Catheterization and Cardiovascular Interventions 83:250–255 (2014)

Transcatheter Occlusion of the Patent Ductus Arteriosus in Infants: Experimental Testing of a New Amplatzer Device John L. Bass,1*

MD

and Neil Wilson,2

MD

Objectives: This study assessed the feasibility and efficacy of implanting a new miniaturized nitinol device to occlude the patent ductus arteriosus (PDA) in a newborn porcine model. Background: Transcatheter device closure is the standard of care for PDA in older children and adults. Currently available technology is not designed for the newborn infant. Methods: The Amplatzer Duct Occluder II 0.5 is a new transcatheter Nitinol device without fabric designed to close the PDA with small aortic and pulmonary artery structures. The device was implanted in 8 infant pigs (average weight 2,400 g) after balloon dilation of PDA (average diameter 2.7 mm, average length 5.8 mm) with immediate,  7,  30, and  90 day follow-up by echocardiography, angiography, and final pathological examination. Half were implanted arterial, and half venous. Results: The device was successfully implanted in all animals. There was complete occlusion of the PDA in all cases without obstruction of the pulmonary arteries or aorta. There was complete late endothelialization without thrombus. The only complication was transection of a femoral artery accessed by cutdown. Conclusions: The success of this animal study confirms safety and feasibility of the Amplatzer Duct Occluder II 0.5 (now known as the ADO II AS) for use when the aorta and pulmonary arteries are small. Consideration can be given to transcatheter closure of the PDA in preterm and other small infants with this device. VC 2011 Wiley Periodicals, Inc. Key words: patent ductus arteriosus; cardiac device; pediatric interventions

INTRODUCTION

METHODS

Transcatheter closure of the patent ductus arteriosus (PDA) is the standard of care for the older child with surgical closure reserved for the premature infant. Small aortic and left pulmonary artery diameters in children less than one year of age can lead to protrusion of coils [1–5] or discs [6–9] into the pulmonary arteries or aorta. The large delivery systems of devices also limit their use in the smaller patient. Even though the recently introduced Amplatzer Ductal Occluder II (ADO II) device can pass through a 4F delivery catheter [10], the disc size led to a recommendation of limiting its use to children at least six months of age and with a descending aorta at least 10 mm in diameter. Reports of transcatheter closure of PDA in premature infants [11,12] encouraged further miniaturizing the ADO II device so that it could be used with smaller pulmonary arteries and aorta. The diameter of the discs was reduced to 1mm larger than the waist. Feasibility tests suggested that such a device could be introduced using echocardiography alone raising the possibility of bedside implantation in the premature infant. To evaluate the efficacy and stability of the modified ADO II device with smaller discs, a Good Laboratory Procedure trial was undertaken in an infant porcine model.

Purpose The purpose of this study was to demonstrate the safety and feasibility of transcatheter closure of the patent ductus arteriosus (PDA) in an infant porcine model. A new Amplatzer Ductal Occluder II 0.5 device (now known as the ADO II AS) was designed to minimize interference with small pulmonary arteries and aorta when implanted in a PDA.

C 2011 Wiley Periodicals, Inc. V

1

Division of Pediatric Cardiology, University of Minnesota Amplatz Children’s Hospital, Minneapolis, Minnesota 2 Consultant Pediatric Cardiologist and Honorary Senior Lecturer, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom Conflict of interest: Corresponding author is a consultant, proctor and receives grant funding from AGA Medical LLC. *Correspondence to: John L. Bass, MD, 420 Delaware Street SE, MMC 94, University of Minnesota Amplatz Children’s Hospital, Minneapolis MN 55455. E-mail: [email protected] Received 20 October 2010; Revision accepted 27 November 2010 DOI: 10.1002/ccd.22931 Published online 13 January 2011 in Wiley Online Library (wileyonlinelibrary.com)

New Amplatzer Infant PDA Device

251

Test Device Like the ADO II, the device is constructed of two layers of braided Nitinol wire shaped with a central plug and a disc at each end. To minimize interference with contiguous structures, the discs are only 1mm larger in diameter than the plug (Fig. 1) and articulate up to about 30 . The device is fully recapturable and passes easily through a 4F delivery catheter (AGA Medical LLC, Plymouth MN). Devices with 3, 4, and 5 mm plug diameters and 2, 4, and 6 mm plug lengths were available during this study. Animal Model

The porcine model was chosen because of the similarity of the size of the great arteries to the human infant. Procedure Eight infant piglets weighing 2,300–2,500 g underwent transcatheter implantation of an ADO II AS device. The study was performed in accordance with FDA 21 CFR Part 58 Good Laboratory Practice (GLP) Regulations [13] and in accordance with the USDA Animal Welfare Act (CFR Parts 1, 2, and 3) and the Guide for Care and Use of Laboratory Animals (National Research Council, 1996). 4F sheaths were placed on the day of implant with access to the femoral artery and vein obtained by cutdown. Aortography was performed to initially document the presence or absence and location of a PDA. Echocardiography was performed by transthoracic (TTE) imaging or an Intracardiac Echocardiographic (ICE) probe placed in the esophagus. A PDA large enough for device closure was created by crossing the PDA from the aorta with a guidewire and dilating it with a 4 mm diameter by 12mm long coronary balloon for 1 min twice or 2 min once [14]. Aortography was repeated and the PDA dimensions and diameter of the aorta and left pulmonary artery measured. Imaging equipment was a single plane Philips flat panel detector with magnification correction from a marker pigtail catheter, and measurements made using Allura XPER FD10 software with electronic calipers. On the basis of the PDA measurements, an appropriately sized device was selected for implant. Proximal and distal pulmonary artery and aortic pressures were measured. The 4F delivery catheter was passed through the PDA with a guidewire from the arterial (n ¼ 4) or venous (n ¼ 4) side. The device was threaded onto the delivery cable, immersed in saline, and withdrawn into the loader. The distal end of the loader was passed through a hemostasis Y-connector

Fig. 1. Photograph of two ADO II AS devices showing the retention discs 1mm larger than the waist. The microscrew is at the bottom of the figure. The ruler shows 1 mm markings.

attached to the distal end of the delivery catheter and advanced with the delivery cable. Under fluoroscopic and echocardiographic guidance, the device was delivered into position, deployed, repositioned if necessary and released. Aortic and pulmonary angiography were again performed to confirm position and monitor occlusion (Fig. 2). Proximal and distal pulmonary artery and aortic pressures were measured. Device position, PDA occlusion and obstruction of the pulmonary artery and aorta were evaluated by echocardiography. Sheaths were removed, vessels ligated, and cutdown sites sutured closed. Follow-up echocardiography was performed at 7, 30, and 90 days post procedure, and pressure and angiography at 30 and 90 days post procedure. Vascular access for hemodynamic and angiographic evaluations was obtained by cutdown. Echocardiography was performed by transesophageal ICE or TTE. Animals were euthanized at 90 days (when endothelialization is expected to be complete) after completed assessment. Necropsies were performed with the heart, lungs, and aorta removed en bloc. The aorta and pulmonary artery were opened for gross photography. The specimens were then placed in 10% formalin and sent for pathology. Statistical analysis of changes in gradient across the devices in the pulmonary artery and aorta were performed by Student’s t-test. RESULTS

All PDAs were patent by angiography and echocardiography after balloon dilation. Midpoint PDA diameters ranged from 1.5 to 2.4 mm with a mean of 1.8 mm (Table I). Ductal morphology was assessed according to the criteria of Krichenko et al. [15]. Six PDAs

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Fig. 2. Angiograms immediately after implantation of an ADO II AS device in the porcine model. In panel A a pulmonary arteriogram demonstrates lack of protrusion of the device into the pulmonary artery lumen with no obstruction of the left pulmonary artery. In panel B an aortogram demonstrates complete occlusion of the ductus arteriosus with the aortic retention disc flat against the aortic wall.

TABLE I. Vascular Measurements and Device Selection PDA

Aorta

Pulmonary Artery

Device (mm) Waist  disc  length

Animal #

Ao Diam (mm)

Mid-Point Diam (mm)

PA Diam (mm)

Length (mm)

Diameter (mm)

Diameter (mm)

192 193 194 195 198 199 200 205 Average

3.08 3.20 3.03 2.81 2.13 2.67 2.28 2.54 2.72

1.69 1.72 1.49 2.40 1.87 1.50 1.64 1.94 1.78

0.57 1.84 2.19 2.25 1.90 2.28 0.96 2.86 1.86

3.89 5.88 5.94 7.99 4.86 5.25 6.41 6.44 5.83

3.83 4.86 5.91 8.04 5.54 5.73 5.05 5.70 5.58

3.67 4.79 5.69 5.81 5.37 6.89 5.11 6.11 5.43

were tubular (type C) though sometimes narrowed at the midpoint, while two were type E (ampulla narrowed significantly at the pulmonary end). ADO II AS devices chosen all had a plug diameter of 3 mm (25– 100% larger than the PDA midpoint diameter). PDA lengths ranged from 3.9 to 8 mm (mean 5.8 mm) while the device plug lengths were 2 mm [1], 4 mm [5] or 6 mm [2]. In general, devices shorter than the ductus were chosen when the device diameter was more than 75% larger than the PDA midpoint diameter. All PDAs were successfully accessed and crossed using the delivery catheter and guidewire. Devices were easily deliv-

3 3 3 3 3 3 3 3

       

4 4 4 4 4 4 4 4

       

2 4 4 6 4 4 6 4

ered and recaptured when necessary through the 4F delivery catheter. Average fluoroscopy time was 3 min 6 sec for dilating the PDA and implanting the device. All devices were correctly positioned and position did not change during the study. Occlusion assessed by angiography and echocardiography occurred in 1.97  1.55 min (all less than 5 min), and remained occluded at 7, 30, and 90 day follow-up examinations (Fig. 3). No significant pressure gradients were found into the left pulmonary or aorta distal to the device immediately after implant or at 7, 30, and 90 day evaluations. Catheter and echocardiographic gradient measurements were consistent.

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Fig. 3. Macroscopic photographs of the aortic (A) and pulmonary artery (B) lumens after sacrifice at three months. The retention discs of the ADO II AS device are completely endothelialized.

All device retention disks were covered by stable mature neointima (Fig. 3). There was diffuse ingrowth of mature fibrous connective tissue embedded in the device and within the surface neointima (Fig. 4). There was good local toleration of the host tissue with no inflammatory or foreign body response. All animals survived the planned duration of the study period. A single animal experienced right hind limb lameness resulting from right femoral artery perforation during recovery and throughout the remainder of the study. However, the animal grew and was otherwise healthy. The complication was related to arterial damage of access, and not to the device. DISCUSSION

Transcatheter closure of the PDA may be accompanied by protrusion of the closure device into the aorta or left pulmonary artery causing obstruction to flow. In the modern era, this has been reported with coil occlusion of the PDA [1–5] as well as with the ADO1 device [6–9]. Aortic obstruction with the ADO1 device may be caused by the acute angle that the PDA has with the descending aorta causing the disc to protrude [8]. Most recently, the ADO II device with articulated discs designed to lie flat against the aorta and pulmonary artery performed well in an animal model without causing aortic or pulmonary artery obstruction [10].

Fig. 4. Photomicrograph of an ADO II AS device showing complete coverage of the retention discs by neointima. There is diffuse ingrowth of mature fibrous connective tissue embedded in the device.

However, the discs are 6 mm larger than the waist, and its use is recommended for children weighing over 6 kg, or with a descending aortic diameter of at least 10 mm. The ADO II AS device seems ideal for these smaller infants and children. Transcatheter PDA closure is generally performed in children at least two to six months of age for symptoms of pulmonary overcirculation or to prevent

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infective endocarditis. However, one of the associated causes of the persistently patent ductus arteriosus is premature birth. These preterm infants often need closure because of the effect of increased pulmonary flow on associated pulmonary disease, or symptoms of heart failure [16,17]. Surgical closure of the PDA in preterm infants can be performed at the ‘‘bedside’’ in the newborn intensive care unit [18] and there is a nearly 100% closure rate. The complication rate is low. Transcatheter PDA closure in the preterm infant must compete with the safety of surgical closure. To be considered an alternative to surgical closure, transcatheter closure of the PDA in preterm infants must also be performed at the bedside (and therefore under echocardiographic guidance). The occlusion rate must be 100% with no embolization of devices or obstruction of the aorta or left pulmonary artery. Arterial access and delivery are necessary to avoid instability during catheter manipulation through the right side of the heart, especially under echocardiographic guidance. There should be minimal vascular trauma. During feasibility trials of the ADO II AS device, implantation guided by echocardiography alone in four animals was successful suggesting that ‘‘bedside’’ closure is possible. A device designed for PDA closure in the small infant should have a low profile on both aortic and sides pulmonary artery. A recent echocardiographic study by Trefz et al. [19] measured aortic and pulmonary artery dimensions in a series of 55 premature infants undergoing surgical PDA ligation. They found a mean aortic diameter of 4.9 mm and a mean PDA diameter of 2.3 mm in preterm infants over 1,250 g, close to those in the infant piglets included in the present study. It seems likely that the effectiveness of ductal occlusion and lack of aortic and pulmonary artery obstruction found in this study could be replicated in larger premature infants undergoing transcatheter PDA occlusion with this device. A possible shortcoming of this study is the PDA tissue character. Ewert [20] has reported that the tubular PDA in infants stretches more easily requiring larger devices to maintain stability, while this was not a problem in the porcine model of a dilated PDA. Finally, the ADO II AS device requires a 4F delivery catheter that can be used without a sheath to minimize femoral arterial trauma. A 3F delivery catheter would be ideal in the very small infant. The ADO II AS performs well in the infant porcine model. There is complete and persistent occlusion of the PDA. There is no obstruction of the aorta or left pulmonary artery. The device has the good characteristics of the standard ADO II including delivery through a 4F system, retrievability, high occlusion rate, articu-

lation of the discs to minimize interference with pulmonary arteries and aorta, and symmetry to allow placement from either venous or arterial routes. The ADO II AS is promising for occlusion of PDA in infants and clinical trials are indicated. REFERENCES 1. Corey LM, Vermilion RP, Shim D, Lloyd TT, Beekman III RH, Ludomirski A. Pulmonary artery size and flow disturbances after patent ductus arteriosus coil occlusion. Am J Cardiol 1996;78:1307–1310. 2. Patel HT, Cao Q-L, Rhodes J, Hijazi ZM. Long-term outcome of transcatheter coil closure of small to large patent ductus arteriosus. Catheter Cardiovasc Intervent 1999;47:457–461. 3. Forbes TJ, Harahsheh A, Rodriguez-Cruz E, Morrow WR, Thomas R, Turner D, Vincent JA. Angiographic and hemodynamic predictors for successful outcome of transcatheter occlusion of patent ductus arteriosus in infants less than 8 kilograms. Catheter Cardiovasc Intervent 2004;61:117–122. 4. Kuo HC, Ko S-H, Wu Y-T, Huang C-F, Chien S-J, Tiao M-M, Liang C-D. Obstruction of the aorta and left pulmonary artery after Gianturco coil occlusion of patent ductus arteriosus. Cardiovasc Intervent Radiol 2005;28:124–126. 5. Kramoh EK, Miro J, Bigras J-L, Turpin S, Lambert R, Lapierre C, Jin W, Dahdah N. Differential pulmonary perfusion scan after percutaneous occlusion of the patent ductus arteriosus: Onedecade consecutive longitudinal study from a single institution. Pediatr Cardiol 2008;29:918–922. 6. Duke C, Chan KC. Aortic obstruction caused by device occlusion of patent arterial duct. Heart 1999;82:109–111. 7. Al-Ata J, Arfi AM, Hussain A, Kouatli AA, Jalal MO. The efficacy and safety of the Amplatzer ductal occluder in young children and infants. Cardiol Young 2005;15:279–285. 8. Al-Hamish S, Nasir IV. Novel procedure for treatment of aortic obstruction caused by Amplatzer occluder of patent ductus arteriosus. Pediatr Cardiol 2008;29:782–785. 9. Parro-Bravo R, Cruz-Ramirez A, Rebolledo-Pineda V, RoblesCervantes J, Charez-Fernandez A, Beirana-Palencia L, JimenezMoontufar L, Estrada-Loza MdJ, Estrada-Flores J, Baez-Zamudio N, Excobar-Ponce M. Transcatheter closure of patent ductus arteriosus using the Amplatzer Duct Occluder in infants under I year of age. Rev Esp Cardiol 2009;62:867–874. 10. Gruenstein DH, Bass JL. Experimental evaluation of a new articulated Amplatzer ductal occluder device without fabric. Catheter Cardiovasc Interv 2009;74:482–487. 11. Roberts P, Adwani S, Archer N, Wilson N, Catheter closure of the arterial duct in preterm infants. Arch Dis Child Fetal Neonatal Ed 2007;92:F248–F250. 12. Prsa M, Ewert P. Transcatheter closure of a patent ductus arteriosus in a preterm infant with an Amplatzer Vascular Plug IV device. Catheter Cardiovasc Interv 2011;77:108–111. 13. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?CFRPart¼58. 14. Lund G, Cragg A, Rysavy R, Castaneda F, Salomonowitz E, Vlodaver Z, Castaneda-Zuniga W, Amplatz K. Patency of the ductus arteriosus after balloon dilation: An experimental study. Circulation 1983;68:621–627. 15. Krichenko A, Benson LN, Burrows P, Moes CAF, McLaughlin P, Freedom RM. Angiographic classification of the isolated, persistently patent ductus arteriosus and implications for percutaneous catheter occlusion. Am J Cardiol 1989;623:877– 880.

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New Amplatzer Infant PDA Device 16. Thibeault DW, Emmanouilides GC, Nelson RJ, Lachman RS, Rosengart RM, Oh W. Patent ductus arteriosus complicating the respiratory distress syndrome in preterm infants. J Pediatrics 1975;86:120–126. 17. Marshall DD, Kotelchuck M, Young TE, Bose CL, Kruyer L, O’Shea TM. Risk factors for chronic lung disease in the surfactant era: A North Carolina population-based study of very low birth weight infants. Pediatrics 1999;104:1345–1350.

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18. Satur CRM, Walker DR, Diskinson DF. Day case ligation of patent ductus arteriosus in preterm infants: A 10 year review. Arch Dis Child 1991;66:477–480. 19. Trefz M, Wilson N, Acton R, Hess D, Bass JL. Echocardiographic assessment of ductal anatomy in premature infants—Lessons for device design. Echocardiography 2010;27:575–579. 20. Ewert P. Challenges encountered during closure of patent ductus arteriosus. Pediatr Cardiol 2005;26:224–229.

Catheterization and Cardiovascular Interventions DOI 10.1002/ccd. Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).

Transcatheter occlusion of the patent ductus arteriosus in infants: experimental testing of a new Amplatzer device.

This study assessed the feasibility and efficacy of implanting a new miniaturized nitinol device to occlude the patent ductus arteriosus (PDA) in a ne...
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