . . . 19
Christiane Pees, Michael Obladen Congenital Anomaly or Prolonged Adaptation? . . . 19
Clinical Relevance . . . 20
Frequency Depends on Immaturity and Echocardiography . . . 20
Individual Variability . . . 20
Conclusions . . . 23
References . . . 23
Part II: Clinical Features 6 Persisting Ductus Arteriosus and Respiratory Problems . . . 26
Walter Kachel Association with Pulmonary Immaturity / Surfactant Deficiency . . . 26
Association with Pulmonary Infection / Inflammatory Response . . . 26
X-Ray Opacities . . . 27
PDA, Lung Water, and Pulmonary Hemorrhage . . 27
Lung Mechanics . . . 28
Surfactant Substitution . . . 28
Chronic Lung Disease . . . 28
Conclusions . . . 29
References . . . 29
7 Influence on Mesenteric Perfusion and Necrotizing Enterocolitis . . . 31
Josef Sonntag Introduction . . . 31
Mesenteric Perfusion . . . 31
Patent Ductus Arteriosus and Mesenterial Perfusion. . . 31
Necrotizing Enterocolitis . . . 31
Patent Ductus Arteriosus and Necrotizing Enterocolitis . . . 32
Indomethacin Intervention . . . 33
Ibuprofen . . . 33
Indomethacin Versus Ibuprofen . . . 33
Surgical Ligation . . . 34
Conclusions . . . 34
References . . . 34
8 Persisting Ductus Arteriosus and Intraventricular Hemorrhage . . . 35
Rolf F. Maier Cerebral Perfusion . . . 35
PDA, Lung Maturity, and IVH . . . 35
Pharmacological Interventions . . . 36
Conclusions . . . 37
References . . . 37
Table of Contents
VII
Part III: Diagnostics
9 Echocardiographic Assessment . . . 40
Helmut Singer References . . . 44
10 Cerebral Doppler Sonographic Measurements . . . 45
Karl-Heinz Deeg, Burkhard Trusen Intracranial Arteries . . . 45
Doppler Parameters . . . 45
PDA-Specific Flow Patterns . . . 46
Conclusions . . . 48
References . . . 49
Part IV: Interventions 11 Therapeutic Options . . . 52
Axel von der Wense Prevention of PDA . . . 52
Prophylactic Administration of Cyclooxygenase Inhibitors . . . 53
Indomethacin . . . 54
Ibuprofen . . . 54
Hamburg Ibuprofen Study . . . 54
Current Hamburg Concept of PDA Treatment . . 56
References . . . 56
12 Surgical Closure . . . 57
Michael Hübler History . . . 57
Transport to the Operating Room . . . 57
Preparation for Operation in the NICU . . . 58
Perioperative Management . . . 58
Surgical Management . . . 58
Postoperative Management . . . 60
Complications . . . 60
Outcome and Complications in our Center . . . 63
Minimally Invasive Approaches . . . 63
References . . . 64
13 Comparison of Indomethacin and Ibuprofen . . . 65
Bart van Overmeire Properties of Ibuprofen . . . 65
Therapy and Prophylaxis of Patent Ductus Arteriosus . . . 65
Effects on Regional Circulation . . . 67
Pharmacokinetics . . . 67
Conclusions . . . 67
References . . . 68
14 Indomethacin Effects and Side Effects . . . 69
Berndt Urlesberger Effects . . . 69
Management of Symptomatic PDA . . . 69
Management of Asymptomatic PDA . . . 69
Prophylactic Indomethacin . . . 70
Conclusions Regarding Effects . . . 70
Side Effects . . . 70
Impairment of Renal Function . . . 70
Impairment of Cerebral Perfusion . . . 70
Abdominal Side Effects . . . 71
Interference With Blood Glucose . . . 71
Platelet Dysfunction . . . 72
Contraindications . . . 72
Conclusions . . . 72
References . . . 72
15 Complications of Cyclooxygenase Inhibition in Preterm Infants . . . 74
Véronique Gournay Pharmacology . . . 74
Cerebral Effects of COX Inhibitors . . . 75
Pulmonary Effects of COX Inhibitors . . . 75
Renal Effects of COX Inhibitors . . . 78
Intestinal Effects of COX Inhibitors . . . 78
Effect of Ibuprofen on Bilirubin-Albumin Binding . . . 81
Conclusions . . . 82
References . . . 82 VIII Table of Contents
IX
16 Ibuprofen in Infants below 28 Gestational
Weeks . . . 84
Petra Koehne The Timing of PDA Intervention . . . 84
Parameters Characterizing the Hemo- Dynamic Significance of a PDA . . . 85
Early Ibuprofen for Symptomatic PDA in Infants under 28 Weeks Gestational Age . . . 85
Conclusion . . . 90
References . . . 91
17 Intravenous Ibuprofen: State of Registration . . . 92
Marie Christine Fortun Part V: Perspectives 18 Summary and Perspectives . . . 94
Michael Obladen Basics . . . 94
Clinical Features . . . 94
Diagnostics . . . 95
Indomethacin . . . 95
Ibuprofen . . . 96
Surgery . . . 96
Perspectives . . . 97
Subject Index . . . 98 Table of Contents
List of Contributors
Dr. Regina Bökenkamp Department of Anatomy and Embryology,
Leiden University Medical Center, Wassenaarsenweg 62,
Postbox 9602, 2300, RC Leiden, The Netherlands
Prof. Dr. Karl-Heinz Deeg Director, Children’s Hospital, Klinikum Bamberg,
Buger Straße 80, 96049 Bamberg, [email protected]
Dr. Marie-Christine Fortun Regulatory Affairs Director, Orphan Europe (France) SARL, Immeuble »Le Wilson«,
70, avenue du General de Gaulle, F- 92058 Paris, France,
Dr. Véronique Gournay Division of Pediatric Cardiology, University Hospital of Nantes, Hôpital Mère Enfant, 7, quai Moncousu,
44093 Nantes Cedex 1, France, [email protected]
Prof. Dr. Michael Hofbeck Director, Division of Pediatrics II, Universitätsklinikum Tübingen, Hoppe-Seyler-Straße 3, 72070 Tübingen, michael.hofbeck@
med.uni-tuebingen.de
Dr. Michael Hübler Attending Surgeon,
Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Augustenburger Platz 1, 13353 Berlin,
Prof. Dr. Walter Kachel
Director, Department of Pediatrics/
Perinatalzentrum,
SLK-Kliniken Heilbronn GmbH, Am Gesundbrunnen 18–20, 74067 Heilbronn,
Dr. Petra Koehne
Head Physician, Department of Neonatology, Charité Universitäts- medizin Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin,
Prof. Dr. Rolf F. Maier Director, Department of Neonatology and Pediatric Neurology, Klinikum der Philipps-Universität Marburg, Deutschhausstr. 12,
35033 Marburg,
Prof. Dr. Ingo Morano Director, Division of Molecular Muscle Physiology,
Max-Delbrück-Center Berlin, Robert-Rössle-Straße 10, 13092 Berlin,
Prof. Dr. Michael Obladen Director, Department of
Neonatology, Charité Universitäts- medizin Berlin, Campus Virchow/
Campus Benjamin Franklin, Augustenburger Platz 1, 13353 Berlin,
Dr. Christiane Pees Department of Congenital Heart Defects, German Heart Institute Berlin,
Augustenburger Platz 1, 13353 Berlin,
Prof. Dr. Karsten Schrör
Director, Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, [email protected]
Prof. Dr. Helmut Singer Director, Department of Pediatric Cardiology, Klinik für Kinder und Jugendliche der Universität Erlangen-Nürnberg,
Loschgestr. 15, 91054 Erlangen, htsinger@
kinder.imed.uni-erlangen.de
PD Dr. Josef Sonntag Department of Pediatrics, Städtisches Klinikum Lüneburg, Bögelstraße 1, 21339 Lüneburg, josef.sonntag@
klinikum-lueneburg.de
Dr. Burkhard Trusen
Head Physician, Children’s Hospital, Klinikum Bamberg,
Buger Straße 80, 96049 Bamberg, [email protected]
Prof. Dr. Berndt Urlesberger Department of Neonatology, Universitätsklinik für Kinder- und Jugendheilkunde, Auenbrugger Platz 30, A-8036 Graz, Austria, [email protected]
Prof. Dr. Bart van Overmeire Department of Pediatrics, Division of Neonatology, University Hospital of Antwerp, Wilrijkstreet 10, B-2650 Edegem, Belgium, [email protected]
Dr. Axel von der Wense Department of Neonatology and Pediatric Intensive Care, Altonaer Kinder-Krankenhaus, Bleickenallee 38, 22763 Hamburg, [email protected]
X
XI
List of Abbreviations
BPD Bronchopulmonary dysplasia CBF Cerebral blood flow CI confidence interval CLD Chronic lung disease CHD Congenital heart defect
COX Cyclooxygenase (isoforms -1 and -2) ELBW Extremely low birth weight (<1000 g) IVH Intraventricular hemorrhage MHC Type II myosin heavy chain MLC Type II myosin light chain MLCK Myosin light chain kinase NEC Necrotizing enterocolitis NICU Neonatal intensive care unit NNT Number needed to treat NO Nitric oxide
NSAID Nonsteroidal anti-inflammatory drug
OR odds ratio
PaO2 Arterial oxygen partial pressure PCO2 Carbon dioxide partial pressure PGE2 Prostaglandin type E2
PDA Persisting ductus arteriosus PVL Periventricular leukomalacia
Q Volume flow
RBF Renal blood flow
RDS Respiratory distress syndrome = surfactant
deficiency
RI Resistance index
ROP Retinopathy of prematurity RVSP Right ventricular systolic pressure SaO2 arterial oxygen saturation SMC Smooth muscle cells TAV Time averaged flow velocity TR Tricuspid regurgitation
UBC Unbound bilirubin concentration Ved End diastolic flow velocity Ves End systolic flow velocity Vs Peak systolic flow velocity VEGF Vascular endothelial growth factor VLBW Very low birth weight (<1500 g) VSMC Vascular smooth muscle cell
I
Part I Basics
Chapter 1 Developmental Anatomy of the Ductus Arteriosus – 2 Regina Bökenkamp
Chapter 2 Regulation of Smooth Muscle Contraction – 6 Ingo Morano
Chapter 3 Prostaglandin Metabolism and Effects of Inhibitors – 12 Karsten Schrör
Chapter 4 Postnatal Circulatory Adaptation – 15 Michael Hofbeck
Chapter 5 Epidemiology of Persisting Ductus in Preterm Infants – 19
Christiane Pees, Michael Obladen
