Transcatheter Ductus Arteriosus Stenting for Acute Pediatric Pulmonary Arterial Hypertension is Associated with Improved Right Ventricular Echocardiography Strain

Abstract

Background:

Interventional therapies for severe pulmonary arterial hypertension (PAH) can provide right ventricular (RV) decompression and preserve cardiac output. Transcatheter stent placement in a residual ductus arteriosus (PDA) is one potentially effective option in critically ill infants and young children with PAH. We sought to assess recovery of RV function by echocardiographic strain in infants and young children following PDA stenting for acute PAH.

Methods:

Retrospective review of patients <2 years old who underwent PDA stenting for acute PAH. Clinical data was abstracted from the electronic medical record. RV strain (both total and free wall components) was assessed from echocardiographic images at baseline and 3, 6 and 12 months post-intervention, as well as at last echocardiogram.

Results:

Nine patients underwent attempted ductal stenting for PAH. The median age at intervention was 38 days and median weight 3.7 kg. One-third (3of 9) of patients had PAH associated with a congenital diaphragmatic hernia. PDA stents were successfully deployed in eight patients. Mean RV total strain was −14.9 ± 5.6% at baseline and improved to −23.8 ± 2.2% at six months post-procedure (p<0.001). Mean free wall RV strain was −19.5 ± 5.4% at baseline and improved to −27.7 ± 4.1% at six months (p=0.002). Five patients survived to discharge, and four patients survived one year post-discharge.

Conclusions:

PDA stenting for severe, acute PAH can improve RV function as assessed by strain echocardiography. The quantitative improvement is more prominent in the first six months post-procedure and stabilizes thereafter.

Introduction

Pediatric pulmonary arterial hypertension (PAH) is a rare disorder, which can result in significant morbidity and mortality, especially in neonates and infants. The reported annual incidence of varied subtypes of PAH in the pediatric population ranges from 0.48 to 63.7 per 1,000,000 cases [1–3]. Ongoing challenges in the management of PAH include the severity with which it can present and its heterogeneous underlying etiologies, including congenital heart disease (CHD), developmental lung disease, genetic syndromes, and idiopathic disease; as well as congenital diaphragmatic hernia (CDH), a well described developmental entity associated with pulmonary hypoplasia. For acute PAH interventional therapies to decompress the right ventricle (RV) and maintain cardiac output in the setting of severely elevated pulmonary artery pressures including atrial septostomy, surgical, and transcatheter reverse Potts shunt have been described in the literature [4–8].

Treatment options for PAH in infants and young children may be limited due to physical size as well as critical illness. Utilization of a residual patent ductus arteriosus (PDA), which can be accessed by catheterization, may provide RV decompression without requiring surgical intervention. To date, reports of PDA stenting for PAH have been limited to small case series with variable patient populations, causes of PAH and outcomes [9–12].

Assessment of RV strain is a quantitative technique that can be used to assess RV function by echocardiography. With the development of normative values of RV strain, the degree of RV dysfunction can be described and charted over time to elucidate trends [13,14]. RV strain values have been demonstrated to be different in pediatric patients with both CHD-associated pulmonary hypertension (APAH) and idiopathic pulmonary hypertension (IPAH) [15]. In adult patients RV strain is associated with prediction of RV failure [16] and survival [17].

We aimed to describe the trajectory of RV function as assessed by RV strain after PDA stenting for PAH. We additionally aimed to characterize our PDA stenting experience based on patient characteristics, including underlying diagnosis, pre-procedural support, and catheterization, and outcomes, including survival, length of stay (LOS), and ongoing need for pulmonary vasodilator therapy.

Methods

Our study was approved by the Boston Children’s Hospital IRB and a waiver of consent was obtained per the retrospective nature of the study (IRB-P00042655).

We retrospectively identified all patients <2 years of age who underwent ductal stenting for relief of severe PAH from our institutional electronic database. We included all patients in our database who met these criteria without limitation on era. Patients were subsequently evaluated by thorough review of the electronic medical record to confirm that ductal stenting was performed for the indication of PAH. Those who underwent ductal stenting for ductal-dependent cyanotic CHD were excluded.

Patient demographics and clinical variables, including diagnoses, pulmonary vasodilator therapies, severity of critical illness (i.e. vasoactive inotrope (VIS) and inotrope scores (IS)), and secondary outcomes, including duration of mechanical ventilation, duration of extracorporeal membrane oxygenation (ECMO) use, LOS, and one-year survival, were abstracted from the medical record and institutional cardiac database. Hemodynamic, angiographic, and technical catheterization data were reviewed for each patient via catheterization reports and source angiograms.

Apical four chamber views were used to assess RV strain. Images were analyzed using QLAB version 15 (Philips Healthcare, Cambridge, MA) with the TomTec Autostrain RV package tool. The software automatically detected the endocardial border but manual adjustments were made as needed. Values for RV four chamber longitudinal strain and RV free wall longitudinal strain were recorded.

Statistical Analysis

Categorical variables are summarized with frequencies and percentages, and continuous variables with either median (range) or mean ± standard deviation. The trend of RV strain measurements in the months following intervention was estimated using a linear mixed model to account for measurements over time within the same patient. Piecewise continuous models which allow the slope to change in different time periods were considered. Analyses were performed in Stata version 16 (StataCorp, College Station, TX).

Results

Nine patients were identified who met inclusion criteria. Table 1 demonstrates patient characteristics prior to catheterization. The median age at admission was 6 days (0, 571) and median weight 3.5 kg (1.6, 9.5). One-third of patients had idiopathic pulmonary hypertension while one-third of patients had a primary diagnosis of CDH. Five patients were treated with pulmonary vasodilator pharmacotherapy prior to catheterization: two received enteral agents (sildenafil n=2), two received intravenous agents (epoprostenol n=1, treprostinil n=1) and one received both (treprostinil and sildenafil). There was a range of qualitative RV function by echocardiogram prior to catheterization, from normal to severe dysfunction. Table 2 provides additional patient descriptors.

Table 1.

Patient Characteristics

Diagnosis  Idiopathic  CDH  Other	3 (33%) 3 (33%) 3 (33%)
Admission weight (kg)	3.5 (1.6, 9.5)
Admission age (days)	6 (0, 571)
Intubation prior to catheterization	7 (78%)
iNO prior to catheterization	7 (78%)
ECMO prior to catheterization	7 (78%)
VIS  VIS for patients on inotropes, n=4	0 (0, 15) 9.75 (5, 15)
IS  IS for patients on inotropes, n=4	0 (0, 10) 6 (5, 10)
IV PH meds prior to catheterization	3 (33%)
Enteral PH meds prior to catheterization	3 (33%)
Degree of RV dysfunction prior to catheterization  Normal  Mild/borderline  Mild to moderate  Moderate  Moderate to severe	1 (11%) 2 (22%) 1 (11%) 3 (22%) 2 (22%)

Values shown are number (percent) or median (range)

Abbreviations: iNO-inhaled nitric oxide, VIS-vasoactive inotrope score, IS-inotrope score ECMO-extracorporeal membranous oxygenation, IV-intravenous, PH-pulmonary hypertension, RV-right ventricle

Table 2.

Patient Descriptors

Synopsis	Genetic Diagnosis	Survival to discharge (Y/N)	Medications at discharge
1 month-old initially found to have pulmonary hypertension and later found to have interstitial lung disease with a variant of unknown significance in ABACA3. Eventually admitted with hypoxia requiring ECMO at 4 years of age. During that admission underwent lung transplant at 4 years of age and died approximately 1 month after transplant.	Variant of unknown significance in ABACA3	Y	Treprostinil, sildenafil
19-month-old with an ASD and PDA found to have pulmonary hypertension. Underwent 3 subsequent stent redilations. Found after intervention to have SOX17 mutation. Remains on both oral and intravenous pulmonary vasodilators.	SOX17	Y	Treprostinil, tadalafil
21-day-old with idiopathic pulmonary hypertension. Developed coarctation at aortic end of PDA stent and required coarctectomy and PDA stent removal at 6 months old. Ultimately diagnosed with delayed fall in pulmonary vascular resistance. Remains alive with no pulmonary hypertension.		Y	Sildenafil
8-week-old CDH who had undergone repair with worsening pulmonary hypertension. Had additional comorbidities of 16p11.2 duplication, pulmonary sequestration and mild coarctation not requiring intervention. Was subsequently on subcutaneous treprostinil but weaned off. Deceased 3-years post-catheterization, cause unknown.	16p11.2 duplication	Y	Treprostinil, sildenafil
1-month-old with repaired CDH. Had additional comorbidity of imperforate anus and required a colostomy. Care redirected at 7 weeks of age after failed ventilatory strategies.		N
2-week-old who underwent PDA stenting in setting of pulmonary hypertension with unclear etiology. While on ECMO suffered intracerebral hemorrhage and care redirected. Later found to have alveolar capillary dysplasia, FOX and fillamin mutation.	FOX and filamin mutation	N
6-week-old who presented with pulmonary hypertension of unclear etiology. Found later to have pulmonary interstitial glycogenosis. Developed pulmonary overcirculation after treatment with pulmonary vasodilators and required closure of PDA via transcatheter approach. Remains inpatient on intravenous treprostinil.
3-week old with CDH and pulmonary hypertension that underwent stenting. Discharged at 3 months of age on no pulmonary vasodilators.		Y	No medications
1-month-old with idiopathic pulmonary hypertension. Developed ECPR arrest in catheterization laboratory during attempt to stent PDA. Care withdrawn soon thereafter in ICU.		N

Table 3 demonstrates patient characteristics and procedural data related to the catheterization. The median age at catheterization was 38 days (14, 571) and median weight 3.7 kg (3.0, 9.5). Four patients underwent catheterization for the primary indication of PDA stenting. Among the remaining five patients, the decision to stent the PDA was made after hemodynamic and angiographic assessment. Pre-intervention hemodynamics were limited due to the tenuous nature of patients; available hemodynamic data are presented in Online Resource 1. Two PDAs were atretic; one was successfully recanalized while the other could not be. For those that were patent, median minimum PDA diameter was 0.69 mm. PDA stents were successfully placed in 8 patients. All patients received bare metal stents. The median stent diameter was 3.0 mm (2.5, 4.0) and length 15.5 mm (8.0, 18.0). Online Resource 2 demonstrates limited hemodynamic data post-stenting.

Table 3.

Catheterization Data

Age (days)	38 (14, 571)
Weight (kg)	3.7 (3.0, 9.5)
Primary indication for cath  Planned PDA stenting  Hemodynamics/other testing	4 (44%) 5 (56%)
PDA minimum diameter (mm) (n=7a)	0.69 (0.44, 1.64)
Stent diameter (mm) (n=8b)	3.0 (2.5, 4.0)
Stent length (mm) (n=8b)	15.5 (8, 18)
Post intervention duct diameter (mm) (n=8b)	3.2 (2.4, 4.0)
Post intervention mean PA pressure (mmHg) (n=7c)	62 (25, 69)

Values shown are number (percent) or median (range)

Abbreviations: PDA-patent ductus arteriosus, PA-pulmonary artery

^aTwo patients with atretic PDAs

^bUnable to place stent in one patient

^cPost-intervention PA pressure not obtained in patient in whom unable to place PDA stent and one additional patient

RV strain was performed at baseline prior to intervention (n=9), three months (n=6), six months (n=5), and one year (n=4) post-intervention as well as at last the most recent follow-up echocardiogram (n=4). Individual strain values over the first 12 post-intervention months are demonstrated in Figures 1a and 1b. There was a mean improvement in total RV strain from a baseline of −14.9% to −23.8% at six months and −22.3% at one year post-intervention. RV free wall strain demonstrated similar improvement with a baseline mean of −19.5%, improving to −27.7% at six months and −26.0% at one year. Over the first six post-procedure months, the slope of strain improvement was −1.4% per month for total RV strain (p<0.001) and −1.3% per month for RV free wall strain (p=0.002). The improvement in strain plateaued between six months and one year post-procedure with one year total strain ranging

Fig. 1a. Temporal Changes in RV Strain.

Total RV strain from baseline to 12-months post-intervention.

Slope from baseline to 6 months (defined as change in total RV strain for each 1 month increase since intervention) −1.4% per month.

Fig. 1b. Temporal Changes in RV Strain.

Free wall RV strain from baseline to 12-months post-intervention.

Slope from baseline to 6 months −1.3% per month.

−21.1% to −24.4% and free wall −23.2% to −32.4%. Four patients had additional measurements at latest follow-up with a mean total RV strain of −22.8% and free wall −27.5%, respectively. Only two patients had qualitative RV dysfunction post-procedure.

Of the patients in whom stenting was attempted, there were two catheterization-related complications. One patient had an atretic PDA through which a wire traversed into the pericardium and extraluminally during attempts to probe for patency. This patient developed significant hypoxia that improved with patent foramen ovale occlusion but led to impaired cardiac output and ultimately cardiopulmonary arrest with subsequent cannulation to venoarterial ECMO. Her case was further complicated by descending aortic and iliac thrombi. This patient died while on ECMO two days later. An additional patient suffered transient lower-extremity pulse loss that resolved with <24 hours anticoagulation.

Outcomes data for this cohort can be found in Table 4. Median post-catheterization durations of mechanical ventilation and ECMO were 7 days (2, 17) and 4 days (2, 9), respectively. The rate of survival to hospital discharge was 62.5% (5/8), excluding one patient who remains hospitalized at the time of analysis. Of the 7 patients who had one year between catheterization date and analysis, 4 patients (57%) survived to one-year follow-up. Four patients were discharged with ongoing pulmonary vasodilator pharmacotherapy. Of the five discharged patients, 80% (4/5) were prescribed oral pulmonary vasodilators (sildenafil n=3, tadalafil n=1), 60% (3/5) were prescribed treprostinil (ranging in doses from 4–70 ng/kg/min), and 80% (4/5) were receiving continued oxygen therapy. One patient with CDH was discharged with no pulmonary vasodilator therapy. One patient ultimately underwent lung transplantation and subsequently died approximately one month after transplantation.

Table 4.

Outcomes

Ventilator (days) (n=8a)	20 (2, 62)
Ventilator post cath (days) (n=8a)	7 (2, 17)
ECMO duration post cath (days) (n=6b)	4 (2, 9)
ICU LOS (days) (n=8c)	28 (1, 104)
Hospital LOS (days) (n=8c)	44 (17, 134)
Survival to discharge (n=8c)	5 (63%)
IV PH meds at discharge (n=5d)	3 (60%)
Oral PH meds at discharge (n=5d)	4 (80%)
Survival to 1 year (n=7e)	4 (57%)

Values shown are number (percent) or median (range)

Abbreviations: ECMO-extracorporeal membranous oxygenation, ICU-intensive care unit, LOS-length of stay, IV-intravenous, PH-pulmonary hypertension

^aOne patient electively intubated and subsequently extubated in catheterization laboratory

^bOne patient supported with ECMO and decannulated prior to catheterization

^cOne patient remains hospitalized in the ICU at the time of manuscript preparation

^dFive patients survived to discharge

^eTwo patients <1 year post-procedure at time of manuscript preparation

Two patients underwent stent re-dilation at three months and five months, respectively, after initial stent placement. Additionally, there were two patients where the PDA stent was deemed no longer necessary. The first patient no longer had evidence of flow across the PDA by echocardiogram and developed a coarctation at the aortic end of the PDA stent, for which a surgical coarctectomy was performed. The PDA stent, which had become non-functional, was removed at the time of surgery. A second patient developed pulmonary over-circulation, in the setting of left-to-right flow via the PDA stent in conjunction with pulmonary vasodilator therapy (epoprostenol 40 ng/kg/min and sildenafil 1 mg/kg every 8 hours) and underwent catheter-based ductal stent occlusion 20 days after the initial procedure to diminish pulmonary over-circulation.

Discussion

In this retrospective case series of infants and young children with severe PAH, transcatheter PDA stenting for RV decompression was associated with an improvement in RV strain. Further, it was technically feasible with a low complication rate.

RV strain has been demonstrated to have significant differences in patients with PAH compared to normal subjects [15]. Among pediatric patients, specifically, RV strain values have been compared to controls and patients with pulmonary stenosis (as a comparative patient population with increased RV afterload). In patients with IPAH, RV free wall and septal strain have been demonstrated to be significantly reduced independent of the RV systolic pressure [18]. This information, combined with known normative values for RV strain [13,14], enables the ability to use RV strain for the evaluation of systolic function in the setting of PAH.

While PDA stenting for the acute treatment for PAH is not novel, our study demonstrates a sustained improvement in RV function as assessed by RV strain. RV strain values for both total RV strain and free wall RV strain improved significantly in our cohort, most impressively in the first six months post-procedure. At one-year follow-up, mean strain values were largely unchanged. Our findings suggest that the most significant improvement occurs in the first six months, although, importantly, is sustained one year after the procedure and beyond. These findings provide preliminary guidance regarding the degree, timing and duration of RV improvement after PDA stenting for PAH combined with medical therapy.

The utility of RV strain analysis in PAH has been further explored in the adult studies. RV strain values have correlated with functional status, 6-minute-walk distance, pro-B natriuretic peptide (pro-BNP) levels, pulmonary vascular resistance, and pulmonary artery (PA) systolic pressure [17,19]. Fine et al found a 1.46 higher risk of death per 6.7% decline in RV strain [17]. Hardegree et al demonstrated an improvement in RV strain after treatment for PAH and that persistence or progressive worsening of RV strain after treatment was associated with worsening functional class, higher mean PA pressure, increased diuretic use and worse survival [20]. These findings suggest value in the utilization of RV strain as a surrogate of effective PAH therapy in adults and may prove to similarly be important in the evaluation of pediatric PAH in the near future.

There was one severe complication in a patient in whom it was attempted to evaluate for patency of an atretic ductus, resulting in cardiopulmonary arrest, ECPR and eventually death. This highlights that anticipatory planning, including availability of personnel and resources (e.g. mechanical circulatory support), is necessary in this critically ill population. In our cohort, this patient represented one of two in whom the ductus was atretic. In the other patient it was successfully recanalized and stented. This highlights that even if a PDA is not seen by echocardiogram, it may still be possible to proceed with the procedure but requires caution in this unstable population.

The use of a PDA stent creates similar physiology to the reverse Potts shunt, which has been more extensively studied in larger series though typically in older patients. The International Potts Registry reported in aggregate 26 patients, including four from our cohort, who underwent PDA stenting with a median age of 3.5 years [21]. Of the 110 patients included in the registry, the freedom from lung transplant or death was 77% at one year and 58% at five years. Those who survived to discharge had improved functional class, B natriuretic peptide (BNP) and 6-minute walk distances. With regard specifically to PDA stenting for PAH, small case series have demonstrated findings similar to ours including improved qualitative function and potential need for future closure [9,10]. Previous literature has additionally described techniques for the creation of the transcatheter Potts shunt with perforation of the great vessels through percutaneous techniques [6,22]. In both of these case series, the youngest patient was 5.9 years-old. This is in contrast to our patients who were a median of 38 days-old with a median weight of 3.7 kg.

One-third of the patients in our cohort were patients with CDH, in whom PAH can be difficult to manage and ECMO may be utilized to allow postnatal recovery. All three of our patients with CDH were cannulated to ECMO prior to their PDA stenting and two survived to discharge. In patients with CDH, echocardiographic evidence of PAH at two weeks of age has been associated with an increased use of ECMO, death and increased ventilator days [23]. The ability to use the PDA in this diagnosis has been a subject of interest in the literature. Prostaglandin use in CDH has been associated with improved BNP and echocardiographic evidence of PAH [24] as well as increased ductal flow and decreased oxygen requirement [25]. However, conversely, in patients treated with high frequency oscillatory ventilation, the addition of prostaglandin to inhaled nitric oxide correlated with a delay in CDH repair and longer hospitalization with no difference in mortality [26]. It is important to note that the patients evaluated in these studies were likely the sickest children with CDH receiving advanced therapies, and given the proportion with severe CDH, sample sizes were small. While the utility of the ductus remains controversial, the use of PDA stenting may allow weaning from ECMO to avoid related complications, discontinuation of prostaglandin, and mitigate the risk of RV failure.

The major limitation to our study was our small sample size, specifically nine patients who underwent attempted PDA stenting and four with one year follow-up echocardiograms for RV strain assessment. While this limits the generalizability of our results, our study still provides important insight regarding the potential risk-benefit profile of PDA stenting in this high-risk population of critically ill young children with PAH. We are unable to comment on the potential benefits in cohorts of children with less severe illness. With regard to strain measurement, although a high frame rate is suggested to assess strain [27–29], ideal high frame rate images were not always available due to the retrospective nature of this study. In these instances, we utilized the available images at a rate of 30 frames per second. Within this cohort we captured idiopathic PAH, CDH, and developmental lung disease, demonstrating the feasibility for multiple etiologies to PAH. Further research is needed to identify the ideal patient population suitable for ductal stenting as well as the optimal timing, although we suspect various PAH subpopulations are likely to have sustained improvement in RV function.

Conclusion

In infants and young children, ductal stenting for acute, severe, refractory PAH can be considered as a salvage therapy and in this series of patients is associated with improved RV function as assessed by RV strain. Future studies will be needed to identify the optimal candidates for this procedure.