Author + information
- Received June 27, 2016
- Revision received August 12, 2016
- Accepted September 8, 2016
- Published online December 12, 2016.
- Evan M. Zahn, MD∗ (, )
- Daniel Peck, MD,
- Alistair Phillips, MD,
- Phillip Nevin, RN,
- Kaylan Basaker, CVT,
- Charles Simmons, MD,
- Marion E. McRae, NP,
- Tracy Early, MA and
- Ruchira Garg, MD
- The Guerin Family Congenital Heart Program, The Heart Institute and Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California
- ↵∗Reprint requests and correspondence:
Dr. Evan M. Zahn, The Heart Institute, 127 S. San Vicente Boulevard, AHSP-Suite A3600, Los Angeles, California 90048.
Objectives The goal of this study was to describe early and midterm outcomes of extremely premature newborns (EPNs) who underwent transcatheter echocardiographically guided patent ductus arteriosus (PDA) closure.
Background Surgical ligation of PDA in EPNs confers significant risk for procedural morbidity and adverse long-term outcomes.
Methods The Amplatzer Vascular Plug II was used in all cases. Post-ligation syndrome was defined using previously published parameters. Patients were followed at pre-specified intervals, and prospectively collected data were reviewed.
Results Transcatheter closure was attempted in 24 EPNs (mean procedural age 30 days [range 5 to 80 days], mean procedural weight 1,249 g [range 755 to 2,380 g]) and was successful in 88%. The 3 procedural failures were related to the development of left pulmonary artery (LPA) stenosis caused by the device, and all devices were removed uneventfully. Complications included 2 instances of device malposition, resolved with device repositioning, and 1 instance of LPA stenosis, requiring an LPA stent. There were no procedural deaths, cases of post-ligation syndrome, residual PDA, or device embolization. Survival to discharge was 96% (23 of 24), with a single late death unrelated to the procedure. After a median follow-up period of 11.1 months, all patients were alive and well, with no residual PDA or evidence of LPA or aortic coarctation.
Conclusions This newly described technique can be performed safely with a high success rate and minimal procedural morbidity in EPNs. Early and midterm follow-up is encouraging. Future efforts should be directed toward developing specific devices for this unique application.
Patent ductus arteriosus (PDA) is the most common cardiovascular abnormality in extremely premature newborns (EPNs). The resultant left-to-right shunt has been associated with necrotizing enterocolitis, chronic respiratory disease, pulmonary hemorrhage, intraventricular hemorrhage, and death (1,2).
Treatment with cyclooxygenase inhibitors induces ductal constriction and closure in some EPNs, but this therapy is successful only in an estimated 50% to 60% of cases and carries a risk for pharmacological complications such as renal insufficiency and bleeding (3). When medical therapy fails or is contraindicated, surgical ligation may be performed, but surgery has been associated with significant procedural complications, including early cardiorespiratory instability (so called post ligation syndrome [PLS]), pneumothorax, intraoperative bleeding, phrenic nerve palsy, wound infection, and vocal cord paralysis (4–6). More recently, concerns have arisen that surgical ligation may be an independent risk factor for poor neurodevelopmental outcome and chronic respiratory disease (7,8).
Although transcatheter treatment of PDA in children and adults is commonplace (9,10), this therapy has not been widely applied to EPNs for a variety of reasons, including concerns regarding vascular access, overall patient fragility, concerns regarding contrast administration, and lack of a suitable device.
We previously described a new transcatheter technique for the treatment of PDA in this population (11) and herein describe our institutional experience with procedural outcomes, periprocedural events, and early and midterm follow-up.
EPNs with hemodynamically significant PDA were treated initially with 2 doses of indomethacin unless contraindicated. If this therapy failed to result in PDA closure, either conservative expectant medical management and/or PDA closure was pursued, on the basis of the discretion of the neonatology team. If closure was requested, infants were evaluated to determine candidacy for transcatheter closure. Ductal morphology was evaluated with multiplanar transthoracic echocardiographic imaging, and only those infants with ductal length >6 mm were considered candidates. No infant was excluded on the basis of body weight, age, illness severity, or ductal diameter. The Cedars-Sinai Institutional Review Board approved this study.
We have previously described this technique (11), and procedural details are depicted in Figure 1. Briefly, femoral venous access was used exclusively following the first case, which was performed from a retrograde arterial approach (12). For all remaining cases, a 0.014-inch coronary guidewire was advanced under fluoroscopic guidance through the right heart, across the PDA, and into an ileac artery. A 4-F hydrophilic sheath (Flexor, Cook Medical, Bloomington, Indiana) was advanced over the wire into the descending aorta, and an Amplatzer Vascular Plug II (St. Jude Medical, Minneapolis, Minnesota) was implanted through the sheath using a combination of fluoroscopic and echocardiographic guidance. This device is a self-expanding nitinol cylindrical mesh with 3 equal-diameter disks and an unconstrained length of 6 mm. Devices were chosen so that the disk diameter was at least 1 mm greater than the narrowest diameter of the PDA. Prior to release from the delivery cable, the left pulmonary artery (LPA) and descending aorta were carefully evaluated by echocardiography with 2-dimensional imaging and color and spectral Doppler and compared with the pre-procedural imaging. If vascular stenosis related to the device was observed, as defined by a maximal instantaneous gradient >15 mm Hg or an “obstructed” pattern with persistent antegrade diastolic flow, the device was recaptured and either repositioned or removed and replaced with another device of a different size. If on repeat attempt(s) there was persistent stenosis, the patient was converted to surgical ligation. Following release of the device, echocardiographic evaluation of all pertinent structures was repeated. Patients were administered a single intraprocedural and 2 post-procedural doses of antibiotics (cefazolin 25 mg/kg) and a single procedural dose of intravenous heparin (100 U/kg) unless contraindicated. Over the study period the procedure evolved from being performed in the catheterization suite to being performed at the bedside in the neonatal intensive care unit with the assistance of a mobile mini C-arm fluoroscopy unit (Fluoroscan InSight-FD mini, Hologic, Marlborough, Massachusetts) and neonatal procedural bed (Rainbow Flex, NeoForce Group, Ivyland, Pennsylvania) that accommodates the fluoroscopic equipment.
Assessment of PLS
PLS was defined as diminished left ventricular myocardial performance associated with significant alteration in cardiorespiratory stability and/or increased need for vasopressor support (13). Myocardial performance was assessed via transthoracic echocardiography (left ventricular ejection fraction [LVEF]) prior to intervention, within 12 h of intervention, and prior to discharge. Clinical indexes of cardiorespiratory stability (heart rate, blood pressure, systemic oxygen saturation) and the need for increased vasopressor and/or respiratory support were reviewed before and 1, 4, 8, 12, and 24 h following intervention.
Follow-up echocardiography was performed at pre-specified intervals: within 12 h, 1 week, 1 month, 3 months, 6 months, 12 months, and then yearly after the procedure.
Continuous variables are reported as mean values. To evaluate the possibility that the procedure resulted in LPA and/or descending aortic obstruction, paired Student t tests were used to compare pre-procedural, post-procedural, and latest Doppler velocities across these areas. To examine for the possibility that the procedure resulted in PLS, systolic and mean blood pressure, heart rate, and LVEF were measured at various pre-defined scheduled intervals and compared with pre-procedural values using a mixed-effect model in which pre-procedural values were used as the reference value. A p value < 0.05 was considered to indicate statistical significance.
Study demographics are presented in Table 1. A total of 27 severely EPNs (mean birth weight 912 g [range 440 to 2,480 g], mean birth age 27 weeks [range 24 to 32 weeks]) with hemodynamically significant PDA were referred for PDA closure (March 2013 to February 2015). Three patients were not candidates for catheter closure on the basis of ductal length <6 mm. Mean age and weight at the time of the procedure was 30 days (range 5 to 80 days) and 1,249 g (range 755 to 2,240 g), respectively. Fourteen patients had received previous trials of indomethacin, 1 was receiving inotropic support, 19 (79%) required mechanical ventilation, and 1 required nasal intermittent positive pressure ventilation. All patients had type F (fetal type) tubular PDA with a mean minimal diameter of 2.3 mm (range 1.3 to 3.5 mm) and length of 7.6 mm (range 5.8 to 10.6 mm) (14).
Procedural outcomes are reported in Table 2. Procedures were initially performed in the catheterization laboratory (n = 19), but the last 5 cases were performed at the bedside. All PDAs were closed using the Amplatzer Vascular Plug II (3 mm, n = 8; 4 mm, n = 10; 6 mm, n = 3). Mean procedural and fluoroscopy times were 49 min (range 21 to 151 min) and 10 min (range 0 to 28 min), respectively. Procedures were performed using only femoral venous access with 2 exceptions: Patient #1, who underwent retrograde device implantation via the femoral artery, and Patient #8, who required device manipulation via the artery following release (see the following discussion). Devices were successfully implanted and left in place in 21 of 24 patients (88%). All patients had complete ductal closure by color flow Doppler prior to completion of the procedure. All 3 procedural failures (Patients #9, #18, and #24) had devices implanted and removed prior to release from the delivery cable because of concern about device encroachment upon the LPA (Figure 2). All 3 underwent uncomplicated surgical ligation immediately following the catheter procedure.
There were no procedure-related blood transfusions, bloodstream infections, limb ischemia or vascular insufficiency, device embolizations, or deaths. One infant (Patient #17) died 5 months following the procedure of events believed to be unrelated to PDA closure.
Effect of closure on neighboring vessels
For the group as a whole Doppler flow velocity did not increase in the LPA following device implantation (mean LPA flow velocity pre-procedure 1.4 m/s vs. post-procedure 1.5 m/s; p = 0.20) and fell to lower than pre-procedural values during follow-up (mean LPA flow velocity pre-procedure 1.4 m/s vs. latest 1.1 m/s; p = 0.02). The single exception was Patient #23, who developed echocardiographic evidence of moderate LPA stenosis early in follow-up and subsequently required pulmonary artery stent implantation (see the following discussion).
Doppler flow velocities in the descending aorta decreased significantly following PDA occlusion (mean descending aortic flow velocity pre-procedure 1.6 m/s vs. post-procedure 1.2 m/s; p = 0.0001). Two patients (Patients #4 and #8) experienced transient moderate descending aortic obstruction immediately following device release and acute increases in Doppler flow velocity. Both patients underwent successful manipulation of the device using a gooseneck snare, with no obvious ill effects, and complete resolution of aortic obstruction and successful device PDA closure. In 1 of these cases noted previously (Patient #8), arterial access was used to manipulate the device simultaneously from the pulmonic and aortic end.
Immediately after device closure, mean LVEF for the group decreased (pre-procedure 69% vs. post-procedure 63%; p = 0.004) but remained in the normal range, with the exception of 3 patients (Patients #2, #5, and #8), 2 of whom recovered normal LVEF prior to discharge (Figure 3). Neither of these patients had signs or symptoms of low–cardiac output syndrome or heart failure. In Patient #8, who required extensive device repositioning following release, significant septal dyskinesia was noted following the procedure. Although there was no notable change in blood pressure, heart rate, or oxygen requirement, the baby required reintubation and mechanical ventilation for 3 days following the procedure. Although at the time of discharge LVEF was still below normal (48%), it normalized in follow-up.
For the group as a whole, average heart rate increased early (1 to 4 h) post-procedure (pre-procedure 161 beats/min vs. post-procedure 173 beats/min; p = 0.0005), returning to pre-procedural levels by 24 h. No significant changes in systolic and mean blood pressure, oxygen requirement, or inotropic requirement were observed in any patient.
Twenty-three patients (96%) survived to discharge. After a median follow-up period of 11.1 months (range 4.6 to 30.3 months) no patient had residual or recurrent PDA shunt flow. One patient noted previously (Patient #23) developed early LPA stenosis requiring pulmonary artery stent implantation at 3 months of age. At catheterization at 12 months of age, right ventricular pressure was normal, and there was a 10 mm Hg gradient to the distal LPA, which disappeared once the stent was further expanded (from 4 to 7 mm in diameter). No other patient in the series had evidence of progressive LPA or aortic obstruction during follow-up.
LVEFs remained normal in all patients, and no patient had clinical evidence of lower extremity vascular insufficiency.
Although PDA is the most common cardiovascular lesion in EPNs and has been associated with a wide variety of important cardiac and noncardiac morbidities and even mortality (15–19), the treatment strategy for this lesion remains controversial (20). Current therapeutic options, particularly surgical ligation, have unacceptable morbidity, and surgical ligation may actually worsen long-term outcomes, including increasing the risk for bronchopulmonary dysplasia, retinopathy of prematurity, and neurosensory impairment (7,8). These concerns have resulted in a trend toward avoidance of definitive treatment and a movement toward a so-called permissive approach to PDA in EPNs, consisting of fluid restriction, diuretic agents, and increased positive end-expiratory pressure (21). Although several studies have reported outcomes no worse, and in some cases better, than with surgical ligation (22,23), more recent studies have associated this approach with increased mortality and morbidity (19,24). The lack of an evidence-based ideal therapy for PDA in EPNs prompted our group to explore the possibility of performing transcatheter PDA closure in this population.
Although catheter-based PDA closure has been performed successfully for nearly 50 years (25) and has been shown to be among the most successful and safest interventions (26), this therapy has not been routinely offered to EPNs, because of concerns surrounding its safety and efficacy. Recently, however, some investigators have begun to explore this approach. Francis et al. (27) described 8 premature infants (median procedural weight 1100 g; range 930 to 1,800 g) who underwent successful transcatheter PDA closure using multiple coils and a combination of angiography and echocardiography to guide the procedure. Although these investigators reported successful closure in all 8 patients, on the basis of their experience they estimated that only 10% of their EPN population were candidates for this procedure, because of limitations of coil technology. Bentham et al. (12) subsequently described a retrograde arterial echocardiographically guided technique of PDA closure at the bedside in 3 premature newborns using a variety of devices. Although the approach was successful in all, the investigators noted the inherent risks of using femoral arterial access, including vascular insufficiency and limb loss. In addition, they noted that without the aid of fluoroscopy or venous access, device retrieval and/or manipulation would be quite difficult or impossible should a complication arise.
Based in part on these pioneering efforts, our group developed a novel method of echocardiographic transvenous PDA closure (11) designed specifically for this unique and challenging patient population. The advantages of our technique include the following: 1) minimal fluoroscopic exposure; 2) avoidance of arterial access and contrast media; and 3) the ability to perform the procedure at the bedside. Importantly, the use of real-time transthoracic echocardiographic guidance allows the team to accurately assess not only the adequacy of closure but also the possible development of LPA or descending aortic stenosis secondary to device malposition. Using this approach, our multidisciplinary team determined that 89% of our premature neonatal population (24 of 27) referred for PDA closure were reasonable candidates for catheter-based closure, 88% of whom (21 of 24) underwent successful procedures. Importantly, all 6 patients who did not receive devices were sent to surgery because of concerns relating to excessive device length and the potential for obstruction of LPA flow. Protrusion of a PDA device into the descending aorta and LPA stenosis are well-described complications following PDA closure in small children (28). The present study suggests that with careful real-time echocardiographic assessment before, during, and after device occlusion, this potential complication can be identified, minimized, and if discovered treated safely and effectively. Additionally, it is reassuring that in midterm follow-up, LPA Doppler velocities decreased, suggesting that LPA stenosis is unlikely to be a long-term concern in patients who do not exhibit this problem early. Access to a device that would be available in a variety of shorter lengths, particularly those <4 mm, would likely lead to an increase in patients who are suitable for this procedure, improve the success rate, and reduce complication rates. Such a device, the Amplatzer Duct Occluder II–Additional Sizes currently exists but is unavailable in the United States at this time (29). Advantages of this device include a variety of diameters and lengths that are more suitable for this population, a smaller delivery catheter rather than a long delivery sheath, and a softer delivery cable.
In this study, we also attempted to examine whether this new technique would be less likely than surgery to produce signs and symptoms of cardiorespiratory compromise, commonly referred to as PLS. Patients with PLS experience hemodynamic instability, increased need for inotropic support, and escalation of respiratory support in the 24 h immediately following PDA ligation. The etiology of PLS is not precisely known but likely includes the inability of the premature neonatal myocardium to tolerate acute increases in afterload, resulting in impaired left ventricular performance and pulmonary edema. It is also possible that mechanical manipulation of the left lung required during surgical ligation contributes to this clinical scenario. Infants undergoing surgery at <28 days of age seem to be at an increased risk for this complication (13,30). Clinical PLS was not observed in our study. Although there was echocardiographic evidence for diminished left ventricular systolic function following catheter-based PDA closure and virtually all patients had transient elevations in heart rate, significant changes in blood pressure, oxygen requirement, or need for increased inotropic support were not observed with the exception of a single patient who had a complicated procedure. This is particularly salient when one considers that our patient population was of a similar postnatal age (30 days vs. 18 days) and weight (1,249 g vs. 1,085 g) at the time of PDA closure compared with a high-risk group (<28 days of age) who underwent surgical ligation described by Teixeira et al. (13), in which the incidence of PLS was 27.6% and decreased systolic blood pressure and increased oxygen requirements were the norm. Recently it has been shown that earlier recognition and management of PLS may improve the post-operative course following PDA ligation in EPNs (30). We believe that our present study makes a case for evaluating the effect that catheter-based closure might have on the occurrence and severity of PLS as well.
This was a retrospective, single–treatment arm study with the usual biases of such investigations. Although standard criteria to determine which premature infants should undergo PDA closure do not currently exist, all study patients treated with catheter-based closure met criteria for surgical ligation at our institution. The present study design prevents any conclusions about how outcomes of a catheter-based PDA device closure strategy compare with medical or surgical therapy.
Transcatheter echocardiographically guided closure of PDA in EPNs can be performed with a high degree of success and an acceptable complication rate. Early follow-up suggests promising sustained results. Future efforts should be aimed at optimizing the availability of appropriate devices for this population and ultimately comparing the long-term outcomes of PDA device closure versus current treatment strategies in these patients.
WHAT IS KNOWN? PDA is the most common cardiac problem in premature newborns, accounting for significant morbidity and mortality. Current surgical and medical therapies are suboptimal.
WHAT IS NEW? We describe a new technique for performing echocardiographic guided, transvenous catheter-based closure of these defects in EPNs, eliminating the need for surgical ligation in a large percentage of patients.
WHAT IS NEXT? Devices designed specifically for this patient population are needed to improve technical results and minimize complications. Further studies designed to compare the long-term effect of this new procedure with standard medical and surgical therapies are needed.
This study was supported by a research grant from the Fashion Industries Guild. Dr. Zahn is a consultant and instructor for St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- extremely premature neonate
- left pulmonary artery
- left ventricular ejection fraction
- patent ductus arteriosus
- post-ligation syndrome
- Received June 27, 2016.
- Revision received August 12, 2016.
- Accepted September 8, 2016.
- 2016 American College of Cardiology Foundation
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