Acute Respiratory Distress and Oxygen Refractory Hypoxemia in a Term Newborn

A full-term boy is born to a 28-year-old gravida 1 para 1 mother at 39 weeks 3 days’ gestational age via normal spontaneous vaginal delivery. Pregnancy was complicated by gestational diabetes managed with metformin. The mother has no known history of nonsteroidal anti-inflammatory drug (NSAID) or corticosteroid use during the pregnancy. Prenatal anatomy scan with ultrasonography and laboratory findings are unremarkable. The mother’s blood type is O+ and she is negative for group B streptococcus carriage. Membranes ruptured 7 hours prior to delivery and the mother is afebrile. The community pediatrician is asked to attend the delivery due to meconium-stained fluids and category 2 fetal heart rate tracing showing minimal variability.At birth, the patient is in immediate respiratory distress characterized by chest wall retractions with an initial oxygen saturation of approximately 75% in room air. Temperature is 36.8 °C, heart rate is 133 beats/min, and respiratory rate is 100 breaths/min. Birth weight is 3.24 kg (56th percentile) and length is 50 cm (52nd percentile). Apgar scores are 4 (0 = skin color, 1 = heart rate, reflex irritability, muscle tone, and respiratory effort), 7 (1 = skin color, reflex irritability, and muscle tone), and 7 (1 = skin color, reflex irritability, and muscle tone) at 1, 5, and 10 minutes of life, respectively. Gentle oropharyngeal suctioning is performed and is notable for a small number of clear secretions. Supplemental oxygen is initiated at 2 L per minute (50% FiO2) with resolution of chest wall retractions but continued tachypnea. At 10 minutes of life the patient’s oxygen saturation while on low-flow nasal cannula remains in the 70s and is refractory to increased titration of supplemental oxygen. Pre- and postductal saturations are equivalent.On physical exam, the patient does not demonstrate dysmorphic features. His anterior fontanelle is open, soft, and flat. Mucus membranes are moist. He is tachypneic. His lungs are clear to auscultation, and there is good air movement throughout the lungs without crackles, wheezing, or rhonchi. There are no murmurs, rubs, or gallops. Femoral pulses are palpable, equal, and strong bilaterally. Capillary refill is less than 2 seconds. The abdomen is soft, nondistended, and nontender without organomegaly. Neurologic examination is appropriate for his age and gestation. There is acrocyanosis limited to the extremities.The initial blood glucose level is normal at 30 minutes of life at 89 mg/dL (8.9 × 10−5 kg/L). Blood glucose is repeated within the hour and is 25 mg/dL (2.5 × 10−5 kg/L). A bolus of dextrose 10% in water is administered intravenously over 3 minutes, and a continuous infusion of dextrose 10% in water is initiated. Blood glucose 30 minutes later is 45 mg/dL (4.5 × 10−5 kg/L).Initial peripheral venous blood gas is pH 7.33, pCO2 49 mm Hg, pO2 30 mm Hg, pHCO3 25 mm Hg, and BE −1. Initial laboratory results include a normal hemoglobin of 18.0 g/dL (1.8 × 10−1 kg/L) with a reference range of 13.9 to 19.1 g/dL (1.39–1.91 × 10−1 kg/L), a normal hematocrit of 53.5% with a reference range of 39.8 to 53.6%, and low platelet count of 187 × 109/L with a reference range of 218 to 419 × 109/L. The total white blood cell count is reassuring at 8.3 × 109/L with a reference range of 8.0 to 15.4 × 109/L with 47% neutrophils, 43% lymphocytes, 5% monocytes, 4% eosinophils, and 1% basophils. Blood cultures are obtained, and the patient is started on empirical ampicillin and gentamycin. C-reactive protein is below 3.0 mg/L (<3.0 × 10−6 kg/L) with a reference range less than 8.0 mg/L (<8.0 × 10−6 kg/L). The patient’s respiratory support is escalated to nasal continuous positive airway pressure (NCPAP) with a positive end-expiratory pressure of 5 cm H2O (25% FiO2) with oxygen saturations remaining around 70%. A chest radiograph demonstrates an enlarged cardiac silhouette with normal lungs (Figure 1). Given the patient’s continued oxygen saturation of 70% after initiation of supplemental oxygen, he is started on empirical alprostadil (prostaglandin [PG] E1 analog), and an echocardiogram is performed.The differential for hypoxemic respiratory distress in a newborn can be split into 2 general categories: respiratory and nonrespiratory causes. The most common respiratory causes include transient tachypnea of the newborn, respiratory distress syndrome in the newborn, pneumonia, pneumothorax, and meconium aspiration syndrome.1 Transient tachypnea of the newborn classically presents with prominent perihilar interstitial edema that usually resolves within 48 to 72 hours.2 Respiratory distress syndrome is typically characterized by diffuse, bilateral, granular opacities with air bronchograms and hypoaeration.3 Neonatal pneumonia is often seen with either infiltrate, consolidation, cavitation, and/or pneumatocele.4 Pneumothorax is frequently identified with a visible pleural edge with no lung markings past this line.5 Meconium aspiration syndrome is associated with hyperinflated lungs with patchy atelectasis on chest radiograph.6 Pulmonary causes are typically responsive to oxygen administration. Given that our patient’s chest radiograph demonstrated cardiomegaly without significant pulmonary findings and the lack of clinical improvement with oxygen initiation, the most likely etiology was a nonrespiratory cause.Nonrespiratory causes of hypoxemic respiratory distress in a newborn include congenital heart disease, tracheoesophageal fistula, persistent pulmonary hypertension of the newborn, sepsis, and diaphragmatic hernia.1When hypoxemia is refractory to oxygen therapy, a cardiac etiology or persistent pulmonary hypertension of the newborn should be suspected and the hypoxemia should be further evaluated with an echocardiogram to determine the diagnosis. Neonates with congenital heart disease may be asymptomatic, present with progressive heart failure symptoms, or develop acute heart failure with cardiogenic shock.7 Generally, cyanosis in the neonate is caused by either right-to-left shunting and/or inadequate pulmonary blood flow.8 The volume of intra- and extracardiac shunting and the amount of intracardiac mixing of deoxygenated and oxygenated blood are dynamic and may lead to slow but progressive worsening or rapid deterioration in clinical status.Common cardiac causes of neonatal cyanosis within the first hours of life include tetralogy of Fallot with severe right ventricular (RV) obstruction, transposition of the great arteries, Ebstein malformation, pulmonary atresia, and obstructed total anomalous pulmonary venous return. Tetralogy of Fallot is characterized by 4 components: aorta that overrides the ventricular septum, RV outflow tract obstruction, RV hypertrophy, and a ventricular septal defect. The clinical presentation varies with the severity of the RV outflow obstruction, the most severe form being pulmonary atresia causing complete separation from the pulmonary artery, which presents with severe cyanosis. In such cases, PGE1 is required to keep the ductus patent while preparing for surgical correction.7Neonates with transposition of the great arteries have 2 independent cardiac circuits with the aorta arising from the right ventricle and the pulmonary artery from the left ventricle (LV). These parallel circuits require an intracardiac shunt for adequate mixing of deoxygenated and oxygenated blood. In the absence of a large atrial or ventricular septal defect, neonates can be profoundly cyanotic, which requires administering PGE1 to maintain ductal patency or performing an urgent balloon atrial septostomy.7In patients with Ebstein anomaly, there is apical displacement of the tricuspid valve leading to a decrease in the size of the RV chamber. When the RV chamber size is significantly diminished, the effective pulmonary circulation is limited and deoxygenated blood begins shunting into the systemic circulation through either a patent foramen ovale or atrial septal defect, causing cyanosis.9Pulmonary valve atresia is a ductal dependent lesion that requires a ductus arteriosus (DA) for adequate pulmonary blood flow in order to maintain appropriate oxygen saturations. In patients with total anomalous pulmonary venous return, oxygenated blood leaves the lungs through the pulmonary veins, either draining directly into the right atrium, or, after first entering the coronary sinus, into a systemic vein or a confluence adjacent to the posterior wall of the left atrium. When these abnormal connections are significantly narrowed or obstructed, oxygenated blood is unable to drain into the right heart. Therefore, the systemic circulation is primarily composed of deoxygenated blood that reenters the right heart through the systemic veins and across an obligatory right-to-left shunt.10When patients are born with ductal dependent systemic circulation, a patent ductus arteriosus (PDA) is essential to maintain adequate perfusion and end organ function. A PDA maintains perfusion with left-sided heart defects including abnormalities of the aortic arch such as coarctation of the aorta and interrupted aortic arch, aortic valve stenosis, or hypoplastic left heart syndrome.8 Without an adequate LV outflow tract, the systemic circulation is supplied by blood pumped through the DA from the right ventricle. However, these patients typically have some form of intracardiac mixing of oxygenated and deoxygenated blood with either a large atrial or ventricular septal defect.7 Therefore, the blood shunted through the DA is relatively high in oxygen concentration, and cyanosis may not be present at birth. However, as the DA begins to close, there is a disruption in systemic blood flow, and cardiovascular collapse may acutely occur. Given that closure of the DA can take weeks to months to occur, patients may present with signs of inadequate perfusion well after hospital discharge if ductal dependent pathology is not diagnosed prenatally.11Patients with ventricular septal defects, atrioventricular defects, or a large PDA are typically asymptomatic at birth without any appreciable cyanosis.12 As pulmonary vascular resistance decreases and the pressure gradient between the RV and LV increases, there will be increased blood flow across the defect, which can be detected by auscultation. In these patients, the left-to-right shunting of blood causes pulmonary overcirculation, leading to elevated LV end-diastolic pressure and pulmonary edema. This manifests clinically as symptoms of congestion including tachycardia, tachypnea, increased work of breathing, sweating with feeds, and poor weight gain.13An electrocardiogram at 4 hours of life demonstrated right atrial enlargement and RV hypertrophy (Figure 2). An echocardiogram at 5 hours of life while receiving an infusion of alprostadil demonstrated an absent DA, which was replaced with fibrous tissue indicating premature closure of the DA (Figure 3). The RV chamber was severely enlarged with severely decreased systolic function and hypertrophy. The LV was noted to have moderately decreased systolic function with an ejection fraction of 44%. A small secundum atrial septal defect with bidirectional shunting and right-to-left bowing of the atrial septum was noted and was consistent with the restrictive RV physiology. Taken together, these findings were highly suggestive of premature DA closure with the development of subsequent pulmonary hypertension and right heart failure.In fetal circulation, the DA acts as a right-to-left shunt allowing RV outflow to bypass the higher-resistance pulmonary circuit in favor of the lower-resistance systemic circulation.14 With birth and the initiation of ventilation, there is an abrupt drop in the pulmonary vascular resistance resulting in left-to-right shunting through the now patent DA.15 Low partial pressure of oxygen (pO2) in fetal circulation and high levels of PGE1 and PGE2 in utero have been established as primary factors in maintaining the DA during the prenatal period.16,17 At birth, there is an increase in the pO2, and the remaining PGE, which was previously supplied by the placenta, is quickly metabolized by enzymes within the lungs.18 These factors contribute to the functional closure of the DA shortly after birth. Within the first month of life, endothelial proliferation of fibrotic material within the ductal lumen leads to permanent anatomical closure of the DA.19In the absence of another shunt, premature closure of the DA in utero forces all the RV outflow to enter the high-resistance pulmonary fetal circuit. Increased flow through the pulmonary arteries causes increased pulmonary artery wall stress and elevated pressure within the arterioles, leading to intimal fibrosis and the development of pulmonary hypertension. This increased afterload can result in RV dilation and hypertrophy.There is a wide range of presentations for premature DA closure associated with the timing and severity of ductus closure (complete vs partial). Presentations include no symptoms, tachypnea and cyanosis related to pulmonary hypertension and right heart failure, fetal hydrops, and stillbirth.20Premature closure of the DA can be associated with other structural cardiac defects but may also be an isolated finding. Administration of drugs that inhibit PGE synthesis, such as NSAIDs and corticosteroids, are a known cause of premature DA closure and thus are often contraindicated during pregnancy.21,22 Additionally, excessive consumption of sources of polyphenol (such as fruit tea and maté, a herbal tea) during pregnancy has been considered a potential risk factor, as polyphenol is believed to inhibit cyclooxygenase-2 (COX-2) through a mechanism like that of NSAIDs.23,24 COX-2 is an enzyme responsible for converting arachidonic acid to PGH2, which can then be converted into a variety of products including PGE.25 Finally, factors that alter the pO2 and PGE balance during pregnancy, such as smoking, which disrupts PGE synthesis, have also been proposed as potential causes.26,27When premature closure of the DA is diagnosed in utero via fetal echocardiogram, early delivery is critical if there is complete DA closure, heart failure, and/or hydrops fetalis, as they portend a significantly increased risk of mortality.20,26,28 If premature DA closure is identified prior to viable delivery, serial fetal echocardiograms can be performed to monitor right heart function and patency of the DA. Early delivery should be considered in all patients with premature DA closure to reduce and avoid sustained pressures in the pulmonary arteries, which is known to cause pulmonary hypertension, RV remodeling, right heart failure, and in severe cases lead to death.20 In all cases, physicians should recommend that mothers avoid NSAIDS, polyphenol-containing foods, and smoking.Identification of premature DA closure is most likely to occur during the evaluation of a symptomatic neonate. After initial resuscitation, care should be focused on inotropic support if RV dysfunction is present, on supplemental oxygen to promote pulmonary vasodilation, and on pulmonary vasodilators if pulmonary hypertension is severe. Successfully correcting RV dysfunction and pulmonary hypertension has been shown to be a good prognostic indicator.28There are currently no guidelines for the long-term care of patients with premature DA closure. However, once RV function has returned to normal and there is no longer evidence of pulmonary hypertension, patients can expect a full recovery.28Within a few hours of NCPAP and the initiation of alprostadil, the patient’s oxygen saturations improved to 95%. An echocardiogram was then performed and was notable for premature closure of the DA; therefore, the alprostadil infusion was discontinued without issue. Findings of this echocardiogram and subsequent studies are summarized in Table 1. Given our patient’s severe RV dysfunction, he was initially treated with intravenous milrinone for inotropic support and pulmonary vasodilation. Supplemental oxygen and nitric oxide were also administered to support pulmonary vasodilation. A follow-up chest radiograph at 2 days of life noted improvement in cardiomegaly. Blood cultures were monitored, and after 48 hours without bacterial growth, empirical antibiotics were discontinued. Pulmonary hypertension improved over the first 3 days of life, and the patient was slowly titrated off CPAP to room air while maintaining adequate oxygen saturations. Given the improvement in RV function on echocardiogram on day of life (DOL) 3, the patient was transitioned from nitric oxide to oral sildenafil, an oral pulmonary vasodilator, in preparation for hospital discharge. The patient was tapered off milrinone as the LV function returned to normal by DOL 5 and he was able to trial small volumes of bottled breast milk and formula without issue. The patient advanced to 50% of feeds by mouth and the remainder gavaged by DOL 9, and to 90% oral feeds by DOL 14 without tachypnea, sweating, or changes in color. Given continuing improvement in biventricular function and RV hypertrophy, he was discharged home on sildenafil on DOL 14.A repeat echocardiogram at the patient’s 1-month follow-up showed normal biventricular function with mild RV enlargement and severe hypertrophy. At 5 months of age, the patient was weaned off sildenafil given his stable clinical status and in anticipation of an upcoming echocardiogram at his 6-month follow-up. The repeat echocardiogram at 6 months of age and in the absence of sildenafil was notable for normal biventricular function with resolution of RV hypertrophy and no evidence of pulmonary hypertension.Neonates in hypoxemic respiratory distress refractory to supplemental oxygen should raise the physician’s suspicion for congenital heart disease or persistent pulmonary hypertension of the newborn.Premature DA closure is an uncommon cause of hypoxemic respiratory distress in the newborn, with signs and symptoms due to right heart failure driven by pulmonary hypertension.Corticosteroids, NSAIDs, and foods rich in polyphenol are associated with a decrease in PGE synthesis, and thus premature DA closure in the fetus; therefore, these substances are not recommended in pregnant patients.The treatment of premature DA closure is supportive and involves inotropic support for the dysfunctional RV and supplemental oxygen and pulmonary vasodilators for pulmonary hypertension.