Margin between success and failure of PDA stenting for duct-dependent pulmonary circulation.

OBJECTIVES: Percutaneous patent ductus arteriosus (PDA) stenting is a therapeutic modality in patients with duct-dependent pulmonary circulation with reported success rates from 80-100%. The current study aims to assess the outcome and the indicators of success for PDA stenting in different ductal morphologies using various approaches.
METHODS: A prospective cohort study from a single tertiary center presented from January 2018 to December 2019 that included 96 consecutive infants with ductal-dependent pulmonary circulation and palliated with PDA stenting. Patients were divided according to PDA origin into 4 groups: Group 1: PDA from proximal descending aorta, Group 2: from undersurface of aortic arch, Group 3: opposite the subclavian artery, Group 4: opposite the innominate/brachiocephalic artery.
RESULTS: The median age of patients was 22 days and median weight was 3 kg. The procedure was successful in 78 patients (81.25%). PDA was tortuous in 70 out of 96 patients. Femoral artery was the preferred approach in Group 1 (63/67), while axillary artery access was preferred in the other groups (6/11 in Group 2, 11/17 in Group 3, 1/1 in Group 4, P <0.0001). The main cause of procedural failure was inadequate parked coronary wire inside one of the branch of pulmonary arteries (14 cases; 77.7%), while 2 cases (11.1%) were complicated by acute stent thrombosis, and another 2 cases with stent dislodgment. Other procedural complications comprised femoral artery thrombosis in 7 cases (7.2%). Patients with straight PDA, younger age at procedure and who had larger PDA at pulmonary end had higher odds for success (OR = 8.01, 2.94, 7.40, CI = 1.011-63.68, 0.960-0.99, 1.172-7.40,respectively, P = 0.048, 0.031,0.022 respectively).
CONCLUSIONS: The approach for PDA stenting and hence the outcome is markedly determined by the PDA origin and morphology. Patients with straight PDA, younger age at procedure and those who had relatively larger PDA at the pulmonary end had better opportunity for successful procedure.

Introduction

Cyanotic congenital heart diseases with duct-dependent pulmonary circulation are considered neonatal emergencies that need immediate intervention. PDA stenting has emerged as a preferred method for palliation: to maintain adequate oxygen saturation and to promote pulmonary vascular growth. Newer techniques and tools along with improving operators skills have all improved the outcomes in the current era [1-8]. The variations in ductal origin and morphology may be an obstacle for the operator that necessitate alternative approaches other than the femoral artery [9-11]. Little is known about the outcome after PDA stenting in neonates and infants with duct-dependent cyanotic congenital heart disease using different approaches. This study aimed to evaluate the outcome and the indicators of the success for the ductal stenting in various PDA morphology and origin using different vascular approaches.

Patients and methods

A prospective cohort study that included all patients with duct-dependent pulmonary circulation treated by ductal stenting at Cairo University Specialized Pediatric Hospital from January 2018 till December 2019. Patients with untreated sepsis or coagulopathies were excluded. The study was approved from the Faculty of medicine, Cairo University ethical committee. Informed consents were obtained from the patient’s legal guardian for the procedure and the utilization of data. High risk written consent was taken from the guardian of each patient before the procedure according to the institutional rules. Patients and the public were not involved in the study design, analysis, interpretation and writing of the study.

Data were collected in an excel sheet including clinical data (age, body weight and oxygen saturation); echocardiographic data (cardiac anatomical diagnosis, PDA morphology (origin, shape and size); catheterization data (vascular access, description of the PDA [origin, morphology and diameter at both pulmonary and aortic ends], size of the pulmonary arteries, diameter, length and the type of the stent used, fluoroscopy time, radiation time, related complications and added interventions in the same setting). Echocardiographic studies were performed using a 6 MHZ probe of GE Vivid E 5 echo machine (Vingmed Ultrasound AS, Horten, Norway) and cardiac catheterizations were performed using a Philips Allura Xper FD10 catheterization laboratory (Philips North America Corporation, Cambridge MA, USA). Procedural details: all procedures were performed under general anaesthesia, and femoral arterial 4F accesses were obtained followed by IV unfractionated heparin 100 IU/kg bolus plus prophylactic antibiotic. Aortograms in the frontal and lateral projections using pig-tail catheters to identify the ductal origin, morphology, length and diameters at the pulmonary end, and the pulmonary arterial branch anatomy. According to the ductal origin, the patients were divided into: group 1 the PDA arises from the proximal descending aorta; group 2 from the undersurface of aortic arch; group 3 opposite to the left subclavian artery; and group 4 opposite to the innominate/brachiocephalic artery [Fig 1A–1H]. Based on the angiogram, the approach was decided, i.e. whether to proceed via the femoral arterial access or to convert to an alternate axillary, carotid or femoral vein access. The ductus was accessed via a cut pig-tail or Judkins right [JR] catheter, and crossed with 0.014” percutaneous transluminal coronary angioplasty [PTCA] wire [middle support weight guide wire, Boston Scientific, USA] that was parked in one of the branch pulmonary arteries distally. Stents used were pre-mounted bare metal stents [architect, Life Vascular Device Biotech, Barcelona, Spain] or drug-eluting coronary stents [Monorail, Everolimus-Eluting Platinum Chromium, Boston Scientific, USA]. Stent diameter was chosen with respect to the weight of the patient, minimal PDA diameter, and branch pulmonary arteries. Length of stent was chosen to cover the entire length of the duct with proximal end into aorta and distal end into branch PA. In case of branch pulmonary stenosis, the stents aimed to reach distal to the stenosis. The selected coronary stent was tracked over PTCA wire and centered across the PDA. After confirming the position, stent was deployed using the initial nominal pressure then redilated for better apposition. Balloon was then removed after deployment keeping the wire in situ. Repeat angiograms were done to check the stent position and flow to branch pulmonary arteries. After achieving satisfactory results, wire was removed. Post-procedure details: All the patients were transferred to ICU and heparin infusion was maintained for at least for 24–48 hours with monitoring partial prothrombin time to be 2–3 times of normal. Acetylsalicylic acid 5mg/kg/day was initiated when oral feeding was established and overlapped for 12 hours, and continued until undergoing second-stage palliation or repair. Procedural success of PDA stenting was defined as the implantation of a well-seated stent, good flow for both pulmonary arteries and stable SpO2 above 75% and a hemodynamically-stable patient.

Fig 1

Angiography done during cardiac catheterization showing various PDA origins and morphology before and after ductal stenting.

A-B: Group 1 with PDA arises from the proximal descending aorta, C-D: Group 2 with PDA arises from the undersurface of aortic arch, E-F: Group 3 with PDA opposite the left subclavian artery, G-H: Group 4 with PDA opposite the innominate/Brachiocephalic trunk.

Follow-up

Patients were followed during visits by pulse oximetry to assess oxygen saturation, by echocardiography to evaluate stent patency, size of the pulmonary arteries and neointimal proliferation within the stent. Multidetector computed tomography [MDCT] was performed whenever oxygen saturation falls beneath 75%, or prior to planned surgical intervention for preoperative evaluation of the stent patency and the pulmonary arterial growth.

Statistical analysis

Statistical analysis was performed using SPSS Version 20 software [IBM, Armonk, New York] and Med Calc for Windows, version 15.0 [Med Calc Software, Ostend, Belgium]. Numerical data were expressed as median and interquartile range [25th -75th percentiles] while categorical data were expressed as numbers or numbers and percentages. Comparisons between groups were calculated using non-parametric Kruskal Wallis, Mann-Whitney and Wilcoxon signed-rank tests for numerical data, while χ2 tests were used for comparison between groups for categorical data. Logistic regression was performed for evaluation of outcome predictors. Statistical significance was considered if P-values <0.05.

Results

We attempted a total of 96 cases for PDA stenting during the study period: their median age was 22 days [ranging from 2 to 120 days], median body weight was 3.05 kg [2.2 to 3.5 kg], and mean length was 50 cm [47 to 52 cm] and 66 [68.8%] were males [Table 1]. Twelve (12.5% of cases) were smaller than 2.5 kg). Univentricular repair was planned for 55 cases (57.3%) and biventricular repair for 41 cases [42.7%]. Table 1 lists the different cardiac anomalies encountered and the additional procedures that were performed in 27 patients (28.1%). Based on ductal origin, group 1 comprised 67 patients (69.8%); group 2 was 11 patients (11.4%); group 3 was 17 patients (17.7%); and group 4 had only 1 patient (1%) that was not included in the statistical analysis being a single case. Ductal morphologies were either tortuous (70 patients, 72.9%) or straight (26 patients, 27.1%). Based on ductal origin and morphology, the approach to ductal stenting was the femoral artery in 72 patients (75%); axillary artery in 19 patients (19.8%); carotid artery in 3 patients (3.1%); and femoral vein in 2 patients (2.1%). It is of note that 2 cases that were initiated via the femoral artery approach then shifted to the axillary route.

Table 1

Characteristics of patients′ groups categorized based on PDA origin.

	Group 1 (n = 67)	Group 2 (n = 11)	Group 3 (n = 17)	Group 4 (n = 1)	P- value
Age, days	24(11–42)	21(13–46)	19(8–32)	11	0.566
Weight, Kg	3(2.7–3.5)	3(2.5–3.3)	3.3(3–3.7)	3.2	0.415
Diagnosis, n
PA-IVS	24	1	1
PA-VSD	10	4	7	1
PA-TA	15		2
DORV-PA	3	1
Heterotaxy syndrome	7	3	2
Critical PS	3
SV-PA	4	2	5
Ebstein Anomaly	1
Vascular access, n					<0.0001*
Femoral artery	63	4	5
Axillary artery	1	6	11	1
Carotid artery	1	1	1
Femoral vein	2
Using 2 stents, n	1		1
Stent type, n
Drug eluting	10	2	5
Bare metal	46	8	11	1
Stent diameter, mm	3.5(3–4.5)	3.5(3.5–4)	3.5(3.5–4)	4	0.621
Stent length, mm	18(12–28)	18(14–24)	24(14–24)	24	0.022*
PDA shape(tortuous/straight), n	48/19	9/2	13/4	0/1	0.348
Additional procedures, n
Pulmonary valvuloplasty	4	1
Atrial septostomy	13	1
Radiofrequency perforation	4
Aortic valvuloplasty	1
Radiation dose, (Gycm 2 )	39.5(19.8–83.2)	45(24–68)	43(13.2–79)	16	0.648
Fluoroscopy time, (min)	23.2(11.5–37.1)	14(10.8–30.0)	24.5(13.7–30.9)	15.5	0.753
Complications, n
Stent Embolization	2
Femoral artery thrombosis	6		1
Cardiac arrest/CPR	1
Bradycardia	1
Immediate stent thrombosis		1	1
Protrusion to RPA or LPA	2		4
Uncovered aortic end	4	1	1
Success/Failure, n †	54/13	9/2	14/3	1/0	0.966
Discharge/In hospital mortality, n ‡	40/14	8/1	9/5	1/0	0.628
Procedure related Mortality, n	3	1	1
Hospital stay, days	5(1–150)	5(1–28)	6(1–60)	6	0.984
Reintervention (follow up), n	3 (2 BAS, 1 PDA stent	2 (1stent dilatation, 1additional stent)

PA-IVS: Pulmonary atresia with intact ventricular septum, PA-VSD: Pulmonary atresia with ventricular septal defect, PA-TA: Pulmonary atresia with tricuspid atresia, DORV-PA: Double outlet right ventricle with pulmonary atresia, SV-PA: Single ventricle with pulmonary atresia, PS: Pulmonary stenosis, PDA: Patent ductus arteriosus, CPR: Cardiopulmonary resuscitation, RPA: Right pulmonary artery, LPA: Left pulmonary artery. BAS: Balloon atrial septostomy

†: Failed cases were referred for surgical shunt

‡: For the success group

*: Statistically significant.

Successful stenting was achieved in 78 cases (81.25%) of these, 53 patients had a tortuous PDA (67.9%) and in 25 patients the duct was straight (32.1%). Out of the 78 successful cases, 54 were of group 1 (69.2%); 9 patients of group 2 (11.5%); 14 patients of group 3 (17.9%); and the one patient of group 4 (1.3%). The approach was femoral artery in 60 patients (67.9%), axillary artery in 13 patients (16.6%); carotid artery in 3 patients (3.8%); and femoral vein in 2 patients (2.6%). Within the 18 failed cases (18.75%), 17 were of the tortuous morphology (94.4%); 12 were of group 1 (72.2%); 2 were of group 2 (11.1%); 3 of group 3 (16.7%); and none of group 4. The approach was femoral artery in 12 cases (66.7%); and axillary artery in 6 cases (33.3%). The main cause of procedural failure was inadequate parking of the coronary wire in a distal pulmonary arterial branch in 14 cases (77.7%), while 2 cases (11.1%) were complicated by acute stent thrombosis, and another 2 cases with stent dislodgment. Other procedural complications comprised femoral artery thrombosis in 7 cases (7.2%), No patients died on table or within 6 hours of the procedure.

Analysis of results according to ductal origin

Group 1: PDA originating from proximal descending aorta (n = 67)

Successful stenting was achieved in 54 patients (80.6%), while the other 13 cases were referred for surgical shunt. Tortuous ductus was encountered in 48 patients (71.6%). The most preferred access route for PDA stenting in group I was the femoral artery (n = 63, 94%). Regarding procedural complications: two patients experienced acute stent embolization, one patient developed cardiac arrest and successfully resuscitated, and one patient developed bradycardia. All these patients were considered as failures and were referred to surgery. Femoral artery thrombosis occurred in 6 patients that improved after administration of unfractionated heparin. Aortic end was not fully covered in 4 patients, while stent protrusion to one of pulmonary arteries causing jailing of the other branch occurred in another two patients. Forty out of the 54 successful cases (74%) were discharged home while ICU mortality due to sepsis occurred in 11 patients and mortality related to the stenting procedure occurred in 3 patients (Table 1). Pulmonary atresia with intact ventricular septum was the most common cardiac anomaly (n = 24, 58.2%) followed by tricuspid atresia (n = 15).

Group 2: PDA originating from the under-surface of aortic arch (n = 11)

Nine out of 11 patients underwent a successful procedure (81.8%). Eight out of the 9 patients (88.9%) were discharged home. The axillary artery was the most preferred access route (54.5%, n = 6) in this group. One patient developed acute stent thrombosis which required urgent MBT shunt (Table 1). Most of patients in this group had pulmonary atresia with VSD (n = 4), followed by heterotaxy syndrome (n = 3), and PDA was tortuous in 9 patients.

Group 3: PDA originating opposite the left subclavian artery (n = 17)

Successful stenting was achieved in 14 out of 17 patients (82.35%). The PDA was tortuous in 13 patients (76.5%) and the most preferred access route was the axillary artery (64.7%, n = 11). 9/14 patients were discharged home (64%). One patient developed acute stent thrombosis and required urgent surgical shunt (Table 1). Most of patients within this group had pulmonary atresia with VSD (41%, n = 7) or a single ventricle (29.4%, n = 5).

Group 4: PDA originating opposite the innominate artery/brachiocephalic artery (n = 1)

In this patient with pulmonary atresia and VSD, the PDA was accessed through an axillary approach. The procedure was successful without complications and the patient was discharged home 6 days after procedure (Table 1).

Analysis of outcome according to procedure approach

Success was achieved in 60/72 cases (83%) using the femoral approach compared to 13/19 cases (68%) using the axillary approach. All of the 3 cases treated from the carotid approach, and all of the 2 cases approached from the femoral vein were stented successfully.

Indicators of PDA stenting success

On comparing the successfully-treated versus the failed cases, it was noted that success was associated with straight PDA, larger ductal diameter, and younger age. The failed cases had higher exposure to radiation and prolonged hospital stays (Table 2). Logistic regression was performed for evaluation of indicators of successful procedure: patients with a straight ductus were 8 times more likely to be successful; likewise, younger patients and those with larger PDAs had higher odds of a successful procedure (Table 3).

Table 2

Comparison between groups with successful and the failed procedures.

	Successful group (n = 78)	Failed group (n = 18)	P- value
Age, days	19.50(10.00–36.00)	31.50(19.00–60.00)	0.044*
Weight, Kg	3.05(2.80–3.50)	3.15(2.67–4.00)	0.654
RPA z score	-1.02(-2.13- -0.21)	-1.57(-2.36- -0.09)	0.420
LPA z score	-1.00(-1.91- -.25)	-1.31(-2.02- -0.39)	0.611
PDA at aortic end, mm	4.80(4.00–5.00)	4.50(3.35.5.50)	0.603
PDA at pulmonary end, mm	3.00(2.5–3.50)	2.50(2.00–3.00)	0.021*
PDA length, mm	15.80(14.00–18.50)	16.30(15.00–20.00)	0.327
PDA shape, n (%)			0.023*
Tortuous	53.00(67.90)	17.00(94.40)
Straight	25.00(32.10)	1.00(5.60)
Stent diameter, mm	3.5(3.5–4)	3.5(3–4)	0.570
Stent length, mm	18(18–24)	24(16–24)	0.406
Fluoroscopy time (minutes)	17.18(10.60–29.37)	29.95(25.99–43.25)	0.0004*
Radiation exposure (Gycm 2)	34.00(18.00–73.00)	68.00(51.50–104.50)	0.005*
Complications
Femoral artery thrombosis, n (%)	5.00(6.40)	2.00(11.10)
Stent embolization, n (%)		2.00(11.10)
Stent thrombosis, n (%)		2.00(11.10)
Displacement to pulmonary arteries, n (%)	6.00(7.70)
Uncovered aortic end, n, %	5.00(6.40)	1.00(5.55)
Hospital stay, days	4(3–10)	15(6–31)	0.011*

RPA: right pulmonary artery, LPA left pulmonary artery, PDA: patent ductus arteriosus.

Table 3

Indicators of success for PDA stenting.

Predictors	OR	95% C.I.	p value
Straight PDA 1	8.019	1.011–63.68	0.048*
Weight	0.681	0.311–1.489	0.335
Age	0.978	0.960–0.998	0.031*
Axillary access 2	2.38	0.757–7.57	0.138
PDA from middle arch 3	1.08	0.209–5.62	0.924
PDA opposite SCA 3	1.12	0.281–4.49	0.869
PDA length	0.904	0.748–1.09	0.294
PDA size at Pulmonary end	2.94	1.172–7.402	0.022*
Fluoroscopy time	0.959	0.925–0.994	0.021*

1Compared to tortuous PDA

2 compared to femoral axis

3compared to PDA from proximal descending aorta

*: statistically significant, O.R: odds ratio, CI: confidence interval, PDA: patent ductus arteriosus, SCA: subclavian artery.

Follow-up of patients who underwent successful PDA stenting

In our series, six (7.7%) patients in the successful group had minor displacement of the stent into one of the pulmonary artery branches (Fig 2H), three of them needed arterioplasty during cardiac surgery. Most of PDAs were stented using a single stent but sometimes more than one stent could be needed to cover the whole length of PDA. In our cohort, we had 6 patients whose aortic end of the PDA was not covered by the stent; 3 of them underwent successful stenting 3–6 days after the initial procedure and 2 of them maintained saturations >75% and discharged then underwent MBT shunt 2 months later. One patient had failed trials for insertion of another stent then developed desaturation and was referred to surgery. Fifty-eight patients (74%) survived to hospital discharge after a mean period of 4 days (3–9 days). The main cause of mortality was sepsis (90%). A total of 43 patients were followed-up for a period of 3–12 months: whereas 10 patients died in the interim; and 5 patients dropped follow-up. Oxygen saturation ranged from 79–90% showing gradual decline over time (Fig 2). MDCT angiography was performed whenever oxygen saturation falls beneath 75%, or prior to planned surgical intervention. In our cohort, this imaging modality was done for all of the 43 cases at a mean of 4 months post-procedure and showed significant growth of pulmonary arteries (Table 4). Surgical palliation and repair: Nine cases underwent partial cavo pulmonary connection (PCPC), 6 cases underwent Modified Blalock-Taussig Thomas shunt and 3 cases underwent biventricular repair (Fig 3).

Fig 2

Multidetector computed tomography with 3D volume rendering showing PDA stents in different PDA origins.

A-B: PDA from the proximal descending aorta, C: PDA from undersurface of aortic arch, D-E: PDA from opposite the origin of left subclavian artery, F-G;PDA arises opposite the innominate (Brachiocephalic trunk),H:PDA stent is seen protruded into the LPA causing jailing of RPA and associated with RPA origin stenosis. PDA: patent ductus arteriosus, MPA: Mean pulmonary artery, LPA: right pulmonary artery, LPA left pulmonary artery, CCA: common carotid artery.

Table 4

Pulmonary arterial growth and oxygen saturation before and after PDA stenting.

	Initially	Follow-up	P- value
Pulmonary arteries growth based on MDCT angiography at age of 4 months
	Before Stenting	4 months after stenting
RPA Z score	-0.79(-1.91- -0.12)	0.93(0.28–1.82)	<0.0001*
LPA Z score	-1.02(-1.82- -0.38)	0.40(0.24–1.01)	<0.0001*
ygen saturation before and immediately after PDA stenting
	Before PDA stenting	Immediately after PDA stenting
Oxygen saturation	65.00(65.00–70.00)	88.00(85.00–90.00)	<0.0001*

RPA: right pulmonary artery, LPA left pulmonary artery, MDCT: Multidetector computed tomography, PDA: patent ductus arteriosus

*: Statistically significant.

Fig 3

Scheme of the studied population.

Discussion

A debate is ongoing on the preferred method of palliating cardiac anomalies with duct-dependent pulmonary circulation, which is turning in favor of ductal stenting. Better clinical outcomes including less procedural complications, less length of hospital stay, lower risk of diuretic use, better and more symmetrical pulmonary arterial growth [12, 13], and even economically [14] favoring PDA stent. Priority for ductal stenting will be in countries with limited resources [15], long waiting lists, with similar pulmonary arterial growth and distortion rates [12] but on the expense of a minor tendency for more frequent re-interventions. However, a surgical shunt is still necessary for certain patients [1] We sought to study the factors associated with procedural success, in the venue of different ductal morphologies and the utilization of alternate approaches than the classical femoral artery. We did not exclude the prematures less than 2.5 kg like other reports [8, 16–18] for the fear of vascular injury [19, 20]. In fact, we did not have any major vascular complications in this group. Moreover, we report a higher success rate in association with younger age, which advocates for intervening as early as possible in these vulnerable neonates to minimize hospitalization and the related inherent risks of infection, ventilation and metabolic derangements that have a direct impact on the post-procedural outcome. The dose, not only the duration, of prostaglandin infusion might also be a risk factor [21]: proposed by the fact that larger ductuses (and therefore requiring less prostaglandin doses) were associated with a more favorable outcome. Pre-procedural assessment and planning is of utmost importance, the interventionist needs to define the ductal anatomy and select the most appropriate approach and prepare the necessary equipment [8, 15–18]. : A straight PDA was 8 times more likely to be successfully stented, compared to a tortuous PDA. The definition of PDA “tortuosity” is mainly subjective and most of the PDAs with higher degrees of tortuosity were seen arising from the underside of the arch [22]. Similar to several reports, most of our patients (72.9%) had a tortuous PDA [8, 15]. The overall success rate was 81.25%: which is comparable to previously reported success rates ranging from 80 to 100%, with the variation that some of these studies included either a small number of patients or excluded complex ductal morphologies [8, 15–18, 23]. Complex tortuosity especially multiple bends with acute angles is reported to propose higher failure rates of ductal stenting compared to others [23], but could be stented nevertheless [22]. In our study, most of patients who failed PDA stenting had tortuous PDAs compared to patients with successful PDA stenting (94.4% versus 67.9%, p = 0.023). The approach to stent the duct is a major determinant in the success of the procedure [22] as it allows direct access to cannulate the PDA and to obtain a stable wire position which in turn is reflected on the procedural time and radiation exposure. We advocate for femoral access to the PDAs arising from the proximal descending Aorta; and the axillary approach to ductus from the undersurface of the arch and opposite to the left subclavian artery. Similarly, Qureshi et al reported significant association between ductal origin and vascular access choice [22]. In our series, fluoroscopy time and radiation exposure were lower in successful procedures compared to the failed ones. This could be attributed to the increased time allocated to PDA access attempts in failed cases. : Stent embolization and thrombosis is a major complication of ductal stenting procedures. In our cohort, 2 patients developed stent embolization and another 2 patients developed acute stent thrombosis. Some authors reported relatively higher incidence of stent embolization and acute thrombosis [17]. Length of the stent needs to be a few millimeters larger than the measured ductal length, to be able to cover both ends and avoid slipping during balloon inflation [19, 24], given that the inflated stent shortens by 15–20% [1, 25]. On the other hand, protrusion of the stent into one of the branch pulmonary arteries may lead to jailing of the other branch with subsequent stenosis or even disconnection from the main pulmonary artery, reported in up to 22% of cases and usually requires arterioplasty during surgical repair or palliation [22], which in our report was less frequent (7.7%). : In the current series, the in-hospital mortality was relatively higher compared to other reports (25.6%), that we attribute to the delayed referrals from across the country, and the unavailability of small-sized surgical shunts which forces proper patient selection to be overlooked.

Follow-up after ductal stenting

In our cohort, initially, the oxygen saturation significantly increased immediately after PDA stenting then gradually decreased over time (median oxygen saturation at 6 months was 70%), with no significant difference compared to the post-procedural oxygen saturation, p 0.988). Whether due to neo-intimal proliferation [5, 26] or unpaired growth of the pulmonary vascular bed, as PDA stenting promotes the growth of pulmonary arteries and pulmonary vascular bed even with jailing of one of the pulmonary arteries. Data from cardiac catheterization done post-ductal-stenting showed balanced pulmonary arterial growth even with the presence of proximal stenosis at the insertion site of the PDA stent [18, 27, 28]. In our cohort, z-score of pulmonary arteries markedly increased 4 months post-ductal stenting based on MDCT data performed for 37 patients.

Indicators of successful stenting

Patients with straight PDA were 8 times more likely to get successful PDA stenting compared to patients with tortuous PDA. Younger age patients and those who had a relatively larger PDA diameter at pulmonary end had higher odds for successful procedure. This could be explained by the fact that patients with prolonged hospital stay had more complicated hospital courses compared to patients with early stenting before development of complications. The patients with larger PDAs at pulmonary end may have allowed for better access of the PDA as they may ease the passages of wires and catheters. Finally, ductal stenting has a learning curve, with time and more practice significant improvement of outcome even in the complex cases could be achieved.

Limitations

Selection of patients could not be clearly set as frequently PDA stenting is performed as a life-saving procedure when no surgical shunts are available. Although this work is considered one of the largest series of ductal stenting via different accesses in a relatively short period, the numbers during follow-up are small due to high percentage of dropout cases, and longer follow-up is needed. This is a single-centered study, although receiving referrals from all over the country, but lacked the diversity of different operating teams. We did not record the dose or duration of prostaglandin infusion prior to the procedures, which could be an attributing factor to the final outcome. We suggest further studies on the effect of prostaglandins on the outcome.

Conclusion

The success of the PDA stenting depends mainly on three critical factors: the straight morphology of the ductus, younger age at the time of the procedure and a relatively larger PDA diameter at the pulmonary end. The access route for percutaneous PDA stenting is markedly determined by the ductal origin and morphology.

26 Aug 2020

PONE-D-20-24720

PDA stenting in duct-dependent pulmonary circulation: Effects of ductal morphology and origin on procedure approach and outcome

PLOS ONE

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The topic is not novel, but the approach is original and of relevance. However there are some critical aspects that need to be clarified.

Latest evidences are not in favour of PDA stenting in univentricular heart. Thus inclusion criteria should be weel discussed. Is a policy of author's center perform so many PDA stenting. How the Center's volume?

Introduction and Discussion: discuss critically the advantages/disavantages of PDA stenting, according to current leterature

Results:

-data should be discussed firt all together and then divided into subgroups

-Also in the abstract a short summary of global success/complication rate is missing

-Is there a surgical group for comparison?

Limitations section: should be much more robust. Patient's selection criteria is a clear limitation. The choice of the material seems also to be quite arbitrary

Limitations and discussion

Results are in line with previous publication, but complication rate is high. Why to prefer PDA stent to m-BT shunt?

Reviewer #2: Agha et al. Report on a relatively large cohort of consecutive neonates undergone PDA stenting for duct-dependant pulmonary circulation congenital lesion. The concept and the main topic of this article (proper vascular access depeding upon duct morphology) is not new and it has been extensively reported.

Percutaneous axillary artery approach for ductal stenting in critical right ventricular outflow tract lesions in the neonatal period

Colm R Breatnach 1, Varun Aggarwal 2, Khalid Al-Alawi 1, Colin J McMahon 1, Orla Franklin 1, Terence Prendiville 1, Paul Oslizlok 1, Kevin Walsh 1, Athar M Qureshi 2, Damien Kenny 1

Classification scheme for ductal morphology in cyanotic patients with ductal dependent pulmonary blood flow and association with outcomes of patent ductus arteriosus stenting.

Qureshi AM, Goldstein BH, Glatz AC, Agrawal H, Aggarwal V, Ligon RA, McCracken C, McDonnell A, Buckey TM, Whiteside W, Metcalf CM, Petit CJ

Comparison Between Patent Ductus Arteriosus Stent and Modified Blalock-Taussig Shunt as Palliation for Infants With Ductal-Dependent Pulmonary Blood Flow: Insights From the Congenital Catheterization Research Collaborative.

Glatz AC, Petit CJ, Goldstein BH, Kelleman MS, McCracken CE, McDonnell A, Buckey T, Mascio CE, Shashidharan S, Ligon RA, Ao J, Whiteside W, Wallen WJ, Metcalf CM, Aggarwal V, Agrawal H, Qureshi AM.

Circulation. 2018 Feb 6;137(6):589-601. doi: 10.1161/CIRCULATIONAHA.117.029987. Epub 2017 Oct 17.

PMID: 29042354

In addition this reviewer has significant issues regarding this paper:

- Detailed information regarding the sub-group of patients with failed PDA stenting (18 patients, 19%) should be provided, such as specific reason for failure

- There is a concerning high rate of complication (including vascular and stent displacement), this should be discussed and explained

- There is no specific protocol described regarding the institutional approach to duct-dependent lesion. More specifically, is every patient with duct-dependant circulation referred to your insititution considered for PDA stent, irrespective of other parameters? Do you select patient referred for transcatether intervention?

- Do you have a surgical comparins group undergone BT shunt during the same period. Longterm comparison of such groups would be of some interest

- Do you have any follow-up surgical data at the time of corrective surgery regarding this patient population?

- Did you ever change vascular access after baseline angiography? In other words, were you always able to correctly identify PDA morphology and establish the correct vascular approach using pre-procedural echocardiography?

- There are significant procedural data missing: type, timing and dosing of anticoagulation, description of angiography, type of wire used to deploy stent.

- Long term follow up data are essential

**********

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Reviewer #1: Yes: Massimiliano Cantinotti

Reviewer #2: No

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8 Jan 2021

Rebuttal Letter

The authors thank the editors and the reviewers for their valuable comments, this letter includes a response to the individual remarks

General Comments

1. The title was adjusted to “Margin between success and failure of PDA stenting for duct-dependent pulmonary circulation” according to the journal’s requirements

2. Data availability and minimal data set: The main Excel is added as supplement

3. Tables included in the main manuscript

4. Figure legends added at end of manuscript

5. Authorship: the author (Baher Hanna) and (Mai Hussein) that were missed in the initial manuscript were re-added. And their contribution to the manuscript was added.

6. Definition of a successful procedure was added under “patients and methods”

Reviewer One:

- Latest evidences are not in favor of PDA stenting in univentricular heart. Thus inclusion criteria should be well discussed. Is a policy of author's center perform so many PDA stenting. How the Center's volume?

We added 3 extra references (25-28) that compare PDA stents to surgical shunts that tend to favor PDA stenting. Our institution performs around 900 catheterization cases per year: on average 50 of them are PDA stenting. Over the past 3 years, the small sized 3 and 3.5mm surgical shunts have been very sparse in the country and we resolve to PDA stenting as a life-saving procedure even in some cases in which a BT shunt would have been the choice if available.

- Introduction and Discussion: discuss critically the advantages/disadvantages of PDA stenting, according to current literature

The first paragraph under “Discussion” was edited as such

- Also in the abstract a short summary of global success/complication rate is missing

Added to the abstract

- Results: data should be discussed first all together and then divided into subgroups

The section “Results” was edited accordingly

- Is there a surgical group for comparison?

No, the aim of our study was to evaluate the different approaches for PDA stenting and the parameters reflecting the outcome in this specific cohort, rather than comparing results to surgical shunts. As mentioned earlier, in our country we are commonly obliged to perform a life-saving intervention due to the unavailability of small sized BT shunts.

- Limitations and discussion: Results are in line with previous publication, but complication rate is high. Why to prefer PDA stent to m-BT shunt?

In our institution, complications of neonatal MBTS are higher than PDA stents. A study to compare both is yet to be done.

- Limitations section: should be much more robust. Patient's selection criteria is a clear limitation. The choice of the material seems also to be quite arbitrary

The “Limitations” section was edited accordingly

Reviewer Two:

- The concept and the main topic of this article (proper vascular access depending upon duct morphology) is not new and it has been extensively reported.

We are mainly concerned with the indicators of a successful procedure based on the ductal morphology, origin and approach

- Detailed information regarding the sub-group of patients with failed PDA stenting (18 patients, 19%) should be provided, such as specific reason for failure

Results have been added to contain detailed information on the subgroups, details for procedural failure are discussed under “results” and Supplement Tables

- There is a concerning high rate of complication (including vascular and stent displacement), this should be discussed and explained

This was mentioned in “results” The main cause of procedural failure was inadequate parked coronary wire inside one of the branch of pulmonary arteries (14 cases; 77.7%), while 2 cases (11.1%) were complicated by acute stent thrombosis, and another 2 cases with stent dislodgment. Other procedural complications comprised femoral artery thrombosis in 7 cases (7.2%), No patients died on table or within 6 hours of the procedure.

- There is no specific protocol described regarding the institutional approach to duct-dependent lesion. More specifically, is every patient with duct-dependant circulation referred to your institution considered for PDA stent, irrespective of other parameters? Do you select patient referred for transcatether intervention?

In our institution, we are frequently obliged to perform life-saving PDA stenting because of the unavailability of small sized surgical shunts in the country. This was mentioned under “limitations”.

- Do you have a surgical comparisons group undergone BT shunt during the same period. Long-term comparison of such groups would be of some interest

No we currently do not, such a study is yet to be done.

- Do you have any follow-up surgical data at the time of corrective surgery regarding this patient population?

Fifty-eight patients (74%) survived to hospital discharge after a mean period of 4 days (3-9 days). A total of 43 patients were followed-up for a period of 3-12 months: whereas 10 patients died; and 5 patients dropped follow-up. Oxygen saturation ranged from 79-90% showing gradual decline over time (figure 2). MDCT angiography was performed whenever oxygen saturation falls beneath 75%, or prior to planned surgical intervention. In our cohort, this imaging modality was done at a mean of 4 months post-procedure and showed significant growth of pulmonary arteries (Table 3). Surgical palliation and repair: 9 cases underwent partial cavo pulmonary connection (PCPC), 6 cases underwent Modified Blalock Taussig Thomas shunt and 3 cases underwent biventricular repair (Figure 3).

- Did you ever change vascular access after baseline angiography? In other words, were you always able to correctly identify PDA morphology and establish the correct vascular approach using pre-procedural echocardiography?

It is our routine to perform an initial aortogram through the femoral artery, accordingly to which the approach is decided. In 2 cases the approach was switched during the procedure. This is mentioned under “results”.

Based on ductal origin and morphology, the approach to ductal stenting was femoral artery in 72 patients (75%); axillary artery in 19 patients (19.8%), carotid artery in 3 patients (3.1%), and femoral vein in 2 patients (2.1%). It is of note that 2 cases that were initiated for femoral artery approach then shifted to the axillary route

- There are significant procedural data missing: type, timing and dosing of anticoagulation, description of angiography, type of wire used to deploy stent.

These data were added under “patients and methods”

Procedures: The femoral arterial access was obtained in all patients by 4 French short sheath, 100 units/kg unfractionated intravenous heparin and prophylactic antibiotic was given to every patient followed by aortogram using 4 French pigtail catheter. Patients were divided into 4 groups according to PDA origin: Group 1 with PDA from proximal descending aorta, Group 2 with PDA from undersurface of aortic arch, Group 3 with PDA arising opposite the subclavian artery and Group 4 with PDA arising opposite the innominate/brachiocephalic artery [figure1A-H]. Based on this angiogram data, the length of the stent and its diameter was selected as well as the best access route, i.e. whether to proceed with the femoral arterial access or to convert to another approach like axillary, carotid or femoral vein access. Two different types of catheters either 4 French cut pigtail or 4 French right Judkin [JR]were used for encroaching of PDA. PDA was crossed with 0.014 inch percutaneous transluminal coronary angioplasty [PTCA] wire [Middle Support Weight guide wire, Boston Scientific, USA] and it was parked in either of the branch pulmonary arteries . In all cases, pre-mounted bare metal stents [architect, Life Vascular Device Biotech, Barcelona, Spain] or drug-eluting coronary stents [Monorail, Everolimus-Eluting Platinum Chromium, Boston Scientific, USA]. The diameter was chosen with respect to the weight of the patient, size of the PDA, its constricted segment and branch pulmonary arteries. Length of stent was chosen to cover the entire length of the duct with proximal end into aorta and distal end into branch PA..The selected coronary stent was tracked over PTCA wire and placed across the PDA with its proximal end in the aorta and distal end in branch pulmonary artery. After confirming the position of the stent, it was deployed with its initial nominal pressure then re-dilated for better apposition. Balloon was removed after deployment keeping the wire in situ. Injection was done again to check the position of the stent, flow across the stent and branch pulmonary arteries. After achieving satisfactory results, wire was removed. In cases of branch pulmonary artery origin stenosis, we aimed to deploy the stent distal to the stenosed segment. After stent implantation, angiogram injection was performed to confirm the stent position. All the patients were shifted to ICU and received unfractionated heparin infusion on 20 IU/kg/hr for 24-48 hours (partial prothrombin time was maintained 2–3 times of normal). All the patients were given antiplatelets in form of aspirin on 5mg/kg/day that was continued until undergoing second-stage palliation or repair. Procedural success of PDA stenting was defined as the implantation of a well-seated stent, good flow for both pulmonary arteries and stable SpO2 above 75% for a hemodynamic-stable patient.

- Long term follow up data are essential

Our study’s end-point was the 2nd surgical intervention; either the cavo-pulmonary shunt for univentricular heart or biventricular repair as definitive surgery.

Regarding Data Availability statement, I have specified where the minimal data set underlying the results described in the manuscript can be found in .

https://doi.org/10.5061/dryad.ht76hdrdk.

Margin between success and failure of PDA stenting for duct-dependent pulmonary circulation submitted with https://doi.org/10.5061/dryad.ht76hdrdk. There may be a delay for processing before the item is available.

Submitted filename: Rebuttal Letter PDA stent.docx

Click here for additional data file.

21 Jan 2021

PONE-D-20-24720R1

Margin between success and failure of PDA stenting for  duct-dependent pulmonary circulation

PLOS ONE

Dear Dr. Agha,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: (No Response)

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: I Don't Know

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

Reviewer #4: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: This report details a remarkably large series of ductal – dependent pulmonary circulation cases palliated with PDA stenting from a Low-Middle Income Country. Over 2 years, they collected 96 consecutive cases with an 81% early success rate, for which they should be congratulated. However, due to a lack of simultaneous surgical shunt availability, they were unable to compare this series to anything except external historical controls. Thus, this is intrinsically just a description of a cohort from a single center having a single procedure, and not a scientific comparison study. Although the procedures reported are not novel or new, yet the group was able to discern predictors (risk factors) for success or failure such that better outcomes occurred in younger patients with straighter and larger ducts. Given their resource limitations, it is perhaps not surprising that only 74% of cases survived to hospital discharge, and that 90% of deaths were due to sepsis.

Several comments can be made. Firstly, regarding statistics, it is noted that of the 4 groups of anatomical types, group 4 had only 1 patient. It is not certain that in this case of pulmonary atresia/VSD with a “duct” from the innominate artery, wasn’t really a MAPCA being stented. In any case, the statistics in Table 1 give p values after 4 groups. How was the n=1 group handled? Please explain and consider deleting group 4 as a single exception, or adding the case to group 3. In fact, the 4 anatomical groups are a little unconventional and need a reference to the literature (unless I missed that).

Please state if there was any difference between bare metal and everolimus drug eluting stent groups.

The smallest size patient appears to be 2.1 kg in the Table, and the vascular complication rate is not excessive in light of 12 patients under 2.5 kg. Can the authors expound in the Discussion on their recommendations for smallest body size acceptable, and if their anticoagulation protocol changes with different risk factors.

There is no long - term follow up beyond 1 year, as noted in the study limitations.

The Discussion is long for a single case series and the authors should try to be more terse. They should emphasis the uniqueness of this series:

1. This was accomplished in a country with limited resources in regard to surgical shunts.

2. The use of a short 4F femoral artery sheath was associated with fewer than expected vascular complications.

3. The selection of the axillary/other approach after careful analysis was associated with successful outcomes.

Please discuss the differentiation of tortuous duct coming from an unusual site of origin versus MAPCA in the presence of pulmonary atresia.

The authors appear to give some results for the first time in the Discussion section (branch PA stent protrusion, oxygen saturation trends), which should be stated clearly in the results section first.

The Limitations section is good.

The Track Changes I received in the first version of the manuscript were not complete, but were, however, well explained in the Rebuttal letter.

The paper is well written but does need some editing of English language. The Figures and Tables are good and Supplemental materials complete. The References are relevant.

Specific Comments:

1. References #25 and #28 appears to be identical and must be corrected.

2. Line 237 on page 9 – Start a new paragraph here.

3. Where are the Figures 2 and 3 referred to on page 10?

Reviewer #4: Dear Authors

We sit every week in conference and debate this question

You have a large cohort but gave us very little data , if I need to decide for a patient what rout to go - BT shunt or stunting, please help me

here are some issues you need to address

1. Why have you decided to go for a stent, that is from how many total patients did you decide to go for a BT shunt and how many were referred for stenting? What were the criteria for each group?

2. What were the comorbidities for each patient?

3. Did the comorbidities play a role in deciding who should go to each of the procedures?

4. What was the outcome between the BT shunt group and the stented group – and why?

Moreover, when looking at the data

5. What additional precedures were done (in the table there is a short list -pulm valvuloplasty, septectomy and more) – did it change the procedure, were the outcomes different, do you recommend these elaborate long procedures?

6. What is tortuous? How long, what was your definition? Rarely do we see a completely straight PDA, most of the have bents and more – how did you address this, what and with what modality

7. What is failure – do you mean procedure aborted? When did you decide to abort 20% of the stenting- after the first fluoroscopy? Ofter you saw you cant pass through? Any other special complications?

8. What was your mode of device selection and when did you decide to put 2 stents in one PDA?

Make this into the Cairo Guidelines for smaller programs which may use your knowledge

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

Reviewer #4: Yes: Shai Tejman-Yarden MD Mac MBA

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

21 Jun 2021

General Comments

1. The title was adjusted to “Margin between success and failure of PDA stenting for duct-dependent pulmonary circulation” according to the journal’s requirements

2. Data availability and minimal data set: The main Excel is added as supplement

3. Tables included in the main manuscript

4. Figure legends added at end of manuscript

5. Authorship: the author (Baher Hanna) and (Mai Hussein) that were missed in the initial manuscript were re-added. And their contribution to the manuscript was added.

6. Definition of a successful procedure was added under “patients and methods”

Reviewer One:

- Latest evidences are not in favor of PDA stenting in univentricular heart. Thus inclusion criteria should be well discussed. Is a policy of author's center perform so many PDA stenting. How the Center's volume?

We added 3 extra references (25-28) that compare PDA stents to surgical shunts that tend to favor PDA stenting. Our institution performs around 900 catheterization cases per year: on average 50 of them are PDA stenting. Over the past 3 years, the small sized 3 and 3.5mm surgical shunts have been very sparse in the country and we resolve to PDA stenting as a life-saving procedure even in some cases in which a BT shunt would have been the choice if available.

- Introduction and Discussion: discuss critically the advantages/disadvantages of PDA stenting, according to current literature

The first paragraph under “Discussion” was edited as such

- Also in the abstract a short summary of global success/complication rate is missing

Added to the abstract

- Results: data should be discussed first all together and then divided into subgroups

The section “Results” was edited accordingly

- Is there a surgical group for comparison?

No, the aim of our study was to evaluate the different approaches for PDA stenting and the parameters reflecting the outcome in this specific cohort, rather than comparing results to surgical shunts. As mentioned earlier, in our country we are commonly obliged to perform a life-saving intervention due to the unavailability of small sized BT shunts.

- Limitations and discussion: Results are in line with previous publication, but complication rate is high. Why to prefer PDA stent to m-BT shunt?

In our institution, complications of neonatal MBTS are higher than PDA stents. A study to compare both is yet to be done.

- Limitations section: should be much more robust. Patient's selection criteria is a clear limitation. The choice of the material seems also to be quite arbitrary

The “Limitations” section was edited accordingly

Reviewer Two:

- The concept and the main topic of this article (proper vascular access depending upon duct morphology) is not new and it has been extensively reported.

We are mainly concerned with the indicators of a successful procedure based on the ductal morphology, origin and approach

- Detailed information regarding the sub-group of patients with failed PDA stenting (18 patients, 19%) should be provided, such as specific reason for failure

Results have been added to contain detailed information on the subgroups, details for procedural failure are discussed under “results” and Supplement Tables

- There is a concerning high rate of complication (including vascular and stent displacement), this should be discussed and explained

This was mentioned in “results” The main cause of procedural failure was inadequate parked coronary wire inside one of the branch of pulmonary arteries (14 cases; 77.7%), while 2 cases (11.1%) were complicated by acute stent thrombosis, and another 2 cases with stent dislodgment. Other procedural complications comprised femoral artery thrombosis in 7 cases (7.2%), No patients died on table or within 6 hours of the procedure.

- There is no specific protocol described regarding the institutional approach to duct-dependent lesion. More specifically, is every patient with duct-dependant circulation referred to your institution considered for PDA stent, irrespective of other parameters? Do you select patient referred for transcatether intervention?

In our institution, we are frequently obliged to perform life-saving PDA stenting because of the unavailability of small sized surgical shunts in the country. This was mentioned under “limitations”.

- Do you have a surgical comparisons group undergone BT shunt during the same period. Long-term comparison of such groups would be of some interest

No we currently do not, such a study is yet to be done.

- Do you have any follow-up surgical data at the time of corrective surgery regarding this patient population?

Fifty-eight patients (74%) survived to hospital discharge after a mean period of 4 days (3-9 days). A total of 43 patients were followed-up for a period of 3-12 months: whereas 10 patients died; and 5 patients dropped follow-up. Oxygen saturation ranged from 79-90% showing gradual decline over time (figure 2). MDCT angiography was performed whenever oxygen saturation falls beneath 75%, or prior to planned surgical intervention. In our cohort, this imaging modality was done at a mean of 4 months post-procedure and showed significant growth of pulmonary arteries (Table 3). Surgical palliation and repair: 9 cases underwent partial cavo pulmonary connection (PCPC), 6 cases underwent Modified Blalock Taussig Thomas shunt and 3 cases underwent biventricular repair (Figure 3).

- Did you ever change vascular access after baseline angiography? In other words, were you always able to correctly identify PDA morphology and establish the correct vascular approach using pre-procedural echocardiography?

It is our routine to perform an initial aortogram through the femoral artery, accordingly to which the approach is decided. In 2 cases the approach was switched during the procedure. This is mentioned under “results”.

Based on ductal origin and morphology, the approach to ductal stenting was femoral artery in 72 patients (75%); axillary artery in 19 patients (19.8%), carotid artery in 3 patients (3.1%), and femoral vein in 2 patients (2.1%). It is of note that 2 cases that were initiated for femoral artery approach then shifted to the axillary route

- There are significant procedural data missing: type, timing and dosing of anticoagulation, description of angiography, type of wire used to deploy stent.

These data were added under “patients and methods”

Procedures: The femoral arterial access was obtained in all patients by 4 French short sheath, 100 units/kg unfractionated intravenous heparin and prophylactic antibiotic was given to every patient followed by aortogram using 4 French pigtail catheter. Patients were divided into 4 groups according to PDA origin: Group 1 with PDA from proximal descending aorta, Group 2 with PDA from undersurface of aortic arch, Group 3 with PDA arising opposite the subclavian artery and Group 4 with PDA arising opposite the innominate/brachiocephalic artery [figure1A-H]. Based on this angiogram data, the length of the stent and its diameter was selected as well as the best access route, i.e. whether to proceed with the femoral arterial access or to convert to another approach like axillary, carotid or femoral vein access. Two different types of catheters either 4 French cut pigtail or 4 French right Judkin [JR]were used for encroaching of PDA. PDA was crossed with 0.014 inch percutaneous transluminal coronary angioplasty [PTCA] wire [Middle Support Weight guide wire, Boston Scientific, USA] and it was parked in either of the branch pulmonary arteries . In all cases, pre-mounted bare metal stents [architect, Life Vascular Device Biotech, Barcelona, Spain] or drug-eluting coronary stents [Monorail, Everolimus-Eluting Platinum Chromium, Boston Scientific, USA]. The diameter was chosen with respect to the weight of the patient, size of the PDA, its constricted segment and branch pulmonary arteries. Length of stent was chosen to cover the entire length of the duct with proximal end into aorta and distal end into branch PA..The selected coronary stent was tracked over PTCA wire and placed across the PDA with its proximal end in the aorta and distal end in branch pulmonary artery. After confirming the position of the stent, it was deployed with its initial nominal pressure then re-dilated for better apposition. Balloon was removed after deployment keeping the wire in situ. Injection was done again to check the position of the stent, flow across the stent and branch pulmonary arteries. After achieving satisfactory results, wire was removed. In cases of branch pulmonary artery origin stenosis, we aimed to deploy the stent distal to the stenosed segment. After stent implantation, angiogram injection was performed to confirm the stent position. All the patients were shifted to ICU and received unfractionated heparin infusion on 20 IU/kg/hr for 24-48 hours (partial prothrombin time was maintained 2–3 times of normal). All the patients were given antiplatelets in form of aspirin on 5mg/kg/day that was continued until undergoing second-stage palliation or repair. Procedural success of PDA stenting was defined as the implantation of a well-seated stent, good flow for both pulmonary arteries and stable SpO2 above 75% for a hemodynamic-stable patient.

- Long term follow up data are essential

Our study’s end-point was the 2nd surgical intervention; either the cavo-pulmonary shunt for univentricular heart or biventricular repair as definitive surgery.

Submitted filename: Rebuttal Letter PDA stent.docx

Click here for additional data file.

7 Jul 2021

PONE-D-20-24720R2

Margin between success and failure of PDA stenting for  duct-dependent pulmonary circulation

PLOS ONE

Dear Dr. Agha,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: (No Response)

Reviewer #4: All comments have been addressed

Reviewer #5: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: I Don't Know

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: My previous comments on this manuscript are not addressed in the response by the authors, so I have no further comments at this time.

Reviewer #4: The authors answered my questions and the paper has a huge impact on the field. I strongly advise to publish

Reviewer #5: I am not an expert at the first-version review, so I only comment on whether the author's answer to the question from the expert at the first-version review is adequate.

1) The purpose of the research: The abstract states that it is necessary to analyze the factors of the success of the operation. In fact, it is grouped and compared according to the origin of the PDA. In the following discussion, it is said that this study mainly wants to analyze the situation of different approaches and influence the success of the operation. The indicators that the author ultimately wants to be clear need to be consistent. If the main research in the discussion is the influence of different approaches on the success rate，why not group them using approaches?

2) In the method part, the second reviewer asked the author to give a detailed description of the inclusion and exclusion criteria. The author’s answer was not very detailed. Although there are intermittent descriptions in the method part of the article, such as weight, coagulation dysfunction, etc., it should be systematically Write down the inclusion and exclusion criteria for patients who actually undergo PDA stent placement; this is also a question raised by the reviewer in the limitation section.

3) The results part: there are overlaps description in results. The first two paragraphs are for the explanation of the patient's baseline data. There is no need to write approach groupings. Is it better to describe in the procedure part? And data in the table does not need to be described all them again. It is possible to group by PDA origin, but in fact, according to the author's results, the procedure approach, PDA distortion, and complications of groups 2-4 are similar, and can be used as a unified group for comparison with the first group. Regarding the follow-up part, 43 patients were followed up for 3-12 months. How many cases were actually followed up for 4 months? What is the actual number of people undergoing MDCT angiography 4 months after surgery? This is not described in detail. “The detailed information regarding the sub-group of patients with failed PDA stenting should be provided ”which was proposed by the second reviewer, was not discussed adequately.

**********

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Reviewer #3: No

Reviewer #4: Yes: Shai Tejman Yarden MD MSc MBA

Reviewer #5: No

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28 Sep 2021

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: (No Response)

Reviewer #4: All comments have been addressed

Reviewer #5: (No Response)

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: I Don't Know

Reviewer #4: Yes

Reviewer #5: Yes

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

Reviewer #4: Yes

Reviewer #5: No

The manuscript has been revised and the language edited

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: My previous comments on this manuscript are not addressed in the response by the authors, so I have no further comments at this time.

Reviewer #4: The authors answered my questions and the paper has a huge impact on the field. I strongly advise to publish

Reviewer #5: I am not an expert at the first-version review, so I only comment on whether the author's answer to the question from the expert at the first-version review is adequate.

1) The purpose of the research: The abstract states that it is necessary to analyze the factors of the success of the operation. In fact, it is grouped and compared according to the origin of the PDA. In the following discussion, it is said that this study mainly wants to analyze the situation of different approaches and influence the success of the operation. The indicators that the author ultimately wants to be clear need to be consistent. If the main research in the discussion is the influence of different approaches on the success rate，why not group them using approaches?

The approach to PDA stenting is directly related to its origin, this has been clarified in the final edition

2) In the method part, the second reviewer asked the author to give a detailed description of the inclusion and exclusion criteria. The author’s answer was not very detailed. Although there are intermittent descriptions in the method part of the article, such as weight, coagulation dysfunction, etc., it should be systematically Write down the inclusion and exclusion criteria for patients who actually undergo PDA stent placement; this is also a question raised by the reviewer in the limitation section.

As indicated in the “material and methods” section (lines 1-3), all cases presenting for ductal stenting during the 2 year study period were included, only excluding those with untreated sepsis or coagulopathy.

3) The results part: there are overlaps description in results. The first two paragraphs are for the explanation of the patient's baseline data. There is no need to write approach groupings. Is it better to describe in the procedure part?

Done

And data in the table does not need to be described all them again. It is possible to group by PDA origin, but in fact, according to the author's results, the procedure approach, PDA distortion, and complications of groups 2-4 are similar, and can be used as a unified group for comparison with the first group.

The authors believe that grouping the PDA according to its origin would be more informative to the interventionist who is planning for the procedure, therefore needs to decode on the best approach based on the PDA anatomy.

Regarding the follow-up part, 43 patients were followed up for 3-12 months. How many cases were actually followed up for 4 months? What is the actual number of people undergoing MDCT angiography 4 months after surgery? This is not described in detail. “The detailed information regarding the sub-group of patients with failed PDA stenting should be provided ”which was proposed by the second reviewer, was not discussed adequately.

All cases were assessed routinely by MDCT angiography prior to Glenn, but not after the operation. This was adjusted in the results.

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

Reviewer #4: Yes: Shai Tejman Yarden MD MSc MBA

Reviewer #5: No

Submitted filename: rebuttal letter-2.docx

Click here for additional data file.

11 Oct 2021

19 Oct 2021

Rebuttal Letter

The authors thank the editors and the reviewers for their valuable comments, this letter includes a response to the individual remarks

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #3: (No Response)

Reviewer #5: All comments have been addressed

________________________________________

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

Reviewer #5: Yes

________________________________________

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: No

Reviewer #5: Yes

________________________________________

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #3: Yes

Reviewer #5: Yes

________________________________________

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #3: Yes

Reviewer #5: Yes

________________________________________

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: This is the second revision I have reviewed after I sent comments for revision. Incredibly, the authors have still not addressed my suggestions. For example, References #25 and 28 are still identical. The fact that "Group 4" only contains 1 member and yet is dealt with statistically, is not acceptable.

I have nothing further to say, and will not render any other decisions. I WILL NOT REVIEW THIS MANUSCRIPT AGAIN.

The changes made are:

- group 4: indicated that it was not included in statistical analysis being a single case, the corresponding column from table 1 has been deleted

- reference number 28 has been deleted and the numbering within the text adjusted

Reviewer #5: All questions mentioned in previous review have received more detailed and serious responses.The writing of the article has also been thoroughly improved.

________________________________________

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: No

Reviewer #5: No

Submitted filename: New Microsoft Word Document.docx

Click here for additional data file.

1 Nov 2021

24 Jan 2022

Rebuttal letter

The authors thank the editors and the reviewers for their valuable comments, this letter includes a response to the individual remarks

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #5: All comments have been addressed

Response: Thank you for your kind response

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: No

Reviewer #5: Yes

Response: Thank you for your kind response. The conclusion was based upon the supported data and results of statistical significance

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: No

Reviewer #5: Yes

Response: Thank you for your kind response .

Numerical data were expressed as median and interquartile range [25th -75th percentiles] while categorical data were expressed as numbers or numbers and percentages. Comparisons between groups were calculated using non-parametric Kruskal Wallis, Mann-Whitney and Wilcoxon signed-rank tests for numerical data, while χ2 tests were used for comparison between groups for categorical data. Logistic regression was performed for evaluation of outcome predictors. Statistical significance was considered if P-values <0.05.

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #5: Yes

Response: Thank you for your kind response

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #5: Yes

Response: Thank your for you kind response

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: This study reports on the use of PDA stenting in the setting of resource-constrained country where availabiity of surgica shunt is limited. Although of some interest this reviewer think that this study is not adding significant novelty to the field.

Reviewer #5: All questions mentioned in previous review have received more detailed responses. No more suggestions.

Response: Thank you for your kind response. Priority for ductal stenting will be in countries with limited resources, long waiting surgical lists and unavailability of small B-T shunt so the authors think about the treatment of duct dependent pulmonary circulation and different factors that predict the outcome of this procedure.

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #5: No

Submitted filename: new Rebuttal 2.docx

Click here for additional data file.

23 Feb 2022

Margin between success and failure of PDA stenting for  duct-dependent pulmonary circulation

PONE-D-20-24720R5

Dear Dr. Agha,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: No

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: No

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: No

Reviewer #5: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: This manuscript has been revised and this reviewer recognize the effort by these authors. However, I still continue to think that procedural indication is unclear, main study results are not novel, in addition suggesting PDA stenting over shunt is a delicate and unresolved matter in managing neonates with ductal-dependant pulmonary circulation and this study does not offer any insights to this regard.

Reviewer #5: No more suggestions.

All comments have been addressed carefully.

In the case of limited resources, catheter stenting is a hope for research subjects, and refining the prognosis and characteristics of catheter-dependent pulmonary circulation stenting can provide more patients with accurate and effective interventions

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #5: No

25 Mar 2022

PONE-D-20-24720R5

Margin between success and failure of PDA stenting for duct-dependent pulmonary circulation

Dear Dr. Agha:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Robert Jeenchen Chen

Academic Editor

PLOS ONE