Echocardiographic Predictors and Incidence of Left Ventricular Dysfunction Following Transcatheter Patent Ductus Arteriosus Closure in Extremely Premature Infants

doi:10.21203/rs.3.rs-5005236/v1

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Echocardiographic Predictors and Incidence of Left Ventricular Dysfunction Following Transcatheter Patent Ductus Arteriosus Closure in Extremely Premature Infants

https://doi.org/10.21203/rs.3.rs-5005236/v1

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Background:

Left ventricular (LV) dysfunction is a known complication after ligation of patent ductus arteriosus (PDA). An increasing number of premature and extremely low birth weight (ELBW) infants undergo transcatheter closure of PDAs. The aim of this study was to evaluate incidence and predictors of LV dysfunction after transcatheter PDA closure in ELBW infants.

Methods:

Subjects undergoing PDA closure from 2020–2022 who were ELBW (< 1 kg) and extremely premature (gestational age < 29 weeks) at birth were included. A single cardiologist reviewed each pre- and post-intervention echocardiogram and calculated LVEF.

Results:

67 subjects were included with a mean gestational age of 24.8 weeks and birth weight of 648.2 g. Mean age and weight at time of procedure were 7.9 weeks and 1722.4 g, respectively. All patients had normal LVEF pre-procedure (mean LVEF 67.0%) with a significant decline post-procedure to 60.3% (p < 0.001). Post-procedure, 81% of subjects maintained normal LVEF (> 53%). 55% of patients did have a decline in EF > 5%. There was no significant difference in post-procedure LV dysfunction in relation to pre-procedural PDA size, left atrial or LV dilation. All subjects recovered function with a median time to observed normal LVEF of 6 days.

Conclusions:

LV dysfunction develops in 19% of ELBW infants undergoing PDA device occlusion, is usually mild in severity, and normalizes in all subjects. The size of PDA, degree of left heart dilation does not predict LV dysfunction in this population.

Patent ductus arteriosus (PDA) causes significant morbidity and mortality in premature infants and they are more likely to have a persistent and hemodynamically significant PDA than term infants^1,2,3. There is no consensus in the cardiology or neonatology communities regarding early closure versus observation of the PDA in premature infants^4,5, and although some studies have shown that observation does not increase morbidity⁶, the opinion behind early closure is that it may decrease morbidities such as chronic lung disease and pulmonary hypertension. Left ventricular (LV) dysfunction is a known sequelae following ligation or device closure of a PDA in any patient and is likely a result of decreased preload after ligation of the PDA, as well as an increase in ventricular afterload.⁷ In a premature infant, afterload sensitivity of the immature myocardium may result in important changes in LV ejection fraction (EF) post-procedure and may increase the risk of significant cardiac dysfunction for premature infants, compared to term counterparts⁸. Due to the risk of a PDA to premature infants and the demonstrated safety and efficacy of transcatheter closure^9,10,11,12, smaller and younger infants are undergoing transcatheter device closure of PDAs. Although there have been reports on echocardiographic findings that could be associated with post-procedural LV dysfunction^13,14, it has remained difficult to predict which patients will develop cardiac dysfunction. Prior studies have studied older infants and should not necessarily be extrapolated to the premature and ELBW population given the characteristics of the immature myocardium, which may be more sensitive to acute changes in loading conditions.¹⁴

Important predictors of post-PDA closure LV dysfunction previously reported include pre-intervention left sided dilation, left atrial (LA): aortic ratio and PDA: aortic ratio¹³ and the LV end-systolic volume and PDA diastolic gradient¹⁴, although these studies were in patients at a mean age of 48 and 33 months-old, respectively. We sought to determine the incidence of LV systolic dysfunction after percutaneous PDA device closure in the ELBW and extremely premature patient population, and if the previously reported predictors of systolic LV dysfunction are applicable.

The Children’s Healthcare of Atlanta Institutional Review Board approved this retrospective study. A waiver of informed consent was granted. An internal database was queried to select subjects who underwent transcatheter PDA device closure from 2020–2022. Patients were included if they were ELBW (< 1 kg) and extremely premature (gestational age < 29 weeks) at birth. Patients with single atrial or ventricular level shunts were included, but those with additional or complex congenital heart defects were excluded. Patients were additionally excluded if there was inadequate echocardiographic imaging. Demographics and clinical data were extracted from the medical record. Blood pressure was taken as the closest recorded value to the time of the echocardiogram while heart rates were taken directly from the echocardiogram. An echocardiogram is routinely done within 24 hours pre- and post-procedure at our institution for premature PDA device closures.

A single blinded reader reviewed each pre- and post-intervention echocardiogram and calculated LVEF using the area-length method¹⁵ from parasternal short axis and apical four-chamber imaging. Mildly depressed function was defined as an LVEF < 53%, moderately depressed as LVEF < 40% and severely depressed as LVEF < 30%, based on convention of the American Society of Echocardiography.¹⁶ LA: aortic ratio was measured from two-dimensional imaging in the parasternal long axis. Additional measurements made on the echocardiograms were LV internal diameter in diastole in two-dimensional imaging from parasternal long axis (with z-scores calculated to standardize to patient body-surface area) and PDA systolic dimension on two-dimensional imaging at the narrowest point. PDA systolic dimension to aortic root diameter was additionally used as a surrogate for PDA size. If the patient had LV dysfunction, follow up echocardiography reports were reviewed for normalization of function. It is our practice to transfer subjects back to their respective referring institutions post-procedure if clinically stable to do so. Thus, LVEF was not calculated on follow up echocardiograms, as many patients did not have images available to review, but all subjects had follow up echocardiogram reports available in the medical records.

Statistical analysis was completed using SPSS Statistics version 28.0.0.0. Continuous variables were compared using paired t-test. Pearsons correlation and paired t-tests were used to compare variables in the two groups of interest: no LV dysfunction or LV dysfunction post-procedure.

A total of 67 subjects met inclusion criteria. Baseline demographics are detailed in Table 1. Subjects’ gestational ages ranged from 22 to 28.4 weeks and birth weight range was 350 to 1000 g. No patient had a known genetic syndrome. Mean age at intervention was 7.9 weeks with a range of 3 to 20 weeks. Thirty-three subjects (49%) received diuretics prior to PDA occlusion. A majority of subjects (n = 54; 81%) were exposed to pharmacologic therapies for ductal closure prior to transcatheter closure.

Table 1

Patient Demographics
Patient Demographics (n = 67)
Male, n (%)	30 (48)
Birth Weight (grams)	648.2 ± 148.0
Gestational age (weeks)	24.8 ± 1.6
Ethnicity / Race, n (%)
White	14 (21)
Black	48 (72)
Hispanic	3 (4)
Asian	2 (3)
Procedure
Age (weeks)	7.9 ± 4.4
Corrected gestational age (weeks)	32.8 ± 5.2
Weight (grams)	1722.4 ± 1284
Height (cm)	37.9 ± 6.6
BSA	0.12 ± 0.05
PDA diameter (mm)	2.7 ± 1.3
Pharmacologic attempt at PDA closure	54 (81)
BSA = body surface area; PDA = Patent ductus arteriosus
Data are expressed as mean ± standard deviation or n (%).

Baseline echocardiographic features are demonstrated in Table 2. All patients had normal LVEF pre-procedure (Table 2) with a mean EF of 67%. There was a statistically significant although clinically small increase in systolic and diastolic blood pressure, and decrease in heart rate at the time of the post-procedure echocardiogram. On pre-procedure echocardiogram, there was LA dilation with a mean LA: aortic ratio of 1.8. There was not significant LV enlargement pre-intervention, with a mean LV internal diameter z-score of 1.4. Both the LV and LA internal dimension and the LA: aortic ratio decreased significantly on the post-procedure echocardiogram. Thirteen (19%) subjects had a decline in function to mildly depressed or greater, and there was a significant overall decline post-procedure to 60.5% (p < 0.001) (Fig. 1) and a total of 37 (55%) subjects had a decline in EF of greater than 5%. Of 13 subjects who developed depressed function, 77% (n = 10) had mildly depressed function and 23% (n = 3) had moderately depressed function. The findings in Table 3 demonstrate that there were no statistically significant differences in the pre-procedure echocardiographic findings between the groups of patients who developed depressed LV function and those that did not. All subjects recovered function without additional inotropic support with a median time to observed normal LVEF of 6 days (range 3–30 days) post-procedure. There was variable follow up echocardiogram timing given that many patients returned to the referral center within 1–2 days after procedure completion, whether they had cardiac dysfunction or not. There was no significant difference in post-procedure LV dysfunction in relation to pre-procedural PDA size, left atrial dilation, or LV dilation (Table 3).

Table 2

Echocardiographic Features
	Pre-Intervention Echo	Post-Intervention Echo	p value
Heart rate	155.8 ± 21.3	148.9 ± 15.1	0.03
SBP (mmHg)	67.9 ± 13.4	72.2 ± 15.2	0.01
DBP (mmHg)	35.9 ± 11.3	42.8 ± 12.3	< 0.001
LAs (cm)	1.2 ± 0.3	1.1 ± 0.3	< 0.001
LA: Ao	1.8 ± 0.4	1.4 ± 0.3	< 0.001
LVIDd (cm)	1.8 ± 0.4	1.7 ± 0.4	0.01
LVIDd z-score	1.4 ± 1.6	0.8 ± 1.3	< 0.001
LVEF	67.0 ± 7.5	60.3 ± 11.0	< 0.001
N = 67 unless otherwise specified. Data are expressed as mean ± standard deviation. Two-sided p values are shown for t-tests. SBP = systolic blood pressure; DBP = diastolic blood pressure; LAs = left atrial size at end-systole; LA:AO = Left atrial to aortic ratio; LVIDd = Left ventricular internal diameter at end-diastole.

Table 3

Comparison of clinical features and pre-intervention echocardiographic data in patients without LV dysfunction post-procedure to those with LV dysfunction
	No LV Dysfunction (N = 54)	LV Dysfunction (N = 13)	p value
Clinical Features
BW (g)	653.7 ± 153.9	625.5 ± 123.5	0.5
GA	24.8 ± 1.5	24.9 ± 1.9	1
Procedure age (weeks)	7.7 ± 4.4	8.6 ± 4.5	0.4
Procedure weight (g)	1690.4 ± 1173.2	1855.4 ± 1723.0	0.7
cGA (weeks)	32.6 ± 5.0	33.5 ± 5.9	0.6
Pre-Intervention Echocardiographic Features
LVEF (%)	67.6 ± 7.1	64.6 ± 8.6	0.2
LVID z-score	1.3 ± 1.5	1.7 ± 1.6	0.4
LAs	1.2 ± 0.3	1.3 ± 0.3	0.2
LA: Ao	1.8 ± 0.5	1.8 ± 0.3	0.9
PDA diameter (mm)	2.8 ± 1.3	2.5 ± 1.1	0.5
PDA: Ao	0.4 ± 0.2	0.3 ± 0.1	0.2
N = 67 unless otherwise specified. Data are expressed as mean ± standard deviation. Two-sided p values reported for t-tests. SBP = systolic blood pressure; DBP = diastolic blood pressure; BW (g) = birth weight (grams); GA = gestational age (weeks); cGA = corrected gestational age (weeks); LAs = left atrial size at end-systole; LA: Ao = left atrium to aorta ratio; LVID = left ventricular internal dimension; LVEF = left ventricular ejection fraction; PDA: Ao = patent ductus arteriosus to aortic ratio.
This figure demonstrates the pre and post-procedure LV ejection fraction (%) for every subject.

Twelve (18%) subjects had a residual PDA on follow up echocardiogram, but none were larger than trivial or small and none required re-intervention for the residual shunt. No patient had an intra-procedural complication, but two subjects did have a post-procedure complication, one of device embolization requiring repeat catheterization and the other with thrombus in the femoral vessel that required pharmacologic treatment. Additionally, two patients developed moderate or greater tricuspid regurgitation, one of which had depressed function and one did not. Six patients died within the follow up period, but none due to the procedure. Only one of the patients who died also had LV dysfunction and that patient died several months later due to tracheostomy dislodgement.

PDA device closure in premature infants, and in particular ELBW infants, has been increasing in frequency. As such, the question of incidence and clinical importance of post-procedure LV dysfunction is important to investigate, given unique characteristics of the immature myocardium with extremely premature infants. Prior literature has investigated larger and older infants than our population. The Amplatzer Piccolo Occluder multicenter non-randomized single arm trial for PDA closure by Sathanandam et al demonstrated successful PDA closure in 99% of patients less than 2 kg¹⁷. In this study, 33 patients were included with a weight of 700 g to 1 kg. A study by Baspinar et al demonstrated safety of transcatheter closure in 69 infants less than 6 kg, 16 of them who were premature with a mean weight of 1.7 kg, quoting success of device closure in 94% of the infants who were not premature and 81% of those who were premature.¹² In regards to specific investigation into cardiac dysfunction following transcatheter closure of PDA, to our knowledge, this is the largest study analyzing a large group of patients less than 1000 g and less than 29 weeks gestation at birth. A study by Bischoff et al investigated echocardiographic changes in a group of 50 subjects who were extremely premature and ELBW, with findings demonstrating decreased LV systolic and diastolic function with imaging 1 hour post-procedure, but did not comment on echocardiographic predictive factors for these changes in LV function.¹⁸ Additionally, the subjects in our group were younger at age of intervention than most comparable prior studies. A series by Zahn et al investigated 27 premature infants with a mean procedural age of 30 days, although the infants birth weights ranged from 440 to 2480 g and gestational age from 24 to 32 weeks.¹⁹ This series reports 13% of subjects develop LV systolic dysfunction within 12 hours post-procedure, with subsequent recovery to normal in all infants, although with small sample size this represents only 3 out of the 27 subjects. One prospective study by Gupta et at evaluated echocardiographic predictors of post-procedure cardiac dysfunction and analyzed 32 patients who were a median of 35 months at time of intervention.¹⁴ Another by Hou et al analyzed 191 patients with a median age of 23 months at time of intervention.¹³ Incidence of LV systolic dysfunction was 25% and 14% in these studies, respectively. Given variations in sample size, one can come to the reasonable conclusion that these studies represent similar incidence of LV dysfunction with our study adding a larger number of subjects who are extremely premature and ELBW. Additionally, we demonstrated that although there is a significant decrease in LVEF, clinically significant changes are uncommon, and all subjects with depressed LVEF recovered normal function. While 19% of the group developed some degree of LV dysfunction (EF < 53%), notably, 55% subjects had a decline in LVEF more than 5% from pre-procedural echo. No subjects with LVEF < 53% needed increased inotropes in the acute phase post-procedure, with the caveat that stable patients were transferred back to referring institutions and it is unknown if they had additional inotropic needs between the time of return to referring institution and recovery of LV dysfunction.

Previously documented echocardiographic predictors of LV dysfunction post-PDA ligation (LA: Ao ratio, PDA: Ao ratio, LVID) were not found to be predictive of LV dysfunction in our cohort^13,14. However, as expected, the left atrial and left ventricular dilation did improve on post-intervention echocardiogram. The inability to predict post-procedure LV dysfunction in this group based on pre-intervention left sided dilation or size of the PDA may be due to a shorter duration of time of exposure to the physiology compared to subjects in other studies. Age at time of procedure was not different between the group that developed LV dysfunction and those who did not in our group. A question of the clinical significance of the LV dysfunction is raised. Given that all subjects recovered normal function without addition of inotropic support and the complications were no different in the group with and without dysfunction, the dysfunction at least retrospectively seems clinically unimportant. These data are reassuring that acute PDA closure in a population of very premature and ELBW infants can be accomplished successfully, without an increased risk of clinically significant acute LV dysfunction.

Limitations of this study include those of any single-center, retrospective study. However, there is an added limitation given that many of the subjects were referred to our center for PDA device closure and returned to the referring institution shortly thereafter. Information from the referring institution is available in the medical records but may not be complete. It would be expected that all subjects would have attempted pharmacologic closure of the PDA, but as seen in the results only 81% did. Data regarding the respiratory support needs and inotropic changes at the referring hospital post-procedure are not available, limiting the analysis to the 24 hours post-procedure in most cases. Additionally, all cases had a post-procedural echocardiogram ~ 24 hours post-PDA occlusion at our institution, but timing of echocardiograms after development of LV dysfunction was variable, up to 33 days in the longest case, due to the subjects’ return to referring institution. This makes assessing the timing of LV functional recovery a bit less predictable, though uniform functional recovery was observed within the timeframe evaluated and only one subject had a follow up echocardiogram with abnormal function prior to the study with recovered function. Given variable timing of follow-up echocardiograms, the duration to recovered function that we calculated is more a factor of the timing of follow up imaging. Review of follow-up echocardiograms was also limited to review of reports from referring institutions, and echocardiogram images were not accessible, which has the potential to introduce variability into assessment of LV function. It would be interesting to evaluate a comparable group of subjects undergoing surgical ligation to evaluate if there is a similar degree of LV dysfunction. Surgical ligation of PDAs is less common at our institution, and we would not have a sufficient number of subjects to conduct a meaningful analysis.

Although acute decrease in LVEF occurs frequently after transcatheter PDA closure in ELBW infants, clinically important LV dysfunction is uncommon. When it does occur, LV dysfunction normalizes in all subjects. This study is important in demonstrating that transcatheter closure of PDA in an ELBW and extremely premature infant does not have a much higher incidence of LV systolic dysfunction than in prior reports in an older population undergoing similar procedures. Further research into the diastolic dysfunction after PDA ligation and interventional closure would be beneficial to fully understand the cardiac implications on ELBW and extremely premature infants after PDA closure.

ELBW

extremely low birth weight

PDA

patent ductus arteriosus

left ventricular

ejection fraction

left atrium

Conflict of Interest Disclosures:

-Dr. Ligon is a proctor and education consultant for Abbott Vascular, Inc.; Dr. Ligon is also a consultant for B. Braun Interventional Systems, Inc.

-No other authors have any financial relationships to disclose.

Funding/Support: No funding was secured for this study.

Data Sharing: The datasets generated during and/or analyzed during this study are available from the corresponding author upon reasonable request.

Contributors Statement:

Marissa Adamson and Erik Michelfelder were responsible for conceptualization, study design, statistical analysis, and drafting of the manuscript. Allen Ligon assisted with conceptualization, data collection, and critical review of the manuscript. Sarah Hash assisted with collection of the data. Shannon Hamrick, Marcos Mills, Shazia Bhombal provided input throughout the study and critically reviewed and edited the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Competing interest reported. Dr. Ligon is a proctor and education consultant for Abbott Vascular, Inc.; Dr. Ligon is also a consultant for B. Braun Interventional Systems, Inc. No other authors have any financial relationships to disclose.

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Echocardiographic Predictors and Incidence of Left Ventricular Dysfunction Following Transcatheter Patent Ductus Arteriosus Closure in Extremely Premature Infants

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Background

Methods

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