143: Transient Tachypnea of the Newborn

Transient tachypnea of the newborn (TTN) is a benign self- limited respiratory distress syndrome of term and late preterm infants related to delayed clearance of lung liquid. The distress appears shortly after birth and usually resolves within 3–5 days. Synonymous terms include wet lung, type II respiratory distress syndrome (type II RDS), transient respiratory distress syndrome, retained fetal lung liquid syndrome, and benign unexplained respiratory distress in the newborn.

It is the most common perinatal respiratory disorder, responsible for 40% of respiratory distress after birth. Incidence varies in the literature from 4 to 11 cases per 1000 singleton live births.

A delayed resorption of liquid from the lungs is believed to be the central mechanism for TTN. The lung liquid inhibits gas exchange, leading to an increased work of breathing. Tachypnea develops to compensate for that. Hypoxia develops because of poorly ventilated alveoli. The following factors are involved:

1. Inactivated/immature amiloride-sensitive sodium channels. During gestation the pulmonary epithelium actively secretes fluid and chloride into the air spaces. During labor a surge of fetal catecholamines (adrenaline, glucocorticoids) are released and the lung switches from active chloride and fluid secretion to active sodium absorption. However, when during labor sodium channels are inactivated or ineffective, this will result in a larger volume of lung liquid at birth, leading to a reduced postnatal respiratory function. Infants born by elective cesarean section have a higher risk of TTN as they are not exposed to the stress (catecholamines) during labor before birth.

   Whatever mechanism is responsible for the liquid remaining in the lung, at birth the transpulmonary pressure created during inspiration is for a major part responsible for the direct lung aeration and clearance of lung liquid (seconds). The pressure moves the column of liquid distally toward the alveolus, where it is transferred passively through the membrane into the interstitium. Then the liquid in the interstitium is slowly absorbed by the lymph and blood vessels (hours), leading to temporarily positive pressure in the interstitium. The role of the activated Na transport from alveolus to interstitium after birth is to prevent the liquid from going back into the alveolus as a consequence of the positive pressure in the interstitium. When the sodium channels are immature or ineffective, liquid will fill the air spaces, leading to a decrease in compliance and diffusion problems, and respiratory distress will occur.

2. Uterine contractions. Infants delivered by elective cesarean miss the lung liquid efflux via the trachea by high transpulmonary pressures caused by uterine contractions. Infants delivered by cesarean and breech deliveries miss the fetal trunk flexion when the head first goes through the birth canal, which increases abdominal pressure, elevates the diaphragm, and increases transpulmonary pressure, thereby forcing liquid out via the nose and mouth.

3. Pulmonary immaturity. One study noted that a mild degree of pulmonary immaturity is a central factor in the cause of TTN. The authors found a mature lecithin-sphingomyelin (L-S) ratio but negative phosphatidylglycerol (the presence of phosphatidylglycerol indicates completed lung maturation) in infants with TTN. Infants who were closer to 36 weeks' gestation than to 38 weeks had an increased risk of TTN. One study demonstrated that a relative surfactant deficiency may play a role in prolonged TTN. Surfactant deficiency leads to an increased surface tension and lowers the compliance of the lung. A layer of surfactant also plays a role in preventing lung liquid from going back to the alveoli.

4. Genetic predisposition. Because of familial clustering of some cases, there is speculation that there may be a genetic predisposition.

   1. Some propose that there may be a genetic predisposition for b-adrenergic hyporesponsiveness, and this plays a role in TTN.

   2. Studies have also revealed that polymorphisms in the b-adrenergic receptor (ADRB)-encoding genes, b 1 Gly 49 homozygosity and TACC haplotype of ADRB2 gene, may predispose to TTN.

   3. Maternal and fetal mutated alleles of the PROGINS progesterone receptor polymorphism reduce the risk for TTN.

1. Cesarean delivery (with or without labor). Labor prior to a cesarean delivery is not protective for TTN.

2. Male gender.

3. Prematurity/late preterm.

4. Macrosomia (birthweight ≥4500 g).

5. Multiple gestations.

6. Prolonged labor with long intervals.

7. Negative amniotic fluid phosphatidylglycerol.

8. Perinatal/birth asphyxia.

9. Fluid overload in the mother, especially with oxytocin infusion.

10. Family history of asthma (especially history in the mother).

11. Breech delivery.

12. Infant of a diabetic mother (2–3 times more common). Reasons could be the increased rate of cesarean sections in this group or the decreased fluid clearance in the diabetic fetal lung.

13. Infant of drug-dependent mother (narcotics).

14. Exposure to B-mimetic agents.

15. Precipitous delivery (rapid vaginal delivery)/absence of exposure to labor.

16. Urban location.

17. Nulliparity.

18. History of infertility therapy.

19. Augmentation of labor/vacuum/forceps delivery.

20. Low Apgar score (<7) at 1 and 5 minutes. A low Apgar at 1 minute was associated the most with TTN.

21. Absence of premature rupture of membranes (PROM).

1. Grunting, maximum respiratory rate >90/min, and an Fio₂ >0.40 within 6 hours of life were associated with an increase in prolonged TTN.

2. Peak respiratory rate in the first 36 hours of life >90/min caused a 7 times increased risk of prolonged tachypnea. This group with prolonged tachypnea had longer hospitalization and antibiotic treatment. The white blood cell count and hematocrit levels were lower in the group with prolonged tachypnea than the group with tachypnea that lasted <72 hours.

3. Absence of labor contractions or reduced labor duration is associated with a more severe course of TTN at term, requiring longer oxygen supplementation.

4. Long-distance land-based transport in neonates with TTN. They required increased respiratory support in the neonatal intensive care unit (NICU) and incidence of pulmonary air leak syndrome was higher.

The infant is usually near term, term, or large and premature, and shortly after delivery has tachypnea (>60 breaths/min and can be up to 100–120 breaths/min) or within the first 6 hours of delivery. The infant may also have grunting, nasal flaring, rib retraction, and varying degrees of cyanosis (uncommon, usually mild and responsive to oxygen). The infant often appears to have the classic “barrel chest” secondary to the increased anteroposterior diameter (hyperinflation). One can hear crackles on auscultation. The liver and spleen are palpable because of the hyperinflation. There are usually no signs of sepsis. Some infants may have edema and a mild ileus on physical examination. One can also see tachycardia with usually a normal blood pressure. Neurologically normal and no signs of sepsis. Some clinicians differentiate transitional delay, transient tachypnea, and prolonged tachypnea.

1. Transitional delay. Tachypnea right after birth for usually <6 hours (but can be for 2–12 hours). Grunting can occur right after birth with transitional delay and usually subsides by 2 hours (93%). Transitional delay usually subsides within 6 hours and infants are able to feed orally.

2. Transient tachypnea of the newborn (TTN). Tachypnea that lasts from after birth usually <72 hours. It typically resolves by 12–24 hours. One study found that 74% of infants had resolution of their symptoms by 48 hours.

3. Prolonged tachypnea of the newborn (PTTN). Some infants have prolonged tachypnea, lasting >72 hours. Some have classified this as prolonged tachypnea of the newborn.

TTN is a clinical diagnosis. It is based on clinical and radiologic findings.

1. Laboratory studies

   1. Prenatal testing. A mature L-S ratio with the presence of phosphatidylglycerol in the amniotic fluid may help rule out RDS.

   2. Amniotic fluid sampling at delivery. Amniotic lamellar body counts can predict the occurrence of TTN. It is lower than controls and higher than in infants with RDS.

   3. Postnatal testing

      1. Arterial blood gas on room air shows some degree of mild to moderate hypoxemia. Partial carbon dioxide is usually normal because of the tachypnea. Hypocarbia is usually present. Hypercarbia, if it exists, is usually mild (Pco₂ >55 mm Hg). A mild respiratory acidosis is seen, which can be a sign of fatigue and impending respiratory failure or complication such as a pneumothorax.

      2. Pulse oximetry should be monitored continuously.

      3. Complete blood count (CBC) with differential is normal in TTN but should be obtained if one is considering an infectious process. The hematocrit will also rule out polycythemia.

      4. Other promising tests. Plasma endothelin-1 levels may be higher in RDS compared with those in TTN. This test may prove useful in differentiating RDS from TTN. Interleukin-6 (IL-6) may distinguish proven and clinical sepsis from TTN. This may make it possible to avoid antibiotics in this group of infants. Serum atrial natriuretic peptide levels were lower for infants with TTN than normal infants in one study.

2. Imaging and other studies

   1. Chest radiograph. (See example in Figure 11–16A and B.) The chest radiograph is the diagnostic standard. The typical findings in TTN are as follows:

      1. Hyperexpansion (hyperinflation) of the lungs is a hallmark of TTN.

      2. Prominent perihilar streaking (secondary to engorgement of periarterial lymphatics). Engorgement of the lymphatic system with retained lung fluid and fluid in the fissures.

      3. Mild to moderately cardiomegaly.

      4. Depression (flattening) of the diaphragm is best seen on a lateral view of the chest.

      5. Fluid in the minor fissure and perhaps fluid in the pleural space (pleural effusions), laminar effusions.

      6. Prominent pulmonary vascular markings. “Fuzzy vessels,” a sunburst pattern, peripheral air trapping resulting in increased lung volumes.

      7. Air leaks are rarely seen.

      8. There should be no areas of consolidation.

   2. Lung ultrasonography. An ultrasound sign (“double lung point”) was found to be diagnostic of TTN. Lung ultrasound shows a difference in lung echogenicity between the upper and lower lung areas. It was also noted that very compact comet-tail artifacts in the inferior fields and not in the superior fields (the “double lung point”) was seen in infants with TTN and not seen in other lung pathology or in healthy infants.

3. Other tests. Any infant who is hypoxic on room air must have a hyperoxia test to rule out heart disease. This test is described on pages 606–608.

4. Confirm the diagnosis. TTN is often a diagnosis of exclusion, and other causes of tachypnea should be excluded first. There are many causes of tachypnea and usually the history, physical examination, and initial radiograph will help to narrow down the differential. If still uncertain, the clinical course can help guide you. An infant who does not improve, who worsens, and whose radiograph pattern changes, not following the typical pattern, should alert you that the diagnosis may not be TTN.

   1. Causes of tachypnea are extensive in the newborn. Use the mnemonic TRACHEA to help remember some of the causes of tachypnea in a newborn: T. transient tachypnea of the newborn; R, respiratory infections (pneumonia); A, aspiration syndromes (meconium, blood, or amniotic fluid); C, congenital malformations; H, hyaline membrane disease (now known as respiratory distress syndrome); E, edema; A, air leaks and acidosis.

      1. Respiratory infections (pneumonia)/sepsis. If the infant has pneumonia/sepsis, the prenatal history usually suggests infection. There may be maternal chorioamnionitis, PROM, and fever. The blood cell count may show evidence of infection (neutropenia or leukocytosis with abnormal numbers of immature cells). The urine antigen test may be positive if the infant has group B streptococcal infection. Remember that it is best to give broad-spectrum antibiotics if there is any suspicion or evidence of infection. The antibiotics can always be discontinued if the cultures are negative in 48 hours.

      2. Sepsis.

      3. Congenital cyanotic heart disease. Infants with hypoplastic right and left heart syndromes, tetralogy of Fallot, and transposition of the great arteries can all present after birth. Usually these infants present with cyanosis with few respiratory symptoms. Cardiomegaly may be seen on chest x-ray. The hyperoxia test should be done to rule out heart disease (see Selected References). An echocardiogram should also be done if cyanotic heart disease is suspected.

      4. Respiratory distress syndrome (RDS). (See also Chapter 124.) The infant is normally premature (<34 weeks) or has some reason for delayed lung maturation, such as maternal diabetes. The infant presents with respiratory distress after birth that continues to worsen. The chest radiograph is helpful because it shows the typical RDS reticulogranular pattern with air bronchograms and underexpansion (atelectasis) of the lungs.

      5. Aspiration syndromes (meconium, blood, or amniotic fluid). Infants with meconium aspiration syndrome (most common syndrome) are usually fully or post mature. Blood and amniotic fluid can also be aspirated. All of these aspiration syndromes can present at birth or several hours after birth. Infants usually have more severe respiratory distress than in TTN. The x-ray can be similar to that in TTN but usually has perihilar infiltrates/opacities. TTN can have patchy opacities from fluid in the alveoli. Infants usually require more oxygen and have increased tachypnea and retractions. The blood gases usually show more hypoxemia, hypercapnia, and acidosis. These infants can progress and develop pulmonary hypertension.

      6. Cerebral hyperventilation. This disorder is seen when central nervous system (CNS) lesions (eg, subarachnoid hemorrhage, meningitis, hypoxic ischemic encephalopathy) cause overstimulation of the respiratory center, resulting in tachypnea. Arterial blood gas measurements show respiratory alkalosis. Chest x-ray may show cardiomegaly, normal lungs.

      7. Metabolic disorders. Infants with hypothermia, hyperthermia, or hypoglycemia may have tachypnea.

      8. Polycythemia and hyperviscosity. This syndrome may present with tachypnea with or without cyanosis.

      9. Congenital malformations. (Congenital diaphragmatic hernia, cystic adenomatoid malformations.) These can present with respiratory distress. A chest x-ray will help make the diagnosis.

      10. Pulmonary hypertension.

      11. Pulmonary edema. Secondary to patent ductus arteriosus (PDA) (left- to-right shunt with failure, anomalous venous drainage).

      12. Air leaks (pneumothorax, pneumomediastinum). A chest x-ray is diagnostic.

      13. Primary pulmonary hypoplasia. This can cause persistent tachypnea.

      14. Metabolic acidosis.

1. Preventive

   1. An elective cesarean section (CS) scheduled at a gestational age (GA) of 39 weeks or later may decrease the frequency of TTN. Labor prior to CS did not prevent TTN. Vaginal birth appears to be protective against TTN (even after 37 weeks of gestation).

   2. Establish fetal maturity prior to elective CS.

   3. Antenatal betamethasone prior to elective CS at term reduced the incidence of respiratory morbidity in infants (reduced TTN from 4% of elective CS to 2.1%). The steroids encourage the expression of the epithelial channel gene and allow the lung to switch from fluid secretion to fluid absorption. It induces lung Na⁺ reabsorption by increasing the number and activity of channels even in hypoxia. Also, antenatal glucocorticoids induce maturation of the surfactant system.

   4. Prevent low Apgar scores. A low Apgar score <1 minute is strongly associated with TTN. Improved obstetric surveillance may decrease low Apgar scores.

2. General. Management is supportive.

   1. Oxygenation. Initial management consists of providing adequate oxygenation. Start with extra oxygen via hood or nasal cannula and deliver enough to maintain normal arterial saturation. If there is increased work of breathing and oxygen need >30%, then nasal continuous positive airway pressure (NCPAP) is an effective alternative treatment. CPAP gives a continuous positive pressure on the airways, helping to oppose the reentry of liquid and maintaining functional residual capacity. Intubation criteria vary per center, but we intubate when oxygen need is >40% when on a CPAP of 8 cm H₂O. Other diseases should be considered, but administration of exogenous surfactant promotes a dramatic clinical response in infants with TTN needing intubation and mechanical ventilation, underlining the role of surfactant deficiency in severe TTN.

   2. Maintain a neutral thermal environment.

   3. Antibiotics. Most infants are initially treated with broad-spectrum antibiotics (usually ampicillin and gentamicin) for 48 hours until the diagnosis of sepsis or pneumonia is excluded (controversial). In a randomized controlled trial of restrictive fluid management in TTN, all 73 infants with TTN were not treated with antibiotics and none of the infants manifested neonatal pneumonia or bacteremia.

   4. Feeding. Because of the risk of aspiration, an infant should not be fed by mouth if the respiratory rate is >60 breaths/min. If the respiratory rate is <60 breaths/min, oral feeding is permissible. If the rate is 60–80 breaths/min, feeding should be by nasogastric tube. If the rate is >80 breaths/min, IV nutrition is indicated.

   5. Fluid and electrolytes. Should be monitored and hydration maintained. Fluid management is controversial. A small randomized trial in restrictive fluid management in infants with severe TTN showed a reduced duration of respiratory support and hospitalization cost. However, the control group in this trial received a more liberal fluid intake than currently recommended, and although significant, the differences were small.

   6. Diuretics are not recommended. Diuretics have been used in practice in some centers with the rationale of accelerating lung liquid absorption with an immediate diuresis-independent lung liquid resorption and a delayed increase in urine output. Furosemide also causes pulmonary vasodilatation, leading to an improved ventilation/perfusion (V/P) match. However, trials investigating the oral or aerosolized administration of furosemide in infants with TTN have shown no differences in the course of disease.

   7. Inhaled epinephrine. Infants with TTN have low levels of epinephrine, and epinephrine helps to mediate fetal lung fluid absorption. However, inhaled racemic epinephrine did not increase the rate of resolution of tachypnea in one study.

   8. β2-Agonist salbutamol. Stimulation of β-adrenergic receptors with salbutamol upregulates the activity of the sodium channels. A small randomized controlled trial in aerosolized salbutamol versus saline in infants with TTN showed significant improvement in clinical and laboratory findings. Larger studies are needed before this can be recommended as standard therapy.

1. TTN is usually self-limited and usually lasts only 2–5 days.

2. Asthma/wheezing syndromes. Asthma is a multifactorial disease. Recent studies have revealed that TTN is associated with the development of wheezing syndromes (bronchiolitis, acute bronchitis, chronic bronchitis, asthma, or prescription for asthma medication) in early childhood and subsequent diagnosis of childhood asthma. The risk of TTN is increased in babies born to mothers with asthma. In one study the risk was found to be greatest in males of nonwhite race whose mothers lived at an urban address and did not have asthma. Some believe TTN may be a marker for deficient pulmonary function, increasing the (inherited) susceptibility to the development of asthma. Liem et al proposed that environmental and genetic interactions predispose these infants to asthma.

3. Complications (rare). If these occur, it is best to reevaluate the infant.

   1. Some infants can develop prolonged tachypnea (>72 hours) and can progress to respiratory failure (hypoxia, respiratory fatigue with acidosis) and require intubation and mechanical ventilation.

   2. It is very rare, but a few infants may develop air leaks (usually a pneumothorax or pneumomediastinum). There is a higher risk of air leak if the infant is on CPAP. Familial neonatal pneumothorax has been associated with TTN in siblings of 2 families.

   3. Some may develop pulmonary hypertension with right-to-left shunting across the ductus arteriosus or foramen ovale. This may be present because of possible elevation in the pulmonary vascular resistance associated with retained fetal lung fluid and hyperinflation of the lungs and require extracorporeal membrane oxygenation/extracorporeal life support (ECMO/ECLS). (See Chapter 120.)