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-Universi tät

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

1

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.

2

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.

3

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

4

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.

5

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])

6

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

7

pulmonary artery was first published by Davidson in 1955. [9] Most of those direct

shunt variations were abandoned due to pulmonary hypertension and take down

difficulties during the next surgical procedures. Right pulmonary artery stenosis,

pulmonary hyperperfusion, pulmonary hypertension and differential pulmonary

perfusion are possible shunt related sequels before total repair. Many of these

unexpected complications were believed to be related to inaccurate initial

anastomosis of the right pulmonary artery to the aorta, later growth and later aortic

rotation. Some of these reasons, precluding later repair or further consecutive

palliation, made the Waterston shunt and Potts anastomosis disappear by the early

1980s.

Using prosthetic material, central aorto-pulmonary shunts (CAPS) were first

performed by Shumacker and Mandelbaum in 1962. [9, 10] Figure 3

Figure 3. Central aorto-pulmonary shunt using prosthetic material (Source:Yuan S. H, Jing H, Palliative procedures for congenital heart defects [1])

The advantage of this variant is an increasing patency rate in combination with a

more harmonic growth of both pulmonary arteries due to a relatively “excessive”

shunt-flow. [11, 12] A possible disadvantage of central shunting is its proximity to

the sinus of Valsalva which can lead to a significant coronary steal resulting in heart

failure or cardiac arrest. Moreover, direct sternal compression on the central shunt

may be inclined with kinking in the area of the proximal anastomosis. As an

alternative to the classical "Cobra-Head-Anastomosis” technique, Gates and Laks

8

introduced a proximal lateral-to-side anastomosis between the Gore-Tex shunt and

the ascending aorta. [11] The dorsal wall of the shunt is incised for several

millimeters and the proximal open shunt end is clipped.

Mark de Leval and McKay published in 1980 and 1981 an anastomosis between the

innominate artery and the right pulmonary artery by interposing a

polytetraflourethylen prosthesis between both vessels. This so called „modified

Blalock-Taussig shunt“ (MBTS) was initially performed on the ipsilateral side of the

aortic arch, in order to allow the use of a future classic Blalock-Taussig shunt in

growing children. [13, 14] Figure 4

Figure 4. Modified Blalock-Taussig shunt using prosthetic material (Source: Yuan S. H, Jing H, Palliative procedures for congenital heart defects [1])

Nowadays, MBTS is being used worldwide as temporary palliation with acceptable

patency rates until correction or further palliation. MBTS are usually anastomosed to

the contralateral pulmonary artery of the aortic arch.

1.2. Shunt Associated Problems and Possible Drawbacks

Beside some typical surgically associated complications such as shunt stenosis or

distortion of the pulmonary arteries [13, 15-19] shunt surgery carries a range of

possible risks. MBTS shunts can cause pseudoaneurysm formation with secondary

9

infection of the thrombotic material. [20] One the other hand, the foreign material of

MBTS can cause shunt endocarditis. [21]

Life threatening major complications like acute shunt thrombosis with sudden shunt

occlusion and imminent cardio-pulmonary resuscitation are rare. The incidence of

acute shunt thrombosis has been reported between 0-15% in different centers. [11,

22-28] A perioperative hypercoagulative state, low cardiac output and the absence of

a native intima are responsible for early shunt thrombosis, as those factors are part of

Virchow’s triad. Late shunt thrombosis usually results from progressive intimal

hyperplasia with a slow occlusion process. [21] It is less common and occurs with an

incidence of 0-5.3%. [11, 24, 26, 29, 30]

Selection of shunt size and its length are crucial for the postoperative performance. A

ratio of pulmonary artery to systemic-arterial blood flow (Qp:Qs) of approximately

1:1 is striven to be an ideal relationship, but is often difficult to achieve. Early

postoperative excessive pulmonary arterial blood flow results in pulmonary

hypercirculation with pulmonary edema and low cardiac output. [12, 31-33] In

contrast reduced systemic to pulmonary artery blood flow in the context of increased

pulmonary vascular resistance results in progressive cyanosis and possible later

organ failure and death despite adequate arterial blood pressure. As pulmonary

resistance decreases with age it counteracts patient growth for a certain time. A

balanced systemic- to pulmonary circulation is thus warranted for most patients until

the next surgical step.

1.3. Experience with "Heparin-Bonded" Shunts

Acute and late shunt-thrombosis are severe complications after palliative congenital

heart surgery. [24, 25, 34] Heparin bonded polytetrafluoroethylene shunts (HBPS)

(Propaten® Vascular Graft; W. L. Gore & Assoc, Flagstaff, Ariz) offer an

intraluminal heparin- active site, which enables binding of the clotting factor

inhibitor Antithrombin III for creation of a thrombosis-resistant surface.

Experience from vascular surgery by using HBPS show reduced platelet

deposition, decrease in inflammatory responses and a reduction of

thrombogenicity. Experience from vascular surgery suggests that HBPS may have a

10

superior outcome in the case of thromboembolic risk than uncoated grafts or

autologous venous material. A reduced morbidity and mortality has also been

described. [35-38]

The use of HBPS as systemic-to-pulmonary artery shunts in children with congenital

heart defects was described for the first time by the German Heart Center in Munich,

reporting no advantage compared to conventional shunts was reported.

Histopathologically, both types of shunt forms partial endothelialization and discrete

intimal proliferation at the time of correction or further palliation. [39]

1.4. Aim of the Study

The aim of this study was to evaluate patient survival and shunt-occlusion rates in

patients with congenital cardiac anomalies, who required systemic to pulmonary

artery shunting with HBPS in a single center. In addition, subgroup analysis of shunt

type (MBTS vs. CAPS) and cardiac morphology (univentricular vs. biventricular)

was scrutinized regarding their influence on HBPS-performance.

11

2. MATERIAL AND METHODS

2.1. Patients

All patients, who received HBPS between January 2010 and December 2016, were

retrospectively reviewed. Inclusion criteria were age under 3 months, anterior

sternotomy approach and HBPS as initial palliative surgical treatment. Patients were

categorized with respect to their cardiac morphology whether they went the

univentricular or biventricular pathway.

2.2. Surgical Technique

All cardiac procedures were performed via median sternotomy. The pulmonary

arteries and ductus arteriosus were dissected and the anatomic structures evaluated.

In patients with hypoplastic left heart syndrome, it is our institutional policy to

perform Norwood procedures with a right ventricle to pulmonary artery conduit

(“Sano-Shunt”/non-HBPS). These patients were not included in this analysis.

Variants with a morphologic left ventricle, however, were palliated with MBTS. The

decision in other than Norwood patients to proceed with a MBTS or CAPS is made

according to the position, size, and anatomic relation of the pulmonary arteries to the

aorta and its branching patterns. [40] CAPS and MBTS were performed as

previously described. For MBTS, an obliquely fashioned end of the HBPS was

sutured end-to-side to the innominate artery. The straight distal end of the graft was

anastomosed to the right or left pulmonary artery depending on arch and PA-

anatomy. [27] Figure 5A For CAPS, distal end-to-side anastomosis between shunt

and main pulmonary artery, and proximal side-to-side anastomosis between shunt

and aorta were performed. The open end of the shunt was trimmed and clipped close

to the proximal anastomosis after de-airing. [11] Figure 5B

If necessary, cardiopulmonary bypass was admitted. Moderate hypothermia (32-

35°C) was used for standard shunt operations without additional procedures.

Antegrade modified blood cardioplegia was administered if cardioplegic arrest was

necessary. Septectomy in univentricular patients was performed to improve intra-

cardiac mixing at the atrial level. Modified Norwood procedures using MBTS were

12

performed in moderate hypothermia (25-28°C) with regional cerebral perfusion.

Correction of total anomalous pulmonary venous drainage was performed under deep

hypothermia (18°C) with circulatory arrest. After weaning from bypass modified

ultrafiltration was carried out.

Figure 5 AB. Modified Blalock-Taussig shunt (A) and central aorto-pulmonary shunt with proximal end-to-side technique (B).

2.3. Follow-up

Follow-up was accomplished by routine control echocardiography or direct contact

with the referring cardiologist, until July 31st 2017. All patients with systemic to

pulmonary artery shunt are scheduled for cardiac catheterization at the age of 3

months.

Shunt patency was defined as “native” open graft until estimated next surgical

treatment, which was either corrective surgery or bidirectional Glenn procedure.

Additionally, in patients who were not eligible for those two procedures despite open

graft, elective shunt replacement was scheduled whenever patient outgrowth was

suspected.

Shunt thrombosis was managed according to anatomical features by intervention or

surgery. The former included balloon dilatation and stent placement if necessary. The

13

latter comprised new shunting with CAPS, MBTS, right ventricular to pulmonary

artery conduit, or patch enlargement of the right ventricular outflow tract.

2.4. Statistical Analysis

Data were collected using Microsoft Excel 2010. Analysis was performed with SPSS

21.00 (SPSS Inc., Chicago, IL, USA). Descriptive data for continuous variables are

reported as median with ranges or mean ± standard deviation. Categorical variables

are presented as numbers or percentages. Risk adjustment was stratified according to

the Aristotle and RACHS score. Primary end-points were calculated by X²-test and

the Kaplan-Meier method (log-rank) which included survival until the planned next

procedure, and patency of HBPS. Statistical significance was established at a

p-value<0.05.

14

3. RESULTS

3.1. Patient Characteristics and Operative Data

Fifty-two patients with HBPS were identified, of whom all except 3 were operated

on cardiopulmonary bypass. Thirty-five patients received CAPS (67.3%) and 17

patients MBTS (32.7%). Size of HBPS was 3.5 mm in 51 patients (98.1%) and 4 mm

in 1 patient (1.9%). The patient characteristics are summarized in Table 1 and

operative data in Table 2.

Table 1. Patient Characteristics

Value % Median Range

Male 29 55.7

Body weight: (kg) 3.2

3.2 1.8 - 5.72

Age: (days) 8

8 3 - 83

Univentricular morphology

HLHS + variants 13 25

HRHS 19 36.5

Heterotaxy 6 11.5

Biventricular morphology

TOF / DORV 6 11.5

Pulmonary atresia + VSD 5 9.6

TGA + pulmonary stenosis 3 5.8

DORV: double outlet right ventricle; HLHS: hypoplastic left heart syndrome; HRHS: hypoplastic

right heart syndrome; TGA: transposition of great arteries; TOF: tetralogy of Fallot; VSD: ventricular

septal defect

15

Table 2. Operative Data

N % Median Range

Central aorto-pulmonary shunt (CAPS) 35 67.3

isolated 23 44.2

TAPVD correction 2 3.8

Septectomy 7 13.5

Pulmonary artery reconstruction 3 5.8

Modified Blalock-Taussig shunt (MBTS) 17 32.7

isolated 3 5.8

Septectomy 1 1.9

Norwood I 13 25

Shunt size

3.5 mm 51 98.1

4 mm 1 1.9

Aristotle-Score

6.8 6.3-15

RACHS

3 3-6

Surgery time (minutes)

255.5 112-574

Bypass time (minutes)

68 23-360

Aortic crossclamp time (minutes)

37 8-118

Temperature (° C )

32.5 19.2-36.4

RACHS: risk adjustment for congenital heart surgery

16

Two patients initially scheduled for biventricular repair went the univentricular

pathway. In 2 patients the decision for further palliation was made during the

second step operation due to straddling mitral valve in a patient with corrected

transposition and pulmonary atresia originally planned for Senning/ Rastelli, and

due to “remote” ventricular septal defect in a patient with double outlet right

ventricle and malposition of great arteries. In addition, one patient with corrected

transposition and pulmonary atresia, who received bidirectional Glenn at second

step was referred to further “1 and 1/2 repair” and was classified to biventricular

patients. Thus in total, 14 patients (26.9%) were stratified to be biventricular and

38 patients (73.1%) to have functionally univentricular morphology.

3.2. Survival

Early mortality (30 days) was 5.8% (n=3). Another 3 patients died during their

hospital stay. Hospital mortality was 0% in biventricular patients and 11.5% (n=6)

in univentricular patients (p = 0.27). Six of the latter died with HBPS in situ, all non-

shunt related. Causes of death were heart failure (n=5) and sepsis (n=1).

Median duration until next palliative or corrective surgical procedure was 141 days

(range: 0 - 463). At the end of follow-up, 1 patient had HBPS still in situ.

Estimated second procedure included corrective surgery (n=10; 19.2%), bidirectional

Glenn (n=25; 48.1%) and shunt replacement (n=5; 9.6%). Reasons for new shunting

despite open HBPS (univentricular n=4; 7.7%, biventricular n=1; 1.9%) were

intraoperative hemodynamic instability (n=1; 1.9%), non-eligibility for biventricular

repair (n=1; 1.9%) or bidirectional Glenn (n=1; 1.9%), pulmonary artery distortion

(n=1; 1.9%) and bronchial obstruction (n=1; 1.9%).

A flow-chart until next surgical treatment including take-down of HBPS is shown in

Figure 6.

17

Figure 6. Flow chart of HBPS treatment algorithm. CAPS: central aorto-pulmonary shunt; MTBS: modified Blalock-Taussig shunt; RVOT: right ventricular outflow tract

18

Survival until planned second procedure in patients with biventricular morphology

was 100% and in patients with univentricular morphology 84 ± 6% (p = 0.14).

Figure 7

Figure 7. Kaplan-Meier survival

19

3.3. Shunt Patency

Shunt patency was 90 ± 4% after a median duration of 133 days (range: 0 - 315

days). There was no significant difference between uni- and biventricular

patients regarding the freedom from shunt-thrombosis (biventricular:

85 ± 1% vs. single ventricle: 92 ± 5%; p=0.48). Incidence of early shunt

thrombosis in univentricular patients was 5.3% (n=2) and in biventricular 14.3%

(n=2) (p = 0.61), whereas late thrombosis was 2.6 % which occurred in 1

univentricular patient. Figure 8

Figure 8. Kaplan-Meier freedom from shunt thrombosis until next planned surgical treatment.

20

When discriminating between CAPS and MBTS, shunt patency was 88 ± 6% and

94 ± 6% (p=0.55), respectively. Incidence of early shunt thrombosis with CAPS was

8.6% and with MBTS 5.9%. Late thrombosis was rare and occured in one patient with

CAPS (n=1; 2.9%/ p = 1.00). Figure 9

Figure 9. Kaplan-Meier freedom from shunt thrombosis until next planned surgical treatment compared between distinct shunt modifications. CAPS: central aorto-pulmonary shunt; MTBS: modified Blalock-Taussig shunt

Shunt revision due to subtotal occlusion was performed in 5 patients (9.6%) and was

necessary either intraoperatively (n=3), early postoperatively (n=1) after 3 days on

ICU, or late post operatively (n=1) after 32 days. Data regarding shunt thrombosis are

summarized in Table 3.

21

Table 3. Shunt Thrombosis

Group Weight Age

Shunt

size Secondary

procedure

Onset of

Thrombosis Outcome

(kg) (days) (mm) (days)

Intraoperative shunt thrombosis after:

1. CAPS single ventricle 3.7 18 3.5 CAPS 0 discharged after Glenn

2. MTBS + septectomy single ventricle 2.6 5 3.5 CAPS 0 discharged after Glenn

3. CAPS biventricular 2.4 8 3.5 RVOT-

opening 0 discharged after correction

Postoperative shunt thrombosis after:

1. CAPS (3 days) biventricular 3.6 9 3.5

RVOT-

opening 3 discharged after correction

Late shunt thrombosis:

1.CAPS + TAPVD correction single ventricle 3.2 14 3.5 CAPS 41 discharged after Glenn

CAPS: central aorto-pulmonary shunt; MTBS: modified Blalock-Taussig shunt; TAPVD: Total Anomaly Venous Drainage; RVOT: right ventricular outflow tract.

22

Subtotal graft occlusion was managed by shunt resection and patch enlargement of

the right ventricular outflow tract in biventricular patients (n=2), and shunt revision

in univentricular patients (n=3). A resected and opened graft with thrombotic

material is shown in Figure 10.

Figure 10. Intraoperative shunt thrombosis in a resected HBPS

23

4. DISCUSSION

This study demonstrates outcomes after placement of HBPS in the context of

palliative congenital heart surgery. Cardiac morphology included patients with

univentricular and biventricular cardiac pathology, both eligible for further corrective

or palliative surgery.

4.1. Survival

Survival until the next elective procedure in biventricular patients was excellent

(100%). However in patients with univentricular morphology, outcome was

significantly less promising (84%). Patient attrition was not shunt-related and mainly

influenced by the underlying disease including hypoplastic left heart

complex/syndrome and heterotaxy. [41]

Palliative shunt surgery is reported with early mortalities between 0% and 18.2%

[11, 12, 22, 23, 27, 28, 32, 33, 42-45], and late mortalities between 3.8% and 19%.

[32, 33, 46] Reasons for unfavorable outcome were excessive pulmonary flow,

sepsis, and arrhythmia or shunt thrombosis.[12, 33, 46] Mortality early and late after

shunt operations is significant, despite being a non-complex surgical procedure.

Bove et al reported an in-hospital-mortality of 8.7% and later interstage mortality of

5.1% among 150 MBTS-patients operated between 1995 and 2013. [47] Fenton et al

reported an interstage mortality of 7.1% in biventricular patients and 19% in patients

with univentricular morphology. The authors pointed out, that autopsy-proven shunt

thrombosis was one of the leading causes of interim sudden death. [46] In order to

reduce the risk of shunt thrombosis, biologic material like saphenous venous

homograft for MTBS has been introduced by Erez et al. in 17 infants less than 3

kilograms. Hospital mortality for the entire cohort was 6.3% and survival rates until

shunt take-down 58% in the univentricular group and 90% in the biventricular group.

[42] Alsoufi et al reported significantly higher hospital mortality in univentricular

patients but comparable survival until next elective procedure when compared to

biventricular patients. [44] Other groups were not able to show a significant effect for

univentricular morphology as predictor of death or shunt dysfunction. [12, 27, 48]

24

4.2. Shunt Patency

Incidence of early and late shunt thrombosis was 7.6% and 1.9%, respectively. The

observed results are in accordance with the experience of other studies concerning

systemic-to-pulmonary shunting, where early and late shunt thrombosis ranged

between 0-15 % [11, 22-28] and 0-5.3% [11, 24, 26, 29, 30], respectively.

Shunt patency in our cohort was 90 ± 4% with no significant difference between uni-

and biventricular patients. This seems different to some other studies, in which shunt

thrombosis seemed to occur more often in univentricular patients (5.5-18.1%) when

compared to biventricular patients (4.7-7.1%). [27, 46]

One possible reason for shunt thrombosis in our cohort was reduced HBPS blood

flow, as a consequence of continuous low output syndrome after weaning from

cardiopulmonary bypass, or concurrent flow due to sustained antegrade perfusion of

the pulmonary artery via the RVOT. Stasis of blood flow enhances thrombosis as a

well-known part of Virchow’s triad. [39]

There was no significant difference between CAPS to MBTS regarding their patency

rate. When looking at other studies with selective use of either procedure, this

finding is confirmed by other authors, where early shunt thrombosis by using CAPS

0-16.7 % [11, 23, 24] and with MBTS between 5 -14.9% [22, 24-28], whereas late

thrombosis was 0% [11] and 0-5.3%. [24, 26, 29, 30]

All patients with shunt thrombosis could be successfully referred to further palliative

surgery. In one patient balloon dilatation of subtotal late shunt thrombosis was

performed as a bridge to shunt replacement. Five additional patients needed shunt

intervention for anatomical reasons or successive narrowing of the shunt, which

might be related to aggravating intimal hyperplasia. [39] Other studies reported that

9.7-17% of their patients needed catheter-reintervention after systemic-to-pulmonary

shunting. [31, 34]

4.3. HBPS

Studies from vascular surgery reported that heparin-bonded vascular grafts provided

improved patency rates and limb salvage in patients with peripheral vascular disease.

25

[38] Daenens et al. reported a similar 1-2 years patency rate when comparing

heparin-bonded grafts to autologous saphenous vein grafts. [49] Kirkwood et al.

suggested that heparin-bonded vascular grafts should be the conduit of choice for all

prosthetic bypasses. [37]

There is a limited number of reports in the literature regarding the use of HBPS in

the palliative setting of congenital heart surgery for newborns. In a small series,

Hörer et al. compared HBPS to classic polytetrafluorethylene shunts and revealed

equally good clinical outcomes for patients with both types of shunts. The

histopathological workup revealed a faster process of endothelialization with HBPS

within the first 30 days, which may prevent the patient from shunt thrombosis in the

early interim period. However, the process of intimal proliferation was not affected

by HBPS, still exposing the patient to the risk of late shunt thrombosis. [39]

4.4. Limitations

Limitations of the study are inherent to the retrospective nature of data retrieval.

Historical influences on patients outcome related to improvements in surgical

techniques and intensive care protocols over the study period cannot be excluded.

4.5. Conclusion

The use of HBPS is safe and seems to warrant systemic to pulmonary perfusion

sufficiently. Despite the covalent binding of Heparin in the HBPS inner layer, Shunt-

thrombosis cannot be excluded totally and occurs predominantly early. However,

those patients can be transferred relatively safe to further palliative treatment,

indicating a delay in the process of shunt occlusion by using HBPS.

26

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31

6. ABBREVIATIONS

CAPS central-aorto-pulmonary shunt

DORV double outlet right ventricle

HBPS heparin-bonded polytetra-fluorethylen shunts

HLHS hypoplastic left heart syndrome

HRHS hypoplastic right heart syndrome

MBTS modified Blalock-Taussig shunt

RACHS risk adjustment for congenital heart surgery

RVOT right ventricular outflow tract

TAPVD total anomalous pulmonary venous drainage

TGA transposition of great arteries

TOF tetralogy of Fallot

VSD ventricular septal defect

32

7. LIST OF FIGURES

Figure 1. Classic Blalock-Taussig Shunt

Figure 2. Potts Anastomosis

Figure 3. Central aorto-pulmonary shunt using prosthetic material

Figure 4. Modified Blalock-Taussig shunt using prosthetic material

Figure 5.

A. modified Blalock-Taussig-shunt

B. central aorto-pulmonary shunt with proximal end-to-side technique

Figure 6. Flow chart of HBPS treatment algorithm

Figure 7. Kaplan-Meier survival

Figure 8. Kaplan-Meier freedom from shunt thrombosis until next planned

surgical treatment

Figure 9. Kaplan-Meier freedom from shunt thrombosis compared between

distinct shunt modifications until next planned procedure

Figure 10. Intraoperative shunt thrombosis in a resected HBPS

33

8. LIST OF TABLES

Table 1. Patient Characteristics

Table 2. Operative Data

Table 3. Shunt Thrombosis

34

9. ACKNOWLEDGEMENTS

I would sincerely like to thank Professor Dr. med. Robert Cesnjevar for the

opportunity to do research in his department and the continuous support and

guidance.

I would like to honourly thank PD Dr. med. André Rüffer for his supervision,

patience, and time.

I would like to kindly thank the team of the Department of Pediatric Cardiac Surgery

in Erlangen, Dr. med. Ariawan Purbojo, Robert Blumauer, MD, for supporting my

scientific work.

Professor Jürgen von der Emde for the invitation to Germany.

My parents, Endang Ambar Rukminingsih, SP.d and Dasaad Achsany, M.B.A for all

supports. My sisters and their families, Shintia Adny Noviarukmi, S.H, M.Kn,

Mayang Adny Puspitaning Dewi, S.AB, Ihwan Handy Rosiyanto, M.D, FIHA,

Aribowo, S.T, M.T.

Mrs. Monika Prowosnik, Mrs. Simone Marten, Mrs. Natalie Seifert, Mr. Frank

Münch, Mrs. Manuela Bader, Mrs. Sabrina Mandelkow, Ms. Teresa Adt, Ms.

Johanna Jahnke, Ms. Vanessa Maley, for helping me as long as I have been working

here.

35

10. DISCLAIMER

I certify that my Dissertation is my own work and an original report of my research.

Part this work has been presented at the 7th World Congress of Pediatric Cardiology

and Cardiac Surgery, Barcelona, Spain, 2017.

A journal publication of this work is in progress and will be submitted, soon.

Erlangen, 16.08.2017

Yuletta Adny Ambarsari