Prenatal premature closure of the ductus arteriosus and acute PH

Authors: Pasinee Kanaprach (Neonatal Hemodynamics Fellow); Thien-An Lam (RN); Tiscar Cavallé-Garido (Pediatric Cardiologist); Gabriel Altit (Neonatologist).

Date: June 19, 2024

Introduction

Prenatal closure of the ductus arteriosus (DA) in utero can lead to significant neonatal complications, including persistent pulmonary hypertension of the newborn (PPHN). This case report discusses a neonate with prenatal DA closure, the ensuing PPHN, and the multidisciplinary management approach taken in the neonatal intensive care unit (NICU).

Case Presentation

Antenatal follow-up had not detected any abnormalities. Baby was born at term, with an appropriate weight for gestational age and Apgar scores of 5, 5, and 6 at 1, 5, and 10 minutes, respectively. Initial resuscitation steps included positive pressure ventilation (PPV) due to a heart rate (HR) of less than 100, and placement on continuous positive airway pressure (CPAP) at 10 minutes of life with FiO2 80%. The infant had some mild to moderate retractions at that time. The patient was transferred to the NICU at 30 minutes of life. Arterial cord gas analysis showed a pH of 7.30, CO2 of 52, bicarbonate of 24, and a base excess of -1.7.

Upon admission to the NICU, baby required CPAP with FiO2 80% to maintain saturation levels in the mid-80s. There were no clinically significant differences in pre- and post-ductal saturations. A blood gas analysis at one hour of life revealed a pH of 7.26, CO2 of 63, bicarbonate of 28.3, base excess of -1, lactate of 2.7, and glucose of 2. A chest X-ray indicated a small right pneumothorax. The infant's physical examination was unremarkable, with normal heart sounds and good perfusion. Despite FiO2 of 100%, saturations remained at 90-92%, desaturating to 50% when crying. The infant was intubated and started on inhaled nitric oxide (iNO) at 20 ppm, which improved oxygen requirements to 65%.

Echocardiography at 10 hours of life confirmed pulmonary hypertension, a closed ductus arteriosus, moderate right ventricular hypertrophy (RVH), moderately to severely reduced right ventricular (RV) systolic function, and a moderate atrial septal defect (ASD) with right-to-left shunting. The infant's condition required inotropic support with milrinone, epinephrine, and hydrocortisone, along with sedation using fentanyl, dexmedetomidine, and midazolam. Initial ventilatory support with ACVG was followed by high-frequency oscillatory ventilation (HFOV) and later high-frequency jet ventilation (HFJV). Rapid Comprehensive Developmental Disorder panel with pulmonary hypertension panel was done and did not result in any anomalies. Baby progressively recovered (see figure below) and inotropic support was progressively weaned. Inhaled nitric oxide was weaned with a bridge using sildenafil (enteral). The sedation was also progressively weaned. By DOL 21, the patient had recovered (extubated in room air) and was off the sildenafil. The RV hypertrophy persisted but was improving, probably outlining some regression of the long-standing RV remodelling. Baby was discharged at 1 month of life in room air.

Chest radiography outlining increased lung expansion and "black" lungs - low pulmonary vascular flow.

Discussion

The pathophysiology of prenatal premature ductal closure involves significant alterations in fetal hemodynamics, leading to increased pulmonary vascular resistance and subsequent PPHN postnatally. This condition can be exacerbated by perinatal asphyxia and abnormal pulmonary vasoconstriction. Potential maternal risk factors include the use of NSAIDs and other nutritional products (polyphenol-rich foods), although this was not documented in Baby's case.

Prenatal ductal closure, or premature closure of the ductus arteriosus (DA), disrupts the normal fetal circulation and significantly impacts neonatal outcomes by leading to persistent pulmonary hypertension of the newborn (PPHN), thought to be due to reactive pulmonary vascular remodelling due to increased pulmonary blood flow in fetal life in a constricted pulmonary vasculature. Under typical circumstances, the DA allows blood to bypass the fetal lungs and flow directly from the pulmonary artery to the aorta. Premature closure of this duct, however, forces blood to be redirected through the pulmonary circulation, significantly increasing pulmonary blood flow in a vascular network that is constricted. This abnormal state promotes maladaptive remodeling of the pulmonary vasculature, characterized by increased muscularization and adventitial thickening of the pulmonary arteries. As a result, at birth, the neonate’s pulmonary vasculature remains abnormally constricted and resistant to the sudden decrease in pulmonary vascular resistance that should occur as the lungs expand and oxygenate. This sustained high pulmonary vascular resistance impedes adequate oxygenation, leading to systemic hypoxemia and right ventricular (RV) strain as the heart attempts to overcome the elevated pressure in the pulmonary circuit. The RV usually faces increased afterload in fetal life, leading to increased remodelling by RV hypertrophy, which leads to RV diastolic impaired performance in post-natal and increased right atrial pressure. With the combination of low pulmonary blood flow due to high PVR, leading to low left atrial preload, and the increased RA pressure, there is right to left shunting at the inter-atrial shunt level, leading to hypoxic blood entering the systemic circulation. Additionally, the premature closure of the DA may result in diminished perfusion of the lungs, further exacerbating the hypoxic environment and perpetuating the cycle of elevated pulmonary pressures and inadequate oxygenation characteristic of PPHN.

The differential diagnosis of persistent pulmonary hypertension of the newborn (PPHN) encompasses a variety of etiologies, each requiring distinct management strategies. PPHN, or acute pre-capillary pulmonary hypertension of the newborn, often results from the failure of the natural mechanisms that lead to the post-natal decrease in pulmonary vascular resistance (PVR). This failure is frequently secondary to factors that stress the fetus, such as asphyxia, acidosis, infection, respiratory distress syndrome, or other maladaptive conditions of the newborn, including severe anemia. Other conditions associated with the persistence of high PVR include pulmonary hypoplasia and surfactant deficiency. Pulmonary hypoplasia can contribute to decreased pulmonary vascular surface area, adding a fixed component to the condition and may occur in the context of long-standing oligohydramnios. Conditions leading to increased pulmonary vascular resistance also include significant intra-uterine growth restriction, especially in the context of maternal hypertensive disorders.

Diseases causing post-capillary pulmonary hypertension include pulmonary venous stenosis and conditions with increased left atrial pressure, such as significant mitral stenosis, mitral insufficiency, or significant left ventricular dysfunction or hypoplasia. In our case, pulmonary venous hypertension resulting from pulmonary venous obstruction was less likely as it typically manifests with increased pulmonary vascular markings and edema on chest radiography. In pre-capillary acute pulmonary hypertension, chest radiography typically showcases very dark and oligemic lung fields, as was observed in this case.

Conditions that can present with acute pulmonary hypertension include those with long-standing increases in right atrial and right ventricular preload, leading to excessive pulmonary blood flow in fetal life. These conditions include Vein of Galen malformation and hepatic arteriovenous malformation. Genetic conditions may be associated with early-onset pre-capillary pulmonary arterial hypertension, even within the neonatal period, such as trisomy 21, trisomy 18, and single-gene defects in BMPR2, TBX4, and SOX17. Additionally, diffuse lung disorders and interstitial lung diseases (ILD) of infancy, including alveolar capillary dysplasia with or without misalignment of the pulmonary veins (ACD-MPV), though rare, can present similarly. Pulmonary interstitial glycogenosis (P.I.G.) is associated with severe PPHN but usually presents with abnormal chest X-rays (CXR) showing bilateral infiltrates. Other maladaptive disorders of the lungs that can lead to pulmonary hypertension include alveolocapillary dysplasia. Congenital diaphragmatic hernia may also present with acute pulmonary hypertension that can be multifactorial, involving high PVR, pulmonary hypoplasia, acidosis, hypoxia, left ventricular hypoplasia, and left ventricular dysfunction.

Management and information:

In this context there PDA is closed and there has been likely pre-natal ductal closure. As such, there is RV remodelling (hypertrophy), which leads to high RV end-diastolic pressure and a significant volume of hypoxic blood entering the systemic circulation at the level of the atrium, leading to pre-ductal desaturation. Pre and post-ductal saturation are the same because there is no duct! The RV may be failing. While these patients may remain with lower saturations for a while because of the R-L shunt at the atrial level, it is important to be patient. Agents like iNO and milrinone may be used to relax the pulmonary vascular bed. Inotropy may be necessary to support the RV function (dobutamine or epinephrine). Occasionally in significant RV hypertrophy, one may consider rate-control (such as esmolol). However, beta-blockers may also have some degree of myocardial depression and one should be particularly cautious in that context.
If the duct has been closed for a long time, it is unlikely that PGE will function as a strategy to re-open it.
- If the ductus has been closed for an extended period in utero (e.g., weeks), intimal thickening, fibrosis, and remodeling may make it refractory to PGE1. If closure was recent or incomplete, PGE1 may still be theoretically effective in reopening the PDA.
Milrinone may be considered to help the RV relax if the baby is not hypotensive and has good urine output (because it tends to renaly accumulate and can cause significant systemic vasodilation) - Reference.
Ishida H, Kawazu Y, Kayatani F, Inamura N. Prognostic factors of premature closure of the ductus arteriosus in utero: a systematic literature review. Cardiology in the Young. 2017;27(4):634-638. doi:10.1017/S1047951116000871
- "We analysed the data of 116 patients from 39 articles. Of these, 12 (10.3%) died after birth or in utero. Fetal or neonatal death was significantly correlated with fetal hydrops (odds ratio=39.6, 95% confidence interval=4.6–47.8) and complete closure of the ductus arteriosus (odds ratio=5.5, 95% confidence interval=1.2–15.1). Persistent pulmonary hypertension was observed in 33 cases (28.4%), and was also correlated with fetal hydrops (odds ratio=4.2, 95% confidence interval=1.3–4.6) and complete closure of the ductus arteriosus (odds ratio=5.5, 95% confidence interval=1.6–6.0). Interestingly, maternal drug administration was not correlated with the risk of death and persistent pulmonary hypertension."
- "Persistent pulmonary hypertension of the newborn was observed in 33 cases (28.4%), 14 of which required mechanical ventilation (42.4%), including five patients who received nitric oxide inhalation. Fisher’s exact tests revealed that persistent pulmonary hypertension was significantly correlated with fetal hydrops (p=0.015; odds ratio 4.2, 95% confidence interval 1.3–4.6) and fetal right heart dilatation (p=0.0014; odds ratio 8.6, 95% confidence interval 1.4–22.1), but not with maternal drug administration (p=0.245) and fetal tricuspid regurgitation (p=0.108)." ... "Patients who could survive the perinatal period, regardless of persistent pulmonary hypertension, had no neurological or cardiac complications for at least 1–10 months; however, 11 patients (9.5%) had mild right ventricular hypertrophy or tricuspid regurgitation without any clinical symptoms, as detected by follow-up echocardiography at 1–6 months of age."

Presentation on Prenatal Closure of the Ductus

PrematurePDAclosure.pdf

Initial Echocardiography

Parasternal views

Parasternal long axis view (PLAX) with a sweep towards posterior outlining the significant RV hypertrophy. One may also appreciate that the RV is subjectively dilated and struggling in terms of function.

PLAX with anterior sweep outlining the RVOT being hypertrophied. One may also appreciate during the sweep the presence of the crossing of vessels, ruling out transposition of great arteries.

PLAX with colour. One may appreciate the flow filling the pulmonary arteries, as well as the opening and closing of the aortic valve.

PLAX with colour outlining flow filling through the tricuspid valve in the posterior view and some degree of mild tricuspid regurgitation.

M-Mode in the PLAX outlining the motion of the various walls. Here the shortening fraction was 19%. However, there is septal dyskinesis in the context of pulmonary hypertension rendering this marker not-reliable regarding LV performance.

Parasternal short axis view (PSAX) outlining the relationship of the RV to LV.

PSAX sweep with colour. No obvious evidence of a ventricular septal defect, although these can be mixed when the PVR are high and there is reduced flow velocities through a potential inter-ventricular septal defect.

PSAX with colour box outlining the flow through the pulmonary valve and filling the right and left pulmonary arteries that are of good caliber.

Apical views

Apical 4 chamber view. Significant right ventricular hypertrophy. Dysfunctional Right Ventricle. Apex is very crowded (muscular hypertrophy). In these contexts, you have to rule out etiologies of increased afterload of the RV that would lead to pressure overload causing RV remodelling. This includes RVOT obstruction, pulmonary stenosis and pulmonary hypertension.

Sweep in the Apical 4 chamber view outlining the RVOT coming out of the RV anteriorly, with opening and closing of the pulmonary valve. There is no obvious sign of RVOT obstruction to explain the significant RV hypertrophy.

RV Fractional Area Change calculated at (3.21-2.12)/3.21 = 34%

Tricuspid annular plane systolic excursion (TAPSE) by M-Mode. Here the value is measured at 4.32 mm - which corresponds to a Z-Score of -7.8. This outlines significant systolic compromise of the right ventricle.

Apical 2 chamber view. There is some minimal pericardial effusion. There is adequate LV function (subjective).

Apical 4 chamber view outlining the LV and RV filling. One may also appreciate some mild tricuspid regurgitation in ventricular systole.

Tricuspid regurgitant jet velocity outlining that the RV-RA gradient is 47.50. This patient has a right to left atrial shunt, outlining that the RA pressure is likely 5mmHg+. As such, one may assume that the RV systolic pressure is at least 52.5 mmHg. In this case, this may even underestimate the true RV pressure.

Apical 5 chamber view outlining the LV output.

LVO was decreased in this patient, possibly related to the decreased LV preload from low pulmonary blood flow. There is a contributor to LV preload from the LA.

RV inflow velocities outlining E velocity less than A velocity. This can be within normal limit in the first week of life, but outlines that there is likely increased RV end-diastolic pressure restricting some of the filling velocity in the early passive phase of diastolic filling.

LV inflow velocities. The patern of E/A less than 1.0 is acceptable in the first week of life while the baby still transitions to the post-natal circulation.

The TDI outlined a RV s' of 4.1 cm/s and less. This corresponds to a Z-score of -2.58, outlining there is some degree of RV systolic dysfunction.

RV dilatation and decreased function in the apical view.

Anterior sweep with some dilation of the main pulmonary artery. The opening and closing of the pulmonary valve is well observed.

Subcostal view

Right to left inter-atrial shunt.

Subcostal view (long-axis) outlining the right to left atrial shunt, leading to systemic desaturation (deoxygenated blood entering the systemic circulation at the atrial level). In strict right to left atrial shunting, one must absolutely rule out total anomalous pulmonary venous return.

Subcostal view (short-axis) outlining that the inter-atrial shunt is right to left. Sweep outlining that the RV is hypertrophied and dilated, with flattening of the septal curvature in systole (even bowing towards the LV).

Suprasternal, Ductal, Crab views

Arch view outlining normal caliber of the aorta without presence of obstruction.

Branching of the pulmonary arteries outlining that the right and left pulmonary artery are of normal caliber with forward flow.

Ductal view outlining the absence of a ductus in this newborn that is within a few hours of life with significant acute pre-capillary pulmonary hypertension (acute PH / persistent pulmonary hypertension of the newborn).

"Crab view" outlining the pulmonary venous drainage coming to the left atrium. It is important to outline this in patients with strict right to left shunt at the level of the inter-atrial shunt.

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