AUTHOR INFORMATION

Section 1 of 12

Authored by Terry Chin, MD, PhD, Associate Professor of Pediatrics, University of California Irvine School of Medicine; Associate Director, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, Miller Children's Hospital at Long Beach Memorial Medical Center

Coauthored by Yazan Said, MD, Fellow, Department of Pediatric Pulmonology, Miller Children's Hospital/University of California, Irvine; Girija Natarajan, MD, Assistant Professor, Division of Neonatology, Children's Hospital of Michigan & Wayne State University; Ibrahim Abdulhamid, MD, Assistant Professor of Pediatrics, Wayne State University; Director of Pediatric Pulmonary Medicine, Clinical Director of Pediatric Sleep Laboratory, Children's Hospital of Michigan

Terry Chin, MD, PhD, is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, European Respiratory Society, Joint Council of Allergy, Asthma, Immunology, and Western Society for Pediatric Research

Edited by Susanna A McColley, MD, Director of Cystic Fibrosis Center, Associate Professor, Department of Pediatrics, Divisions of Pediatric Pulmonary and Critical Care, Children's Memorial Medical Center of Chicago, Northwestern University; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Heidi Connolly, MD, Program Director of Pediatric Critical Care Fellowship, Assistant Professor, Department of Pediatrics, University of Rochester and Children's Hospital at Strong; Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Associate Professor, Department of Clinical Pediatrics, State University of New York at Stony Brook; and Michael R Bye, MD, Professor of Clinical Pediatrics, Columbia University College of Physicians and Surgeons; Acting Director, Department of Pediatric Pulmonary Medicine, Columbia University Medical Center

Author's Email:	Terry Chin, MD, PhD
Editor's Email:	Susanna A McColley, MD

eMedicine Journal, November 17 2006, VOLUME 7, Number 11

INTRODUCTION

Section 2 of 12

Background: Pulmonary hypoplasia or aplasia is part of the spectrum of malformations characterized by incomplete development of lung tissue. The severity of the lesion depends on the timing of the insult in relation to the stage of lung development and the presence of other anatomic anomalies. The hypoplastic lung consists of a carina, a malformed bronchial stump, and absent or poorly differentiated distal lung tissue. In more than 50% of these cases, coexisting cardiac, gastrointestinal, genitourinary, and skeletal malformations are present, as well as variations in the bronchopulmonary vasculature. To define pulmonary hypoplasia, some investigators have devised specific criteria that are based on reduced lung weight, volume, DNA content, and radial alveolar count.

Pathophysiology: For lung development to proceed normally, physical space in the fetal thorax must be adequate, and amniotic fluid must be brought into the lung by fetal breathing movements, leading to distension of the developing lung. Several factors affect the volume and composition of the amniotic fluid, including the following:

• Volume and pressure
  • The volume of liquid in the lung is determined by the net rate at which liquid is secreted across the pulmonary epithelium (4-5 mL/kg/h) and the rate at which it flows from the trachea into the fetal pharynx. The pressure in the fetal trachea is normally about 2 mm Hg higher than in the amniotic fluid, thus preventing outflow of fetal lung fluid.

  • Any alteration in the critical volume and pressure relationships of amniotic fluid in the trachea and lung during the canalicular stage of fetal lung development at 15-28 weeks’ gestation can induce hypoplasia.

• Composition of lung fluid
  • Lung development is regulated by several transcription factors, such as thyroid transcription factor 1 (TTF-1) family, hepatocyte nuclear family, and peptide growth factors.

  • The presence of growth factors in amniotic fluid indicates that lung development is not solely a pressure phenomenon. Signals from these growth factors are integrated with environmental influences, such as lung fluid volume and hyperoxia, to cause cellular proliferation and differentiation. A key component is the branching morphogenesis that occurs as a result of an interaction between the endodermal and mesenchymal components. Growth factors are produced by mesenchymal tissue and are present in amniotic fluid. Therefore, the expression of a number of growth factors and their receptors, all of which affect fetal lung development, is temporally and spatially regulated.

• Role of the kidney in lung growth
  • Lung development starts during the midtrimester with branching morphogenesis and is completed postnatally with the development of alveoli. Fetal urine is an important component of amniotic fluid during late gestation and contributes to lung growth. During fetal development, the kidney is also a major source of proline. Proline aids in the formation of collagen and mesenchyme in the lung, thus explaining the severe pulmonary hypoplasia in renal agenesis and dysplasias.

  • Pathologically, the hypoplastic lung has reduced lung weight, alveolar number, fewer generations of airways, and hypoplasia of the corresponding pulmonary arteries. Epithelial differentiation is delayed, and surfactant deficiency is associated. In cases of congenital diaphragmatic hernia (CDH) associated with pulmonary hypoplasia, hypertrophy of the contralateral lung has been demonstrated, with associated pulmonary artery hypertension. The hypoxemia in pulmonary hypoplasia stems from hypoventilation and right-to-left extrapulmonary shunting.

  • Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH, with implications of retinoids in the development of the diaphragm and the lung. A nitrofen-induced CDH model shows that lung hypoplasia may precede the diaphragmatic defect, leading to a dual-hit hypothesis.

Frequency:

• In the US: The true incidence is unknown, but the etiologies (in order of frequency) include prolonged rupture of membranes, fetal renal dysplasias and obstruction, and fetal neuromuscular diseases. In cases of premature rupture of membranes at 15-28 weeks’ gestation, the reported incidence of pulmonary hypoplasia ranges from 9-28% (13% in most studies). Lung hypoplasia also occurs in association with diaphragmatic hernia and congenital cystic lung lesions such as cystic adenomatoid malformation (CAM). The occurrence of CDH is estimated at 0.08-0.45 cases per 1000 births.

• Internationally: In Canada, the estimated incidence of CAM is 1 per 25,000-35,000 pregnancies.

Mortality/Morbidity: In different studies, mortality rates of 71-95% have been reported during the perinatal period in patients with pulmonary hypoplasia.

• The following conditions increase the risk of mortality:
  • Premature rupture of membranes at less than 25 weeks’ gestation
  • Severe oligohydramnios (amniotic fluid index <4) for more than 2 weeks
  • Earlier delivery

• To avoid mortality from severe lung hypoplasia in association with diaphragmatic hernia or CAM, fetal surgical intervention has been attempted.

• The survival rate of CDH is 55-65%. Most studies report a mortality rate of 25-30% in neonates with CAM. Risk factors for a poor outcome include the presence of hydrops fetalis, with a mortality rate as high as 80-90%. Other indicators include the type of CAM and its size. All of these factors reflect the degree of pulmonary compromise with lesions that result in varying degrees of pulmonary hypoplasia.

Race: No racial predilection has been noted.

Sex: No sex predilection has been noted.

CLINICAL

Section 3 of 12

History: The clinical profile and the time of presentation vary depending on the extent of hypoplasia and other anomalies.

The history may include poor fetal movement or amniotic fluid leakage and oligohydramnios. The neonate may be asymptomatic or may present with severe respiratory distress or apnea that requires extensive ventilatory support. In older children, dyspnea and cyanosis may be present upon exertion, or a history of repeated respiratory infections may be noted.

Physical: The external chest may appear normal or may be small and bell shaped, with or without scoliosis. A mediastinal shift is observed toward the involved side, and dullness upon percussion is heard over the displaced heart. In right-sided hypoplasia, the heart is displaced to the right, which may lead to a mistaken diagnosis of dextrocardia. Breath sounds may be decreased or absent on the side of hypoplasia, especially over the bases and axilla.

Pneumothorax, spontaneous or associated with mechanical ventilation, may occur. Compression deformities due to prolonged oligohydramnios, contractures, and arthrogryposis may be present. The Potter facies (hypertelorism, epicanthus, retrognathia, depressed nasal bridge, low set ears) suggest lung hypoplasia caused by the associated renal defects.

When the etiology of the hypoplasia is a neuromuscular disease, the patient may have myopathic facies, with a V-shaped mouth, muscle weakness, and growth retardation.

Abdominal masses, such as cystic renal diseases and an enlarged bladder, must be sought. Associated anomalies of the cardiovascular, gastrointestinal (eg, tracheoesophageal fistula, imperforate anus, communicating bronchopulmonary foregut malformation), and genitourinary systems, as well as skeletal anomalies of the vertebrae, thoracic cage, and upper limbs, may be found upon examination.

Causes: Pulmonary hypoplasia may be primary, but it is usually secondary, manifested by small fetal thoracic volume caused by compression in the hemithorax due to structures such as abdominal contents in CDH or congenital anomalies such as CAM or cysts.

• Primary: The cause has not been identified. However, experimental models suggest deficiencies in certain transcription factors (eg, TTF-1, GATA factors, hepatocyte nuclear factor HNF3b10) or growth factors (eg, epidermal growth factor and its receptor, EGFR; mitogen-activated protein [MAP] kinase) can result in disordered lung growth.

• Secondary causes include the following:


• • Small fetal thoracic volume
    • CDH

    • CAM

    • Sequestration

    • Pleural effusions with fetal hydrops

    • Malformations of the thorax (eg, asphyxiating thoracic dystrophy)

    • Achondroplasia

    • Thanatophoric dwarfism

    • Osteogenesis imperfecta

    • Thoracic neuroblastomas

    • Hydrothorax

    • Eventration of the diaphragm

    • Abdominal mass lesions
  
  
  
  • Prolonged oligohydramnios
    • Fetal renal agenesis

    • Urinary tract obstruction

    • Bilateral renal dysplasia

    • Bilateral cystic kidneys

    • Prolonged rupture of membranes
  
  
  
  • Early rupture of membranes
  
  
  
  • More severe oligohydramnios (amniotic fluid index <4)
  
  
  
  • Longer latent period before delivery
  
  
  
  • Decreased fetal breathing
    • CNS lesions

    • Lesions of the spinal cord, brain stem, and phrenic nerve

    • Neuromuscular diseases (eg, myotonic dystrophy, spinal muscular atrophy)

    • Arthrogryposis multiplex congenital

    • Maternal depressant drugs
  
  
  
  • Congenital heart diseases with poor pulmonary blood flow
    • Tetralogy of Fallot

    • Hypoplastic right heart

    • Pulmonary artery hypoplasia

    • Scimitar syndrome causing a unilateral right-sided pulmonary hypoplasia
  
  
  
• Trisomies 18,13, and 21



• The role of retinoic acid and antioxidants in pulmonary hypoplasia has been extensively studied. Despite encouraging in vitro work, supplementation with vitamin A has not reduced pulmonary hypoplasia.



• Pressure appears to affect fetal lung growth. Specifically, airway distension may affect various developmental and signaling pathways such as receptor tyrosine kinase growth factors, homeobox genes, transcription factors, retinoid signaling, and oxidation reduction. Experimentally, tracheal occlusion in fetal animals induces lung growth. These encouraging observations in various animal models have led to application to human fetuses with CDH. A US trial was stopped early because the data monitoring board found no difference in the survival rate compared with standard therapy. However, a European trial is currently continuing with promising preliminary results (Deprest, 2005).

DIFFERENTIALS

Section 4 of 12

Atelectasis, Pulmonary
Pneumonia
Pulmonary Hypertension, Persistent-Newborn

Other Problems to be Considered:

Spinal thoracic dysplasia

WORKUP

Section 5 of 12

Lab Studies:

• If the cause of the pulmonary hypoplasia is renal pathology, serum creatinine, blood urea, and electrolytes levels should be measured to assess renal function.

Imaging Studies:

• Targeted fetal ultrasonography may demonstrate renal malformations, oligohydramnios, and decreased fetal movements in fetal neuromuscular diseases. Three-dimensional fetal ultrasonography can be used for direct volume estimation of the fetal lung and definitive diagnosis of pulmonary hypoplasia. The drawbacks of this technique are that maternal obesity, fetal position, and bones may affect the accuracy of the results. Lung area, a gestational age–dependent parameter, and thoracic-to-abdominal circumference ratios have been found to be useful parameters (sensitivity of 81% and 90%, specificity of 100% and 90%, respectively) for the evaluation of pulmonary hypoplasia.



• Doppler ultrasonographic determination of pulmonary artery blood velocity waveforms is one tool used to diagnose pulmonary hypoplasia in the fetus. The pulsatility indices are high, and the peak systolic flow is significantly lower than normal. These findings are attributed to the higher impedance and a delay in pulmonary vessel development.



• Chest radiographic findings are variable; mediastinal shift in severe cases with a homogenous density on the involved hypoplastic side, compensatory herniation of the contralateral lung across the mediastinum, bell-shaped chest, and rib deformities may be observed (see Image 1, Images 3-4, Image 6). Diaphragmatic hernia (see Images 8-10), associated skeletal anomalies (see Image 7), scimitar syndrome, and sequestration may be identified.



• Chest CT scanning may show loss of lung volume and abnormal or absent normal airway branching to the affected lung (see Image 2, Image 9).



• Echocardiography may be used to identify associated cardiac anomalies.



• Angiography is indicated to confirm the diagnosis of any aberrant pulmonary vessels, to rule out scimitar syndrome, and to confirm reduced pulmonary vascular bed.



• MRI or magnetic resonance angiography (MRA) may also be used to identify the smaller pulmonary arterial supply to the affected lung and the presence of other abnormal vascular anatomy (see Image 11).



• Fetal MRI during the second and third trimester constitutes a new method. Different techniques, including MRI volumetry, assessment of signal intensities, and MRI spectroscopy of the fetal lung, have been used clinically to identify abnormal fetal lung growth



• Lung scintigraphy has been used to evaluate the degree of pulmonary hypoplasia in infants with CDH. A recent study (Okuyama, 2006) suggests that lung scintigraphy is useful to predict long-term pulmonary morbidity and poor nutritional status in survivors of CDH.

Other Tests:

• Obtaining an ECG is important to distinguish between dextrocardia and dextroposition caused by pulmonary hypoplasia. In dextrocardia, ECG findings include an inverted P wave and T in lead 1, with negative QRS deflection and a reverse pattern between aVR and aVL. A mirror image progression is observed from V₁ to a right-sided V₆ lead. A tall R in lead V₁ or an RS ratio equal to or greater than 1 also suggests dextrocardia.



• Bronchoscopy or bronchography is indicated because the reduced size of a bronchus and its branches confirms the diagnosis (see Image 5).



• Lung function testing is not helpful in short-term management. However, it may be useful in monitoring the course of the disease in terms of lung maturation and development.



• Initially, patients with CDH have low lung compliance and show a restrictive defect. A recent study shows normalization of all lung function parameters after surgery by age 24 months (Koumbourlis, 2006). As expected, lung function correlated significantly with increase in age, height, and, especially, weight.

TREATMENT

Section 6 of 12

Medical Care:

• Before delivery, and depending on the underlying lesion, a few interventions can be performed to increase the fetal lung volume and improve lung development.


• • Preterm rupture of membranes without signs of fetal distress or intrauterine infection is treated conservatively with or without tocolytics, antibiotics, and steroids in various combinations. Attempts have been made to seal the defect in the membranes by transcervically using “fibrin glue.” However, this technique requires a preliminary cerclage, increases the risk of infection, and has limited efficacy.

  • Serial amnioinfusions are increasingly used in cases of preterm rupture of membranes at less than 32 weeks’ gestation. This procedure, if successful, has been shown to decrease the risk of pulmonary hypoplasia and significantly improve perinatal outcome.
  
  
  
• After delivery, the infant needs respiratory support, which can range from supplying supplemental oxygen to mechanical ventilation, including high-frequency ventilation and extracorporeal membrane oxygenation (ECMO). Ventilatory strategies have veered toward the use of permissive hypercapnia, especially in cases of CDH, with an increased survival rate in several reports. Partial liquid ventilation has also been used, without definite advantages.


• • ECMO is particularly indicated in infants with diaphragmatic hernia associated with pulmonary hypoplasia and when mild hypoplasia is complicated by persistent pulmonary hypertension. A decreased response to nitric oxide is believed to occur with pulmonary hypertension associated with hypoplasia.
  
  
  
  • Surfactant administration of 4 mL/kg in pulmonary hypoplasia secondary to CDH has been shown to be efficacious in improving oxygenation, decreasing the need for ECMO, and improving the survival rate if prophylactically administered at birth. Animal studies have shown that surfactant significantly improved lung mechanics and gas exchange and that lung tissue stores of surfactant protein B and phosphatidylcholine were low in diaphragmatic hernia.
  
  
  
• Dialysis for support of renal function is provided in some cases, but it should be started only after careful consideration. Patients with severe chronic renal impairment with pulmonary hypoplasia have a poor prognosis; the ultimate outcome is difficult to improve, even with optimal renal and respiratory support.

Surgical Care:

• In patients with severe CAM who have an extremely poor prognosis, fetal surgery is possible in certain centers. A multidisciplinary team with expertise in fetal surgery should evaluate both the fetus and the pregnant mother. A major indication for fetal surgery is the presence of hydrops and a gestation of less than 32 weeks. Thoracocentesis can allow for drainage of fluid from the CAM, but the fluid usually rapidly reaccumulates.



• Intrauterine vesicoamniotic shunts and endoscopic ablation of posterior urethral valves are other techniques that are currently used in fetuses with urinary tract obstruction and pulmonary hypoplasia. With careful case selection, pulmonary hypoplasia is prevented, and postnatal renal and respiratory function is improved.



• Percutaneous fetal endoluminal tracheal occlusion (FETO) with a balloon, inserted at 26-28 weeks’ gestation, has been attempted in fetuses with poor prognosis and isolated left-sided CDH, liver herniation, and a lung-to-head ratio of less than 1. This procedure was found to be minimally invasive, may reverse pulmonary hypoplasia changes, and may improve survival rate in these highly selected cases. In addition, the airways can be restored before birth.



• In experimental animals, fetal tracheal occlusion (TO) induces lung growth and morphologic maturation. Fetoscopic TO with a clip may lead to accelerated lung growth and prevent pulmonary hypoplasia. However, a recent study showed that fetal TO used to treat severe CDH resulted in modest improvements in neonatal pulmonary function that are of questionable clinical significance



• After delivery, surgery to correct diaphragmatic hernia, to correct CAM, and to decompress pleural effusions may be life-saving and curative in some cases.



• The optimal time of surgery and the duration of ventilatory support used before surgery are controversial. The decision is made based on the lesion and the center’s preferences.

Consultations:

• Consult a pediatric surgeon for CDH, CAM, or any other lesion that requires surgery. Also, consult a pediatric surgeon in cases that involve pulmonary hypertension or respiratory failure that requires ECMO.



• Consult a nephrologist and a urologist if a renal obstructive, cystic, or agenetic lesion is the cause of the pulmonary hypoplasia.



• Consult a cardiologist and cardiothoracic surgeon if the patient has a causative or coexisting cardiac lesion, such as anomalous pulmonary venous connection.



• Consult a neurologist in cases of congenital neuromuscular diseases.

MEDICATION

Section 7 of 12

Preterm rupture of membranes and an imminent preterm delivery is managed with tocolytics to control contractions and to prevent delivery, as indicated. Maternal steroids to accelerate lung maturity of the fetus are indicated in preterm labor.

Drug Category: Tocolytic agents -- These agents decrease uterine contractility and are used to arrest premature labor and delivery. Ritodrine is a beta2 stimulant, which produces direct relaxation of the uterine smooth muscle and decreases the force and frequency of uterine contractions. It is more specific for uterine and bronchiolar smooth muscle receptors than for the heart or vasculature.

Drug Name	Ritodrine (Yutopar) -- Stimulation of beta2-receptors inhibits contractility of the uterine smooth muscle through the cycle of adenyl cyclase stimulation, which increases intracellular cAMP. This alters cellular calcium balance, thus affecting smooth muscle contractility. May also directly affect the interaction between the actin and myosin of muscle through inhibition of myosin light-chain kinase.
Adult Dose	10 mg PO q2h 0.05 mg/min IV initially, may increase by 0.05 mg/min q10min to typical maintenance dose of 0.15-0.35 mg/min IV
Contraindications	Documented hypersensitivity to drug or sulfites; gestation <20 wk; preexisting maternal medical conditions exacerbated by beta2 stimulation (eg, hypovolemia, cardiac arrhythmias associated with tachycardia or digitalis intoxication, uncontrolled hypertension, pheochromocytoma, bronchial asthma already treated by beta-mimetics and/or steroids); conditions of the mother or fetus in which continuation of pregnancy would be hazardous (eg, antepartum hemorrhage, chorioamnionitis, uncontrolled maternal diabetes mellitus)
Interactions	Beta-blockers antagonize effects; magnesium, digoxin, tricyclic antidepressants, and inhaled anesthetics may enhance risk of cardiotoxicity; MAOIs increase risk of hypertensive crisis and tachycardia; corticosteroids may increase edema risk
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Increases risk of arrhythmias (discontinue if HR >130 bpm); pulmonary edema (4% incidence) may occur, especially in women bearing twins, having polyhydramnios, receiving a blood transfusion, or having anemia or an underlying heart disease; maternal hyperglycemia and neonatal hypoglycemia have been observed with this class of drugs and should be monitored closely

Drug Category: Glucocorticoids -- These agents are used to induce or accelerate lung maturity in a preterm newborn at less than 32 weeks’ gestation or when lung immaturity is known by amniotic fluid assay. Long-acting steroids (eg, dexamethasone, betamethasone) are recommended by a National Institutes of Health (NIH) Consensus Conference panel for all pregnancies at 24-34 weeks’ gestation at risk of preterm delivery, in patients with preterm rupture of membranes at less than 30-32 weeks’ gestation, and in complicated pregnancies with anticipated delivery before 34 weeks’ gestation unless the corticosteroid will have an adverse effect on the mother.

Drug Name	Dexamethasone (Decadron) -- Decreases frequency of respiratory distress syndrome, surfactant therapy, and serious intraventricular hemorrhage. Optimal benefit occurs within 24 h and lasts for 7 d.
Adult Dose	6 mg IM q12h for 4 doses is the maternal prenatal dose
Contraindications	Documented hypersensitivity; systemic fungal infection
Interactions	Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization; may antagonize neuromuscular blocking agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use; caution in CHF, seizure disorder, diabetes mellitus, hypertension, tuberculosis, and osteoporosis

Drug Name	Betamethasone (Celestone Soluspan) -- Decreases frequency of respiratory distress syndrome, surfactant therapy, and serious intraventricular hemorrhage. Optimal benefit occurs within 24 h and lasts for 7 d.
Adult Dose	12 mg IM qd for 2 doses is the maternal prenatal dose
Contraindications	Documented hypersensitivity; systemic fungal infection
Interactions	Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization; may antagonize neuromuscular blocking agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Drug Category: Surfactants -- These agents are administered at birth to newborns to improve lung mechanics and oxygenation when treating airspace disease. Following inhaled administration, surface tension is reduced, and alveoli are stabilized, thus decreasing the work of breathing and increasing lung compliance.

Drug Name	Beractant (Survanta) -- A semisynthetic bovine lung extract that contains phospholipids, fatty acids, and surfactant-associated proteins B (7 mcg/mL) and C (203 mcg/mL).
Adult Dose	Not indicated
Pediatric Dose	100 mg (ie, 4 mL)/kg divided in 4 aliquots intratracheally administered at least 6 h apart
Contraindications	None known
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Must be warmed to room temperature; administer only under carefully supervised conditions because of risk of acute airway obstruction; transient bradycardia, oxygen desaturation, pallor, vasoconstriction, hypotension, endotracheal tube blockage, apnea, and hypercapnia may occur during administration; other adverse effects include pulmonary interstitial emphysema, air leaks, and nosocomial sepsis; monitor heart rate and oxygen saturation during administration; monitor arterial blood gas after administration

Drug Name	Calfactant (Infasurf) -- A natural calf lung extract that contains phospholipids, fatty acids, and surfactant-associated proteins B (260 mcg/mL) and C (390 mcg/mL).
Adult Dose	Not indicated
Pediatric Dose	3 mL/kg intratracheally; may repeat q6-12h; not to exceed 3-4 doses
Contraindications	None known
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Administer only under carefully supervised conditions because of risk of acute airway obstruction; transient bradycardia, oxygen desaturation, pallor, vasoconstriction, hypotension, endotracheal tube blockage, apnea, and hypercapnia may occur during administration; other adverse effects include pulmonary interstitial emphysema, air leaks, and nosocomial sepsis; monitor heart rate and oxygen saturation during administration; monitor arterial blood gas after administration

FOLLOW-UP

Section 8 of 12

Further Outpatient Care:

• Because bronchopulmonary dysplasia (BPD) is likely in survivors of pulmonary hypoplasia, infants have an increased risk of fatality and serious morbidity with upper respiratory tract infection (URI) and lower respiratory tract infection (LRI).



• Respiratory syncytial virus (RSV) prophylaxis should be considered during RSV season in infants younger than 2 years who have required oxygen in the previous 6 months. The dose of palivizumab is 15 mg/kg monthly through the RSV season, which, in most parts of the United States, is from October to March.



• Patients with pulmonary hypoplasia should be considered as having a chronic pulmonary disease. Therefore, once they are older than 6 months, they should receive the influenza vaccine at the start of every influenza season, which is October or November in the United States. The dose of influenza vaccine is 0.25 mL per dose of the split virus vaccine. Children younger than 8 years should receive 2 doses 2 months apart for the first time. Children older than 8 years require 1 dose.



• Similarly, these patients are considered high risk and should be administered the pneumococcal vaccine (PCV 7) at a dose of 0.5 mL intramuscularly until they are aged 5 years.

In/Out Patient Meds:

• Because these patients should be considered as having chronic lung disease, various aerosolized medications such as bronchodilators and corticosteroids should be considered if symptoms suggest reactive airway disease or obstructive airway disease.



• Persistent pulmonary hypertension can be treated with various vasodilators and endothelin inhibitors.

Complications:

• Reduced exercise tolerance, even in mild cases



• Scoliosis in adolescent years



• Recurrent respiratory infections



• Pneumothorax - Spontaneous or as a result of respiratory support



• Persistent pulmonary hypertension caused by a reduced pulmonary vascular bed and worsened by hypoxia or a coexisting left-to-right intracardiac shunt



• Bronchopulmonary dysplasia in survivors of pulmonary hypoplasia caused by prolonged ventilatory support



• Chronic pulmonary insufficiency - May persist in diaphragmatic hernia and pulmonary hypoplasia



• Airway abnormalities, including tracheobronchial compression and tracheomalacia caused by the displaced aorta and enlarged left pulmonary artery

Prognosis:

• Right-sided hypoplasia has a worse prognosis than left-sided hypoplasia, probably because of the loss of the bigger right lung mass and more severe mediastinal shift and great vessel displacement.



• The oligohydramnios tetrad of pulmonary hypoplasia, positional limb deformities, Potter facies, and intrauterine growth retardation has a very poor prognosis.



• A minimum lung volume of 45% compared with age-matched control subjects has been shown to be a predictor of survival in neonates with diaphragmatic hernia treated with ECMO. Similarly, a functional residual capacity of 12.3 mL/kg, about one half the normal capacity, has been thought to be a predictor of survival in pulmonary hypoplasia with CDH.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• When clinically recognized, pulmonary hypoplasia has a poor prognosis. It is frequently associated with severe and irreversible lesions, such as renal agenesis and thanatophoric dysplasia. Therefore, families must be fully informed and encouraged to participate in decisions to start aggressive and invasive treatments. Medical care, respiratory support (eg, ECMO), surgical intervention (eg, fetal surgery), and dialysis should be carefully considered in view of poor outcomes and prognosis.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following is the most common etiology of pulmonary hypoplasia diagnosed in a neonate?

A: Primary cause
B: Renal agenesis in the fetus
C: Posterior urethral valves
D: Prolonged rupture of membranes causing oligohydramnios
E: Myotonic dystrophy

The correct answer is D: Prolonged rupture of membranes causing oligohydramnios is the most common etiology of pulmonary hypoplasia in the newborn. Oligohydramnios is a deficiency in the amount of the amniotic fluid. For lung development to proceed normally, physical space must be adequate in the fetal thorax and amniotic fluid must be brought into the lung with fetal breathing movements. Several factors affect the volume and composition of the amniotic fluid.

CME Question 2: Which of the following clinical signs may suggest a diagnosis of pulmonary hypoplasia in the newborn?

A: Normal-shaped chest
B: Intercostal retractions
C: Cardiomegaly
D: Mediastinal shift
E: Abdominal distention

The correct answer is D: Mediastinal shift towards the involved side with an apparent dextrocardia may indicate pulmonary hypoplasia in the newborn.

Pearl Question 1 (T/F): Patients with pulmonary hypoplasia always present in the newborn period with severe respiratory distress.

The correct answer is False: The neonate may be asymptomatic or may present with severe respiratory distress or apnea that requires ventilatory support. In older children, dyspnea and cyanosis may occur on exertion or a history of repeated respiratory infections may be present.

Pearl Question 2 (T/F): Right-sided pulmonary hypoplasia has a worse prognosis than left-sided hypoplasia.

The correct answer is True: Right-sided pulmonary hypoplasia has a worse prognosis than left-sided hypoplasia because of loss of the bigger right lung mass and a more severe mediastinal and great vessel displacement.

Pearl Question 3 (T/F): Pulmonary hypoplasia associated with Potter facies, limb deformities, and oligohydramnios has a relatively good prognosis.

The correct answer is False: The oligohydramnios tetrad of pulmonary hypoplasia, positional limb deformities, Potter facies, and intrauterine growth retardation has a very poor prognosis.

Pearl Question 4 (T/F): Fetal thoracic mass lesions, such as cystic adenomatoid malformation, are a known cause of pulmonary hypoplasia.

The correct answer is True: Thoracic mass lesions are a known cause of secondary pulmonary hypoplasia.

PICTURES

Section 11 of 12

Caption: Picture 1. Chest radiograph of a newborn with primary pulmonary hypoplasia of the right lung showing shift of the mediastinum to the right hemithorax.
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Caption: Picture 2. CT scan of the same patient as in Image 1 showing absence of the right lung. Note branching of the left lower lobe bronchus (horizontal arrow) and absence of airways in the right side (vertical arrow).
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Caption: Picture 3. A posteroanterior radiograph of a 3-month-old infant with primary pulmonary hypoplasia of the right lung.
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Caption: Picture 4. Lateral view of the same patient as in Image 3 showing one dome of the diaphragm.
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Caption: Picture 5. Bronchogram of the same patient as in Image 3 showing absence of the airways in the right side and presence of the left main bronchus and its branches.
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Caption: Picture 6. A chest radiograph of a 14-year-old child with primary pulmonary hypoplasia of the right side causing secondary scoliosis.
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Caption: Picture 7. A chest radiograph of a newborn with achondroplasia and small chest causing hypoplasia of both lungs.
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Caption: Picture 8. A chest radiograph of a newborn with diaphragmatic hernia in the right hemithorax shortly after birth.
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Caption: Picture 9. CT scan of the same child as in Image 8 showing the presence of abdominal contents in the right hemithorax. Note the presence of the left lower bronchus and its main branches (horizontal arrow) and absence of the right lower lobe bronchus. The liver in the right hemithorax is indicated by the upper arrow.
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Caption: Picture 10. A chest radiograph of a 10-month-old child after repair of a right diaphragmatic hernia showing loss of lung volume in the right hemithorax.
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Caption: Picture 11. MRI/MRA of the same patient in Image 10 showing loss of right lung volume and smaller right pulmonary artery than the left pulmonary artery (arrow).
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BIBLIOGRAPHY

Section 12 of 12

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