Role of sildenafil in a neonate with double outlet left ventricle and pulmonary hypertension

      Abstract

      Double outlet left ventricle (DOLV) is a rare congenital heart defect where the aorta and the pulmonary trunk arise predominantly from the morphologic left ventricle. The clinical manifestations depend upon the location of the ventricular septal defect in relation to the great arteries, degree of pulmonary and aortic outflow tract obstruction, and other associated cardiac defects. We describe a neonate with DOLV, sub-aortic ventricular septal defect, and side-by-side great vessels who continued to require oxygen for desaturation to 60% in the neonatal period. His clinical symptoms were suggestive of persistent pulmonary hypertension, with 5-8% higher saturations in the leg compared to arm. He was started on oral sildenafil and his oxygen requirement decreased from 2 L/min to 0.1 L/min within 24 hours of initiating sildenafil.
      <Learning objective: The clinical manifestation of double outlet left ventricle mimic transposition of great vessels, tetrology of Fallot, or ventricular septal defect depending upon the cardiac lesion. The use of sildenafil has been expanded in the management of infants with non-cardiac as well as cardiac-related pulmonary hypertension. Sildenafil was successfully used in an infant with double outlet left ventricle, sub-aortic ventricular septal defect and rightward aortic root in the management of increased oxygen requirement attributed to pulmonary hypertension. However, close monitoring is required due to the risk of pulmonary over circulation.>

      Keywords

      Introduction

      Double-outlet ventricles with normal atrioventricular connections constitute approximately 1% of congenital heart disease, and less than 5% of those are double outlet left ventricle (DOLV) [
      • Tchervenkov CI
      • Walters III, HL
      • Chu VF.
      Congenital heart surgery nomenclature and database project: double outlet left ventricle.
      ,
      • Van Praagh R
      • Weinberg PM
      • Srebro JP.
      Double outlet left ventricle.
      ]. DOLV was considered to be an embryologically impossible ventriculo-arterial connection until its first description by Sakakibara and colleagues in 1967 [
      • Sakakibara S
      • Takao A
      • Arai T
      • Hashimoto A
      • Nogi M.
      Both great vessels arising from the left ventricle.
      ]. In 1991 through an extensive review of 109 cases, Van Praagh and colleagues attempted to classify this spectrum of disease depending on the location of ventricular septal defect in relationship to the great vessel [
      • Van Praagh R
      • Weinberg PM
      • Srebro JP.
      Double outlet left ventricle.
      ]. In DOLV with transposition physiology, the aortic root is rightward (right anterior or right side-by-side to pulmonary artery) with sub-aortic ventricular septal defect and no pulmonary outflow obstruction. Neonates with D-looped transposition of the great arteries (D-TGA) are at higher risk of persistence of pulmonary hypertension [
      • Roofthooft MT
      • Bergman KA
      • Waterbolk TW
      • Ebels T
      • Bartelds B
      • Berger RM.
      Persistent pulmonary hypertension of the newborn with transposition of the great arteries.
      ,
      • Newfeld EA
      • Paul MM
      • Muster AJ
      • Idriss FS.
      Pulmonary vascular disease in complete transposition of the great arteries: a study of 200 patients.
      ]. There are some case reports describing the use of sildenafil in D-TGA for pulmonary hypertension [
      • Stocker C
      • Penny DJ
      • Brizard CP
      • Cochrane AD
      • Soto R
      • Shekerdemian LS.
      Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery.
      ]. However, the use of sildenafil in DOLV with the clinical feature of pulmonary hypertension has not been described previously.

      Case report

      A male infant was born at 39 weeks gestation via spontaneous vaginal delivery at another hospital. There were no prenatal or postnatal complications and APGAR scores were 8 and 9 at 1 and 5 minutes, respectively. At 4 hours of age, the baby was noted to have cyanosis with oxygen saturations in the right arm between 70 and 75%. He was breathing comfortably with normal blood pressures in all four extremities. He was started on nasal oxygen and his oxygen saturations improved to 80%. A chest radiogram showed no lung pathology. An echocardiogram performed at the other hospital was concerning for transposition of great arteries. Intravenous prostaglandin drip was initiated and he was transferred to our institution.
      An echocardiogram performed at our institution showed aorta and pulmonary arteries arising from the morphologically left ventricle with side-by-side orientation (Fig. 1). The aorta was anterior and rightward of the pulmonary artery (Fig. 2). A non-restrictive, sub-aortic ventricular septal defect with bidirectional shunting was noted (Fig. 1). There was a small restrictive atrial septal defect with bidirectional shunting. The patent ductus arteriosus (PDA) was moderate in size with bidirectional shunt (Fig. 3a). There was mild flow acceleration in the sub-pulmonic area (velocity: 2.2 meters/second). Both the ventricles were of normal size and function.
      Fig 1
      Fig. 1Subcostal view showing aorta and pulmonary artery (PA) arising from the left ventricle with sub-aortic ventricular septal defect (VSD).
      Fig 2
      Fig. 2Suprasternal view showing side-by-side great arteries with aorta to the right of pulmonary artery with proximal bifurcation of the pulmonary artery seen in (b).
      Fig 3
      Fig. 3(a) Suprasternal view showing the aortic arch and right to left shunting (arrow) at the patent ductus arteriosus (PDA) level before starting sildenafil. (b) Suprasternal view showing left to right shunting (dashed arrow) across the PDA after initiation of sildenafil.
      Over the next few hours, the infant's saturations decreased to 60% despite increasing FiO2 to 80% and increasing prostaglandin to 0.05 mcg/kg/min. Therefore, a balloon atrial septostomy was performed. An angiogram injection in the right ventricle showed the outflow to the aorta with no contrast in the pulmonary artery. Diagnostic coronary angiography revealed left anterior descending and right coronary artery arising from anterior sinus and left circumflex artery arising from posterior sinus of the aortic valve. His saturations improved to 80% following balloon atrial septostomy, and he was weaned off prostaglandins by 4 days of life. However, he did not tolerate weaning of oxygen as multiple attempts to wean his FiO2 dropped his saturations below 70%. His right upper extremity (RUE) and right lower extremity (RLE) saturations were compared at rest and during agitation. When weaning oxygen, the saturations in his RLE consistently read 5-8% higher than RUE saturations. Oral sildenafil was initiated on day of life 12 at 0.5 mg/kg/dose every 8 hours for suspected pulmonary hypertension and later escalated to 1 mg/kg every 8 hours. His oxygen saturation stabilized between 80 and 85% in the RUE and his oxygen requirement decreased from 2 L/min to 0.1 L/min O2 by nasal cannula over 24 hours. He was discharged home on 0.25 L/min O2 and sildenafil at 17 days of age. The O2 saturations were similar in the leg and right arm at the time of discharge. His echocardiogram at discharge continued to show bidirectional, non-restrictive shunting across the atrial and ventricular septum. The PDA was small, mildly restrictive, and shunting left to right (Fig. 3b).
      He was seen in the cardiology clinic at 1 month of age and saturations remained 80-85% on 0.25 L O2 and oral sildenafil. His peak sub-pulmonic gradient progressively increased at 5 months of age. His oxygen saturations were maintained in the mid 80s with no evidence of differential cyanosis and weaned off supplemental oxygen by 5 months of age. He was continued on sildenafil until appropriate surgical readiness was achieved at 8 months of age when he underwent surgical repair that included left ventricle to aorta VSD tunnel repair with VSD enlargement, right ventricle to pulmonary artery conduit placement, and partial closure of secundum atrial septal defect (ASD). Post operatively, he was weaned off milrinone drip and supplemental oxygen by post-operative day (POD) 6 and 17, respectively. He was discharged home without any oxygen supplementation on POD 19. His oxygen saturations were close to 100% during a follow up in cardiology clinic at 4 months after surgery, with no clinical and echocardiographic signs of pulmonary hypertension.

      Discussion

      DOLV, similar to double outlet right ventricle, has varied clinical presentations and depends on the compilation of underlying cardiac defects and resulting hemodynamics. Sub-aortic VSD and right anterior aorta with pulmonary outflow tract obstruction leads to a physiology similar to tetralogy of Fallot, whereas those with no obstruction manifest as transposition physiology [
      • Tchervenkov CI
      • Walters III, HL
      • Chu VF.
      Congenital heart surgery nomenclature and database project: double outlet left ventricle.
      ]. As described by Van Praagh and associates, 73% of DOLV cases with situs solitus and normal atrio-ventricular connections had sub-aortic VSD and 90% of them were found to have pulmonary outflow tract obstruction [
      • Van Praagh R
      • Weinberg PM
      • Srebro JP.
      Double outlet left ventricle.
      ]. Our case presented with transposition physiology due to the sub-aortic VSD and side-by-side great vessels (aortic root to the right of pulmonary) with subpulmonic obstruction.
      Persistent pulmonary hypertension of the newborn (PPHN) has been associated with D-TGA with an incidence between 1 and 12.5% [
      • Roofthooft MT
      • Bergman KA
      • Waterbolk TW
      • Ebels T
      • Bartelds B
      • Berger RM.
      Persistent pulmonary hypertension of the newborn with transposition of the great arteries.
      ,
      • Newfeld EA
      • Paul MM
      • Muster AJ
      • Idriss FS.
      Pulmonary vascular disease in complete transposition of the great arteries: a study of 200 patients.
      ]. This conglomerate effect of PPHN and D-TGA has serious implications on the treatment and prognosis, requiring inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation with higher mortality [
      • Roofthooft MT
      • Bergman KA
      • Waterbolk TW
      • Ebels T
      • Bartelds B
      • Berger RM.
      Persistent pulmonary hypertension of the newborn with transposition of the great arteries.
      ,
      • Sallaam S
      • Natarajan G
      • Aggarwal S.
      Persistent pulmonary hypertension of the newborn with D-transposition of the great arteries: Management and prognosis.
      ]. In the past two decades, sildenafil use has expanded in congenital heart disease with pulmonary hypertension in the pre and post-operative period [
      • Stocker C
      • Penny DJ
      • Brizard CP
      • Cochrane AD
      • Soto R
      • Shekerdemian LS.
      Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery.
      ]. Sildenafil acts by inhibiting phosphodiesterase type 5, thereby increasing the bioavailability of cyclic guanosine monophosphate and allowing endogenous NO to cause vascular smooth muscle relaxation [
      • Corbin JD
      • Francis SH.
      Cyclic GMP phosphodiesterase-5: target of sildenafil.
      ]. Sildenafil is used alone or in combination with iNO and other agents to ameliorate pulmonary hypertension.
      Our case had a high oxygen requirement to maintain oxygen saturations failing multiple attempts to wean oxygen. He also continued to have differential saturations (RLE > RUE) of greater than 5% suggesting right to left shunting through the PDA and pulmonary hypertension. His sub-pulmonic obstruction was trivial which could not explain his low saturations responding to oxygen. He was full term, breathing comfortably and had no lung pathology on chest radiogram. As providing oxygen improved his saturations, we suspected persistent pulmonary hypertension, similar to patients with D-TGA. Initiating oral sildenafil at 12 days significantly reduced his oxygen requirements and oxygen saturations were similar between the upper and lower extremities. He was discharged home with close outpatient follow up. His subsequent echocardiograms performed prior to discharge (at day of life 17) and in the outpatient clinic (at 2 months of age) showed left to right shunt across the PDA. We closely followed the patient to observe signs of pulmonary over circulation due to sildenafil, and worsening gradient across the ASD, VSD, sub-pulmonic and aortic outflow. His peak sub-pulmonic gradient progressively increased at 5 months of age that balanced pulmonary blood flow and prevented pulmonary over circulation. There were no objective measures to determine pulmonary hypertension on echocardiogram due to his unique physiology. Therefore, clinical assessment in the form of oxygen requirement and differential saturations guided his management.
      This is the first case describing sildenafil use in patients with DOLV. Sildenafil helped wean his oxygen requirement facilitating safe discharge. Hence, a case-based trial of sildenafil can be considered in DOLV patients with clinical signs of pulmonary hypertension requiring supplemental oxygen.

      Financial support

      This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.

      Authors' contributions

      All authors contributed in drafting the manuscript

      Consent to publish

      Consent was obtained from parent to publish echocardiogram images

      Declaration of Competing Interest

      None.

      Acknowledgments

      None.

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