Author + information
- Received January 8, 1996
- Revision received April 3, 1996
- Accepted May 7, 1996
- Published online October 1, 1996.
- RALPH G. GRABITZ* ()
- ↵*Address for correspondence: Dr. Ralph G. Grabitz, Department of Pediatric Cardiology, Aachen University of Technology, Pauwelsstrasse 30, 52074 Aachen, Germany.
- JAMES Y. COEb
Objectives. We attempted to evaluate the efficacy and tissue reaction of a new miniature interventional ductal occlusion device in neonatal pigs.
Background. A variety of devices are used to close persistent ductus arteriosus (PDA) by interventional measures. Because of the size of these devices, they have not been applied to term or preterm neonates. Newborn piglets are comparable in size and fragility to human term and preterm neonates.
Methods. Memory-shaped double-cone stainless steel coils were mounted on a titanium-nickel core wire. A snap-in mechanism attaches the coil to the delivery wire, allowing intravascular coil retrieval and repositioning. The system was placed through a 3F Teflon catheter. Two piglet models of PDA were used: 1) ductal patency maintained by stents (n = 6), and 2) ductal patency produced by angioplasty (n = 7) to avoid stent-coil interaction.
Results. Placement of the coils within the PDA was possible in all piglets. Before final detachment, the coils were retrieved or repositioned, or both, up to eight times. In all but two piglets the ductus was closed within 1 h of the procedure. The coils were never dislocated and caused no infections or relevant aortic and pulmonary artery obstruction (95% confidence interval for missing complications [0 of 13] extends to 23%). Histologic and electron microscopic studies revealed endothelial coverage of the implants and histiocytic reaction but no local or systemic inflammation or erosion of the implant.
Conclusions. The device was effective in experimental models of PDA. The information obtained warrants initial trials of the device in neonates.
The persistently patent ductus arteriosus (PDA) in preterm and term neonates or small infants is currently closed by prostaglandin synthesis inhibitors (indomethacin) or surgical ligation . Side effects of the medical treatment with indomethacin are related to variable ductal response , decreased renal function , bleeding disorders , increased susceptibility to generalized infections  and decreased cerebral blood flow . Risk inherent to surgical ligations through a left lateral thoracotomy include bleeding, chylothorax, pneumothorax, pulmonary damage and recurrent laryngeal nerve injury or late scoliosis .
Several percutaneous transcatheter techniques for closing the PDA in older children and adults have been described [8–15]; of these, the Rashkind occluder is to date the only system with a large number of implantations in children. The size and relatively large delivery system of these techniques limit their application to newborns. Spring coils to occlude arteries were introduced in 1975 by Gianturco et al. , who used small catheters (2F to 5F) for delivery. The currently available coils, once delivered, are not retrievable into the delivery catheter and therefore have a risk of improper placement or undesirable embolization. Nevertheless, in recent studies these coils were found effective in occluding small ductus [17–19]. Preformed nitinol snares may be used to improve delivery .
This report describes use of an extension of a larger system of retrievable coils already on clinical trial in older children and adults . The device relies on the strong memory effect of certain metals (ANSI 301) to form biconical, double-disk coils whose outer rings in the aorta and pulmonary artery secure smaller rings inside the PDA, causing its mechanical and thrombotic closure. The aim of this study was to miniaturize and modify this system and to evaluate its practicability, efficacy and medium-term biocompatibility, utilizing a neonatal animal model of PDA with the size and fragility of human neonates in which ductal patency is secured either by stents  or by angioplasty .
1.1 Occlusion Device and Delivery System
The PDA occlusion device consists of 1) a “double-cone” spring coil of stainless steel (DIN 1.4310 ≈ ANSI 301) (wire strand diameter 0.015 mm [0.0045 in.], primary coil 0.46 mm [0.018 in.], reconfigured secondary diameter 4 to 6 mm, minimal inner diameter <1 mm, overall length reconfigured 5 to 8 mm [pfm, Cologne, Germany] [Fig. 1, D]); 2) a pusher system with a) a pusher wire (stainless steel coil wire, length 90 cm, Teflon-coated [Fig. 1, B], with a modified base to fit into a holdback mechanism of the safety handle) that is advanced over the b) core wire (Fig. 1, C) (stainless steel [Titanol], length 110 cm, diameter 0.23 mm [0.009 in.], modified tip to control the coils [two rills] and modified base to fit hold back mechanism of the safety handle; 3) a safety handle of stainless steel with an engraved metric scale, two safety mechanisms and one distal ring on its shaft (OccluGrip, pfm, Cologne, Germany); and 4) an introducing catheter (Fig. 1, A) of Teflon (60 cm long, diameter 3F size [1.0 mm], including tip marker (inner gold ring [Fig. 1, e]).
Loading the system. The coil is stretched and mounted on the distal end of the core wire. The proximal end of the core wire is screwed on to the distal safety mechanism of safety grip, the pusher wire is screwed on to the second safety mechanism, thereby allowing the pusher wire to be moved independently of the core wire or vice versa. Advancing the pusher wire or withdrawing the core wire will deploy the ductal coil from the tip of the core wire, allowing it to regain its original double-cone shape. To avoid unintentional final release of the occluding coil, the proximal ring is screwed on the grip at a distance from the safety mechanism that corresponds to the stretched length of the occluding coils less 1 cm. The whole system is then introduced through the delivery catheter in the manner of a conventional guide wire.
Delivering the PDA occlusion device. The tip of the delivery catheter is placed in the descending aorta across the PDA by means of right heart catheterization. Two or three rings of the occluding coil are freed from the core wire and extruded into the aorta, regaining their original shape and forming the distal, outer disk. The whole system is then withdrawn into the aortic ampulla of the duct, where additional loops are released. As the system is withdrawn further across the PDA into the pulmonary artery the final loops forming the proximal disk are released and, achieving a satisfactory positioning, the backup ring is released and the occlusion coil freed from the core wire. As long as the final portion of the coil is attached to the core wire (Fig. 1, f), the system in part or as a whole can be pulled back into the delivery catheter for repositioning.
1.2 Animal Studies
The piglet experiments were conducted according to the guidelines of the German Animal Protection Law and were approved by the state agency supervising animal experimentation. Catheterization of the piglets was performed as a sterile procedure under anesthesia with halothane (0.3% to 0.6%), nitrous oxide and barbiturates using monoplane fluoroscopy. An Ultramark 9 (ATL Technologies) color Doppler machine was used to acquire echocardiographic data. No piglet received antibiotic or antithrombotic agents outside the protocol described later. Before and after the investigations, the piglets were cared for by the sow in a joint pen with heat lamps.
Stented patent ductus arteriosus (stent group). Six newborn piglets (mixed breed), 0.5 to 2 days old and weighing 1,320 to 2,120 g, were anesthetized and artificially ventilated. Through a external jugular venous cutdown a 5F vascular sheath was mounted in the vein and a Berman angiographic balloon catheter (Arrow) was placed across the right ventricle and ductus arteriosus into the descending aorta. A balloon occlusion aortogram demonstrated size, shape and position of the ductus. Through an end-hole balloon catheter a 0.018 in. flexible guide wire was placed across the ductus in the descending aorta. The catheter was then exchanged for a coronary angioplasty catheter with a stent mounted (Palmaz coronary stent, Johnson & Johnson). Inflating the balloon to 5 atm released the stent in the PDA. If necessary, a second stent was placed to cover the full length of the PDA. All ducts were dilated to 4.5 mm. The catheter and wire were removed, and the jugular vein was ligated and the skin closed.
Coil delivery. Ten to 14 days later the piglets were again anesthetized and artificially ventilated. The patency of the stented duct was demonstrated and left atrial (LA)/aortic root (AO) ratio obtained by color Doppler echocardiography. Through a second cutdown ∼1 cm proximal to the one used for stent delivery, 4F sheaths were placed in the external jugular vein and the carotid artery. The location and size of the patent ductus were again demonstrated by aortogram. Through the venous route and the right side of the heart, a 4Fr end-hole delivery catheter (nylon or Teflon) was placed in the descending aorta and the device deployed to occlude the ductus as described before. The pusher wire consisted of stainless steel alone (n = 3), stainless steel plus Teflon coating (n = 1) or stainless steel plus Teflon and heparin coating (n = 2). Different dosages of sodium heparin were given before insertion of the occluding device: a) 1,000 IU heparin/kg body weight (n = 2); b) 100 IU/kg (n = 2); c) only heparinized flush solution (5 U/ml normal saline solution) (n = 4). An additional aortogram was performed 30 to 60 min after final placement of the device. The piglets were killed thereafter and the ductus with the attached aorta and main pulmonary artery (ductal block) were examined macroscopically. In the one piglet with a residual shunt the catheters were removed, the vessels were ligated and the skin was closed. Ten days later closure of the ductus was attempted again adding an additional coil as described before.
Patent ductus arteriosus created by angioplasty (angioplasty group). Eight neonatal piglets (Deutsche Landrasse) aged 3 to 30 h and weighing 1,400 to 1,980 g (median 1,530) were anesthetized and artificially ventilated. Through a 4F vascular sheath in the external jugular vein a pediatric valvuloplasty catheter (balloon diameter 5 mm, length 20 mm; Dr. Osypka GmbH, Grenzach, Germany) was passed over a guide wire through the right side of the heart across the ductus arteriosus. The ductus was dilated to 5 mm 3 times over 5 min with an interval of 5 min. An angiogram 20 min after the last dilation demonstrated ductal patency and dimensions. The valvuloplasty catheter was exchanged for a 3F end-hole Teflon catheter. The coil to occlude the duct was selected (coil diameter reconfigured = minimal ductal diameter plus 1 mm) and deployed as described earlier.
Ten minutes after final placement of the coil, an angiogram into the main pulmonary artery documented positioning of the coils. Apart from heparinized flush solution (5 U/ml normal saline solution), no other antithrombotic agents were used. The catheters and wires were removed, and the jugular vein was ligated and the skin closed. Approximately 1 h after final coil placement color Doppler echocardiography demonstrated complete ductal occlusion. The piglet was returned to the pen to be cared for by the sow.
Color Doppler echocardiography was repeated 2 weeks later (where applicable) to prove persistent occlusion of the duct and to search for possible flow disturbances in the pulmonary artery and descending aorta.
Two to 73 days (mean 40) after ductal closure a second left and right heart catheterization, including angiography, was performed by way of the jugular vein and common carotid artery under general anesthesia before the piglets were killed and the ductal block removed. For gross and microscopic examination the specimens were fixed in 10% formalin or glutaraldehyde. The aortic and pulmonary portions were scanned by electron microscopy, the middle portion prepared for light microscopy. To avoid damage to this section, the coils were carefully removed before embedding.
Patent ductus arteriosus secured by stents. In all six piglets echocardiography revealed ductal patency and an increased LA/AO ratio. Placement of the coils was possible in all animals. In one piglet, delivery of the device required temporary blockade of high ductal blood flow by a 4F balloon wedge catheter (Arrow) placed through the right side of the heart and at the same time serving as the delivery catheter. An aortogram obtained 1 h after proper placement showed only a minute residual shunt. In another piglet with a residual shunt (Piglet 53), the LA/AO ratio was decreased from 2.3 to 1.8, and a second coil placed 10 days later led to a minute residual shunt. In the remaining four of the six piglets the ductus was closed 30 to 60 min after placement of the coil, as assessed angiographically.
The uncoated stainless steel pusher could be easily slid over the core for up to 5 min, independent of systemic heparin sodium dosage (100 or 1,000 IU/kg). Teflon coating of the pusher wires extended the period of adequate mobility over the core wire to at least 20 min. No differences were found between the Teflon-only coating and the Teflon plus heparin coating. Further details are shown in Table 1.
Patent ductus arteriosus created by angioplasty. In all eight piglets dilation of the ductus was possible and produced persistent ductal patency. The minimal inner diameter was 3 mm (maximal 5 mm), and the overall length was 7 to 9 mm. In two piglets the control angiograms revealed paravascular contrast staining in the descending aorta, and the piglets were put back in their cage without coil implantation. Both recovered uneventfully and color Doppler-echocardiography revealed persistent patency of the ductus. In one (Piglet 82), the ductus was closed on day 10; in the other (Piglet 80) the PDA was small but was still open when the piglet entered a different experiment on day 28.
In all seven animals where attempted placement of the ductal occlusion device was possible. Color Doppler echocardiography revealed complete occlusion within 1 h. One animal (Piglet 85) had to be killed prematurely 48 h after coil placement because of diarrhea and feeding problems. Post-mortem examinations included bacteriologic assessment and revealed no signs of localized or generalized bacterial infection. In the other six piglets, color Doppler echocardiography 2 weeks after intervention did not show any residual shunt or turbulent flow in the aorta or pulmonary artery.
Sixteen to 73 days after PDA occlusion, the final angiograms confirmed complete closure of the ductus (Fig. 2). Macroscopic postmortem examination of the ductal orifices showed a variable degree of protrusion of the outer rings of the coils into the lumen of the aorta and pulmonary artery. Depending on the duration of implantation and the degree of protrusion, the coils were completely or partially covered with thin, shiny tissue (Fig. 3). Further details are summarized in Table 1B.
Scanning electron microscopy and histologic study. At higher magnification, most of the coils were seen to be covered by a monolayer of cells resembling endothelial cells (Fig. 4). As assessed 16, 53 and 73 days after implantation, endothelial coverage was more pronounced as the duration of implantation increased. However, the extent of coverage also depended on coil geometry; the more loops protruded into the vessel lumen, the longer it took to build endothelial coverage. Areas not covered by endothelium were clearly thrombogenic, as demonstrated in Fig. 4 (after 2 days of implantation).
A foreign body reaction (grading by the extent of histiocyte layers in the central ductal portion: 1 to 4 = mild; 5 to 10 = moderate; >10 = severe) was noticeable and correlated somewhat with the duration of implantation. There was no reaction after 2 days, a mild reaction after 16 days and a moderate to severe reaction after 73 days. In the piglet with the latter reaction, three additional spindle-shaped foreign bodies were detected in the center of the histiocytic reaction. They were not stained, doubly refractant and measured ∼0.1 × 0.01 mm.
To date, hemodynamically significant PDAs in term and preterm neonates are treated by reduction of fluid intake and administration of diuretic agents, followed by either intravenous infusion of indomethacin or surgical intervention (i.e., thoracotomy and ligation or clipping, or both). Recently, a new minimized invasive approach was introduced using videothoracoscopy for surgical closure . All of these procedures have specific side effects [1–5, 7], prompting our search for alternatives. In older children and adults, interventional PDA closure utilizing different devices has been widely used. The size of such devices limits their use in small neonates. The stepup from a 3F to 4F catheter increases the occupied vessel cross-sectional area by 75%, from 3F to 5F by 175%.
Functional results. Dilating the ductus by angioplasty proved to be as effective as the use of stents. The LA/AO ratio was increased echocardiographically, and in the angioplasty group the ductus stayed patent for at least 10 days in one piglet and for 28 days in another, as demonstrated by color Doppler echocardiography. The stented PDAs were tubular in shape and had a high velocity shunt. In one piglet a temporary balloon occlusion of the PDA was necessary to allow stable coil placement. In the same group, two residual shunts were detected, in one case the high dosage of heparin (1,000 IU/kg) may have contributed to this finding. However, shunt size was significantly smaller after coil placement in the stented PDAs. The angioplasty group was introduced to utilize an animal model with the size and fragility of newborns and to avoid coil-stent interaction in the histologic evaluation. The ductus was closed in all piglets 1 h after coil placement. Minimizing the use of heparin and not having to deal with the same extent of shunt flow may have contributed to the 100% success rate. Because of the small number of animals tested, the 95% confidence interval for failure extends to 43% .
Histopathologic examination. Using sterile procedures, we never found any signs of inflammation clinically, bacteriologically or histologically. Raster electron microscopy of coils 2 days after implantation showed thrombogenicity of the coil surface itself. The histologic examinations in the angioplasty group demonstrated coverage of the intraluminal portion of the coils with a monolayer of endothelial cells as early as 16 days after implantation. Foreign body reaction in the central portion of the ductus as assessed by the number of histiocytic cell layers was absent 2 days after implantation and increased over time.
Clinical implications. Minimizing the size of the introducing catheter is crucial for any interventional therapeutic approach in term or preterm neonates. Our device can be advanced through a 3F catheter by using a regular 0.018 in. guide wire. The ability to withdraw an inadequately placed coil occluder without major manipulations will further decrease the risks of interventional ductal closure in fragile newborns. The PDA in our animal model is longer and probably more tunnel-shaped than that in human neonates. But by selecting different lengths and diameters of reconfigured coils, one can adjust our device to the size and shape of different PDAs. Using the femoral vein in human neonates for a vascular approach will ease the procedure because the U turn in the right ventricle can be avoided, precision of manipulation in the ductus will improve and friction forces of the catheters are minimized. Using monoplane portable fluoroscopic equipment (as in our study) avoids the need to transport an unstable neonate to the catheterization laboratory.
Conclusions. The new miniature device demonstrated effective closure of PDAs in neonatal animal models of PDA. However, our small sample size limits detection of possible complications. Pathologic examination of portions of the coil exposed to the bloodstream showed coverage with a monolayer of endothelial cells. Coils within the PDA induced a histocytic foreign body reaction. The small size of the delivery system and the availability of retrievable coils of various sizes offers a very flexible and, in our animal model, safe system for potential use in small and fragile neonates with PDA.
We thank the Departments of Electronmicroscopy and Experimental Animal Research, Medical Faculty, Aachen University of Technology, for technical support and expertise.
A.1 Abbreviations and Acronyms
LA/AO = left atrial/aortic root
PDA = patent ductus arteriosus
↵1 Drs. Neuss and Redel own patents on aspects of the device described in this article and may receive royalties if and when it is marketed.
- Received January 8, 1996.
- Revision received April 3, 1996.
- Accepted May 7, 1996.
- THE AMERICAN COLLEGE OF CARDIOLOGY
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