SYSTEMIC-TO-PULMONARY ARTERY SHUNTING USING HEPARIN- BONDED GRAFTS (“Systemiko-pulmonale Shunts unter Verwendung von Grafts mit kovalent an der Oberfläche gebundenem Heparin“) Der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades Dr. med. vorgelegt von Ambarsari, Yuletta Adny aus Bangil (Indonesia) Als Dissertation genehmigt von der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg Vorsitzender des Promotionsorgans: Prof. Dr. Dr. h.c. J. Schüttler Gutachter: PD Dr. Andre Rüffer Gutachter: Prof. Dr. Robert Cesnjevar Tag der mündlichen Prüfung: 05. Dezember 2017 TABLE OF CONTENTS ABSTRACT (English Version)……………………………………………..……... 1 ABSTRACT (German Version)……………………………………………..…..... 3 1. INTRODUCTION………………………………………………………….. 5 1.1. Palliative Shunting: A Brief Surgical History……………………................ 5 1.2. Shunt Associated Problems and Possible Drawbacks……………................ 8 1.3. Experience with "Heparin-Bonded" Shunts………………………………... 9 1.4. Aim of the Study…………………………………………………………… 10 2. MATERIAL AND METHODS……………………………………………. 11 2.1. Patients……………………………………………………………............... 11 2.2. Surgical Technique………………………………….……………………… 11 2.3. Follow-up…………………………………………………………………... 12 2.4. Statistical Analysis……………………………………………………….… 13 3. RESULTS…………………………………………………………………... 14 3.1. Patient Characteristics and Operative Data………………………................ 14 3.2. Survival…………………………………….……………………………….. 16 3.3. Shunt Patency………………………………………………………….…… 19 4. DISCUSSION…………………………………………………………….… 23 4.1. Survival……………………………………………………………………... 23 4.2. Shunt Patency…………………………………………………………….… 24 4.3. HBPS……………………………………………………………………….. 24 4.4. Limitations……………………………………………………….……...….. 25 4.5. Conclusion…………………………………….……………………………. 25 5. REFERENCES………….………………………………………………….. 26 6. ABBREVIATIONS………………………………………………................ 31 7. LIST OF FIGURES…………………………………………………….…... 32 8. LIST OF TABLES……………….…………………………………………. 33 9. ACKNOWLEDGEMENTS…………..…………………………………….. 34 10. DISCLAIMER…………………………………………………………….... 35 ABSTRACT (English Version) Objectives: Systemic to pulmonary artery shunting remains an important palliative procedure in the staged management of complex congenital heart defects. The use of Heparin- bonded polytetrafluorethylen shunts (HBPS) should enhance graft patency. This study aimed to review the single-center experience with HBPS in the context of congenital cardiac surgery. Methods: The records of 52 patients treated with HBPS between 2010 and 2016 were retrospectively reviewed. Median age and weight were 8 days (range 3 – 83 days) and 3.2 kg (range 1.8 – 5.7 kg), respectively. Selected shunt size was 3.5 mm in all except 1 patient (4.0 mm). Fourteen patients (26.9%) were planned for future biventricular repair and 38 patients (73.1%) went the univentricular pathway. Shunt modifications included central aorto-pulmonary shunts (n=35; 67.3%) and modified Blalock-Taussig shunts (n=17; 32.7%). Shunt patency and survival until estimated second procedure were calculated using the Kaplan-Meier method. Results: Shunt patency was 90 ± 4% after a median duration of 133 days (range: 0 - 315). Early mortality (30 days) was 5.7% (n=3). Another 3 patients died during their hospital stay. The cause of death was not shunt-related in all patients. Five patients developed subtotal HBPS thrombosis, either intraoperatively (n=3), early postoperatively after 3 days (n=1; 1.9%) or late after 41 days (n=1; 1.9%). Treatment of those patients comprised RVOT-opening (n=2; 3.8%) or new shunting (n=3; 5.8%). Elective shunt take-down was performed during corrective surgery (n=10; 19.2%), bidirectional Glenn (n=25; 48.1%) or shunt replacement (n=5; 9.6%). At the end of follow-up, 1 patient (1.9%) had still a HBPS in situ. The survival rate until planned second procedure was 84 ± 6% in univentricular patients, and 100% in biventricular patients (p=0.14), respectively. 1 Conclusions: The use of HBPS in the context of palliative heart surgery is safe and seems to warrants long-term patency of systemic-to-pulmonary shunts. However, by influencing thrombosis on only one site of Virchow’s triad, shunt thrombosis, occurring predominantly early, cannot be totally excluded. 2 ABSTRACT (German Version) Hintergrund: Komplexe kardiale Fehlbildungen mit vermindertem pulmonalen Blutstrom benötigen bereits im Neugeborenenalter eine palliative Shunt-Anlage zur adäquaten Perfusion des Lungenkreislaufs. Die Verwendung von kovalent an den Shunt gebundenem Heparin („heparin-bonded“) Polytetrafluorethylen-Shunts (HBPS) sollte dabei das Risiko von Graft-Verschlüssen vermindern. In dieser Studie werden die Erfahrungen und das Outcome nach HBPS-Implantation in Patienten mit angeborenen Herzfehlern eines Zentrums zusammengefasst. Methoden: Die Krankenakten von 52 Patienten, welche zwischen 2010 und 2016 einen HBPS als aortopulmonalen Shunt erhalten haben, wurden retrospektiv analysiert. Das Alter lag im Median bei 8 Tagen (Range: 3 – 83 Tage) und das Gewicht bei 3.2 kg (Range: 1.8 – 5.7 kg). Bis auf einen Patienten (4.0 mm) erhielten alle Patienten einen 3.5 mm HBPS. Vierzehn Patienten (26.9%) hatten einen biventrikulär zu korrigierenden Herzfehler und 38 Patienten (73.1%) wurden für eine univentrikuläre Palliation vorgesehen. Als Shunt-Modifikationen wurden zentrale aorto-pulmonale Shunts (n=35; 67.3%) und modifizierte Blalock-Taussig-Shunts (n=17; 32.7%) verwendet. Ergebnisse: Nach einer mittleren Nachbeobachtung von 133 Tagen (Range: 0 – 315 Tage) betrug die Offenheitsrate der HBPS bis zur nächsten chirurgischen Intervention 90 ± 4%. Die Frühmortalität (30 Tage) betrug 5.8% (n=3). Drei weitere Patienten verstarben während des Krankenhausaufenthaltes. Die Todesursachen waren nicht Shunt- assoziiert. Bei fünf Patienten trat eine HBPS-Thrombose auf, welche durch eine Eröffnung des rechtsventrikulären Ausflusstrakts (n=2; 3.8%) oder einen Shunt- Wechsel (n=3; 5.8%) behandelt wurde. Die HBPS-Thrombose trat entweder intraoperativ (n=3; 5.8%), früh postoperativ nach drei Tagen (n=1; 1.9%) oder spät postoperativ nach 41 Tagen (n=1; 1.9%) auf. Bei Patienten mit offenem HBPS entsprach der nächste geplante chirurgische Schritt entweder einer 3 Korrekturoperation (n=10; 19.2%), einer bidirektionalen Glenn-Anastomose (n=25; 48.1%) oder einer erneuten Shunt-Anlage (n=5; 9.6%). Am Ende des Follow-up war bei einem Patient der HBPS noch in situ. Das Überleben bis zur nächsten geplanten Operation mit HBPS-take-down lag bei 84 ± 6% für Patienten mit univentrikulärer Morphologie und 100% für biventrikulär korrigierbare Patienten (p=0,14). Schlussfolgerung: Die Verwendung von HBPS als systemisch-pulmonale Shunts erscheint sicher. Da beim HBPS durch die kovalente Heparin-Bindung im Shunt nur ein Bestandteil der Virchowschen Trias beeinflusst wird, können Shunt-Thrombosen, die vorwiegend perioperativ auftreten, nicht vollständig verhindert werden. 4 1. INTRODUCTION 1.1. Palliative Shunting: A Brief Surgical History A systemic to pulmonary artery shunt establishes pulmonary blood flow in the context of palliative cardiac surgery. Indications for surgery exist in children with ductal dependent or decreased pulmonary blood flow, who are not suitable for complete repair or Glenn palliation at this stage. Moreover, children with single ventricle physiology and obstructed systemic blood flow need systemic to pulmonary artery shunting in the context of “classical” or Norwood-type operations. An ideal shunt is expected to fulfil attributes like technical simple implantation, functionality, long-term patency and easy take-down before repair. [1] The “classic” Blalock-Taussig shunt was reported by Helen B. Taussig and Alfred Blalock on 29 November 1944, who observed improved survival of „blue babies“ with cyanosis when the ductus Botalli was still open. In the absence of a reliable pharmacological long-term-option to keep the duct open, division of the subclavian artery and anastomosis to the pulmonary artery on the same side was adopted. [2, 3] Originally a superior right antero-lateral thoracotomy was chosen as access and the distal right subclavian artery was anastomosed to the right pulmonary artery in an end-to-side fashion. Figure 1 Figure 1. Classic Blalock-Taussig shunt (Source:Yuan S. H, Jing H, Palliative procedures for congenital heart defects [1]) 5 After performing a classic Blalock-Taussig shunt, blood flow to the ipsilateral arm is preserved by collateral arterial vessels. This often leads to a significant reduction in length and muscle mass of the ipsilateral arm compared to the contralateral arm. [4] As an alternative to the “classic” Blalock-Taussig shunt, various techniques were introduced by performing a direct anastomosis between the aorta and one pulmonary artery. In 1946 Potts used a direct anastomosis between the descending aorta and the left pulmonary artery. [5] Figure 2 Figure 2. Potts Anastomosis. (Source: Blanc et al, Potts shunt in patients with pulmonary hypertension [6]) Waterston used a variation of this technique in 1962 by creating a direct shunt between the ascending aorta and right pulmonary artery through the 4th intercostal space via right postero-lateral thoracotomy. [7] This approach was modified by Cooley in 1966 by an antero-lateral thoracotomy. [8] A central aorto-pulmonary shunt performing a direct anastomosis between the ascending aorta and the main 6 pulmonary artery was first published by Davidson in 1955. [9] Most of those direct shunt variations were abandoned due to pulmonary hypertension