The topic of congenital diaphragmatic hernia (CDH) has frequently appeared in the medical literature since its first

description in the early 18th century. Initial theories about the pathophysiology of this condition centered on the presence of the herniated viscera within the chest and the need for its prompt removal. In 1946, Gross reported the first successful repair of a neonatal diaphragmatic hernia in the first 24 hours of life.[1] The medical literature for the next decade addressed congenital diaphragmatic hernia as a surgical problem and discussed various technical aspects of surgical repair, including techniques required to close large defects. In the 1960s, however, Areechon and Reid observed that the high mortality rate of congenital diaphragmatic hernia was related to the degree of pulmonary hypoplasia at birth.[2] Over the past 20 years, pulmonary hypertension and pulmonary hypoplasia have been recognized as the 2 cornerstones of the pathophysiology of congenital diaphragmatic hernia. In recent years, evidence suggests that cardiac maldevelopment may further complicate the pathophysiology of congenital diaphragmatic hernia.[3] See the image below.

Radiograph of a 1-day-old infant with a moderate-sized congenital diaphragmatic hernia (CDH). Note the air- and fluid-filled bowel loops in the left chest, the moderate shift of the mediastinum into the right chest, and the position of the orogastric tube. The 3 basic types of congenital diaphragmatic hernia include the posterolateral Bochdalek hernia (occurring at approximately 6 weeks' gestation), the anterior Morgagni hernia, and the hiatus hernia. The left-sided Bochdalek hernia occurs in approximately 85% of cases. Left-sided hernias allow herniation of both the small and large bowel and intraabdominal solid organs into the thoracic cavity. In right-sided hernias (13% of cases), only the liver and a portion of the large bowel tend to herniate. Bilateral hernias are uncommon and are usually fatal.[4] Congenital diaphragmatic hernia is characterized by a variable degree of pulmonary hypoplasia associated with a decrease in cross-sectional area of the pulmonary vasculature and alterations of the surfactant system. The lungs have a small alveolar capillary membrane for gas exchange, which may be further decreased by surfactant dysfunction. In addition to parenchymal disease, increased muscularization of the intraacinar pulmonary arteries appears to occur. In very severe cases, left ventricular hypoplasia is observed. Pulmonary capillary blood flow is decreased because of the small cross-sectional area of the pulmonary vascular bed, and flow may be further decreased by abnormal pulmonary vasoconstriction.

Congenital diaphragmatic hernia occurs in 1 of every 2000-3000 live births and accounts for 8% of all major congenital anomalies. The risk of recurrence of isolated (ie, nonsyndromic) congenital diaphragmatic hernia in future siblings is approximately 2%.[5] Familial congenital diaphragmatic hernia is rare (< 2% of all cases), and both autosomal recessive and autosomal dominant patterns of inheritance have been reported. Congenital diaphragmatic hernia is a recognized finding in Cornelia de Lange syndrome and also occurs as a prominent feature of Fryns syndrome, an autosomal recessive disorder with variable features, including diaphragmatic hernia, cleft lip or palate, and distal digital hypoplasia.

Mortality has traditionally been difficult to determine. This is partially because of the "hidden mortality" for this condition, which refers to infants with congenital diaphragmatic hernia who die in utero or shortly after birth, prior to transfer to a surgical site. This bias may be especially important when evaluating institutional reports of outcome. A population-based study from Western Australia indicated that only 61% of infants with congenital diaphragmatic hernia are live born. In that study, nearly 33% of pregnancies that involved a fetus with congenital diaphragmatic hernia were electively terminated. Most of the pregnancies (71%) were terminated because of the presence of another major anomaly. Mortality after live birth is generally reported to range from 40-62%, and some authors argue that the true mortality of congenital diaphragmatic hernia has not changed with introduction of new therapies. The presence of associated anomalies has consistently been associated with decreased survival; other associations with poor outcome include prenatal diagnosis, prematurity, low birth weight, and early pneumothorax. Keller et al found that infants with congenital diaphragmatic hernia who have poor outcomes (death or discharge on oxygen) have higher plasma levels of endothelin-1, which is dysregulated in pulmonary hypertension.[6] Severity of pulmonary hypertension was also associated with increasing endothelin-1 levels.

Sex
Most studies report that congenital diaphragmatic hernia occurs equally in males and females.

Age
Although congenital diaphragmatic hernia is usually a disorder of the newborn period, as many as 10% of patients may present after the newborn period and even during adulthood. Outcome in patients with late presentation of congenital diaphragmatic hernia is extremely good, with low or no mortality. As noted in Mortality/Morbidity, population-based studies show that congenital diaphragmatic hernia (CDH) is diagnosed based on prenatal ultrasonography findings in approximately one half of affected infants. Infants may have a prenatal history of polyhydramnios.

Infants most commonly present with respiratory distress and cyanosis in the first minutes or hours of life, although a later presentation is possible. The respiratory distress can be severe and may be associated with circulatory insufficiency, requiring aggressive resuscitative measures. Infants frequently exhibit a scaphoid abdomen, barrel-shaped chest, and signs of respiratory distress (retractions, cyanosis, grunting respirations). In left-sided posterolateral hernia, auscultation of the lungs reveals poor air entry on the left, with a shift of cardiac sounds over the right chest. In patients with severe defects, signs of pneumothorax (poor air entry, poor perfusion) may also be found. Associated anomalies occur in a relatively high percentage of infants. Dysmorphisms such as craniofacial, extremity abnormalities, or spinal dysraphism may suggest syndromic congenital diaphragmatic hernia. The diaphragm initially develops as a septum between the heart and liver, progresses posterolaterally, and closes at the left Bochdalek foramen at approximately 8-10 weeks' gestation.[7] The herniation of viscera in severe congenital diaphragmatic hernia is believed to occur during the pseudoglandular stage of lung development. Lung compression results in pulmonary hypoplasia that is most severe on the ipsilateral side, although both lungs may be abnormal. Pulmonary hypoplasia is associated with fewer bronchial generations, alveoli, and arterial generations. Congenital diaphragmatic hernia can be induced in rat models with administration of the herbicide toxin nitrofen. Studies in these models show that the diaphragmatic defect occurs in the initial stages of diaphragm development, rather than in the later stages. Fetal exposure to nitrofen causes a variable amount of lung hypoplasia. The fact that only 6090% of exposed rat pups demonstrate diaphragmatic defects suggests a dual-hit hypothesis, in which 2 insults (one primarily affecting the lungs and another primarily affecting diaphragm development) contribute to the pathophysiology of congenital diaphragmatic hernia. Congenital diaphragmatic hernia may occur as a nonsyndromic or isolated defect. Less than 2% of such cases are estimated to be familial. Pedigrees consistent with autosomal recessive, autosomal dominant, and X-linked inheritance patterns have been described. More than 10% of infants with congenital diaphragmatic hernia have an underlying syndromic diagnosis, although few gene mutations are currently recognized. Congenital diaphragmatic hernia is a recognized finding of Cornelia de Lange syndrome, an autosomal dominant syndrome with characteristic facial features, hirsutism, and developmental delay. Fryns syndrome is an autosomal recessive condition that includes congenital diaphragmatic hernia as the cardinal feature, along with hypoplasia of the distal digits and other variable abnormalities of the brain, heart, and genitourinary development. An associated gene has not yet been identified, and the prognosis of Fryns syndrome is poor.

Chromosome abnormalities have been reported in as many as 30% of infants with congenital diaphragmatic hernia, which has been described as part of trisomy 13, trisomy 18, trisomy 21, and Turner syndrome (monosomy X). Pallister-Killian syndrome (tetrasomy 12p mosaicism) presents with findings that are similar to those of Fryns syndrome, including coarse facial features, aortic stenosis, cardiac septal defects, and abnormal genitalia. This diagnosis can only be made if a karyotype is determined based on skin biopsy findings. Chromosome deletions on chromosomes 1q, 8p, and 15q have been reported in association with congenital diaphragmatic hernia. Deletions of chromosomes 8p and 15q appear to be associated with heart malformations. Deficiencies in vitamin A availability, metabolism, and signaling have been found to contribute to the development of congenital diaphragmatic hernia in animal models and may also be relevant in human fetal development.[8] Several studies may be indicated in congenital diaphragmatic hernia (CDH). Obtain frequent ABG measurements to assess for pH, PaCO2, and PaO2. Note the sampling site because persistent pulmonary hypertension of the newborn (PPHN) with right-to-left ductal shunting often complicates CDH. The PaO2 is often higher from a preductal (right-hand) sampling site. Serum lactate may be helpful in assessing for circulatory insufficiency or severe hypoxemia associated with tissue hypoxia. Obtain chromosome studies, including microarray analysis, because of the frequent association with chromosomal anomalies. In rare cases (eg, Pallister-Killian syndrome), chromosomal disorders that can be diagnosed only based on skin biopsy findings may be present. If dysmorphic features are observed upon examination, a consultation with a geneticist is often helpful in evaluating the infant and ensuring that chromosome studies include appropriate deletion analysis. As with all critically ill neonates, monitor levels of serum electrolytes, ionized calcium, and glucose initially and frequently. Maintaining glucose levels in the reference range and maintaining calcium homeostasis are particularly important.

Imaging Studies
Obtain a chest radiograph if congenital diaphragmatic hernia is suspected (see the image below).

Radiograph of a 1-day-old infant with a moderate-sized congenital diaphragmatic hernia (CDH). Note the air- and fluid-filled bowel loops in the left chest, the moderate shift of the mediastinum into the right chest, and the position of the orogastric tube.

Placement of an orogastric tube prior to the study helps decompress the stomach and helps determine whether the tube is positioned above or below the diaphragm. Typical findings in a left-sided posterolateral congenital diaphragmatic hernia include air-filled or fluid-filled loops of the bowel in the left hemithorax and shift of the cardiac silhouette to the right. Examine the chest radiograph for evidence of pneumothorax. The incidence of associated cardiac anomalies is high (approximately 25%); therefore, cardiac ultrasonography is needed shortly after birth. Cardiac defects may be relatively minor (atrial septal defect) or life-threatening (transposition of great vessels, hypoplastic left heart, aortic coarctation). In addition, echocardiography is helpful in assessing myocardial function and determining whether the left ventricular mass is significantly decreased. Genitourinary anomalies occur in 6-8% of infants with congenital diaphragmatic hernia; renal ultrasonography should be considered. CNS defects (neural tube defects, hydrocephalus) may be associated with congenital diaphragmatic hernia. Although MRI provides definitive diagnostic information, bedside cranial sonography is generally performed when an infant is considered for extracorporeal support. In that circumstance, the goal is to evaluate for intraventricular bleeding and hypoxic-ischemic changes, as well as to rule out major intracranial anomalies.

Procedures
Endotracheal intubation and mechanical ventilation are required in all infants with severe congenital diaphragmatic hernia who present in the first hours of life. If the diagnosis is known at the time of delivery, avoid bag-and-mask ventilation in the delivery room because the stomach and intestines become distended with air and further compromise pulmonary function. A nasogastric tube should be placed as soon as possible to provide intestinal decompression.

As discussed in Treatment, the goal is to adequately expand the lung but to avoid overdistension; therefore, inspiratory pressures should be kept as low as possible. Consider the use of highfrequency ventilation (HFV) if high inspiratory pressures are required. Place an indwelling catheter in the umbilical artery or in a peripheral artery (radial, posterior tibial) for continuous blood pressure and frequent ABG monitoring. Place a venous catheter via the umbilical vein to allow for administration of inotropic agents and hypertonic solutions such as calcium gluconate. If the liver is in the chest, the catheter will likely not pass through the ductus venosus, and another route must be considered for central venous access. The use of HFV in congenital diaphragmatic hernia remains controversial, and no randomized studies indicate a clear benefit. However, HFV may allow for use of lower ventilator pressures and may help normalize PaCO2. Mean airway pressures should be carefully adjusted to avoid lung overdistension. Frequent radiograph (with a goal of 8-9 rib expansion of the contralateral lung) may help in the ongoing assessment and optimization of lung expansion. Venoarterial or venovenous ECMO support is an adaptation of cardiopulmonary bypass and involves a surgical team;[9] insertion of catheters into the internal jugular vein, internal carotid artery, or both; systemic heparinization; and oxygenation through the use of an artificial membrane lung. Because of its complexity and resource expense, ECMO is available at fewer than 100 centers in the United States. The overall survival rate for infants with congenital diaphragmatic hernia reported to the international Extracorporeal Life Support Organization (ELSO) registry is approximately 52%, which is the lowest rate in all the neonatal conditions treated with ECMO. Although no conclusive evidence shows that ECMO improves survival or outcome for infants with congenital diaphragmatic hernia, it remains a commonly used therapy for severely affected infants.

Histologic Findings
Both lungs appear abnormal, although histologic changes are more severe on the affected side. Bronchi are less numerous, and the overall number of alveoli is reduced. In addition, the lungs appear to be less mature with fewer mature alveoli. Pulmonary vascular abnormalities occur in addition to parenchymal abnormalities, characterized by both a reduction in the cross-sectional area of the pulmonary vascular bed and an abnormal increase in muscularization of pulmonary arteries and arterioles.

Medical Care
Because of associated persistent pulmonary hypertension of the newborn (PPHN) and pulmonary hypoplasia, medical therapy in patients with congenital diaphragmatic hernia (CDH) is directed toward optimizing oxygenation while avoiding barotrauma.[10]

In the delivery room, if the infant is known or suspected to have congenital diaphragmatic hernia, immediately place a vented orogastric tube and connect it to continuous suction to prevent bowel distension and further lung compression. For the same reason, avoid mask ventilation and immediately intubate the trachea. Avoid high peak inspiratory pressures and be alert to the possibility of early pneumothorax if the infant does not stabilize.[11] Infants with congenital diaphragmatic hernia may have immature lung development, and animal studies have indicated that surfactant deficiency may be present. However, reports from the Congenital Diaphragmatic Hernia Study Group indicate that administration of exogenous surfactant does not improve survival, need for extracorporeal membrane oxygenation (ECMO), or long-term outcome. Interestingly, this finding is true for both term and preterm infants with congenital diaphragmatic hernia. Mechanical ventilation strategies are targeted at avoiding high peak inspiratory pressures and synchronizing ventilation with the infant's respiratory effort. In some instances, high-frequency ventilation (HFV) may be helpful in avoiding the use of high peak inspiratory pressures, although this modality is best used at a center with experience in assessing and maintaining optimal lung distension. Infants with congenital diaphragmatic hernia are critically ill and require meticulous attention to detail for subsequent medical care, including continuous monitoring of oxygenation, blood pressure, and perfusion. A minimal stimulation approach that reduces handling and invasive procedures, such as suctioning, is suggested. Maintain glucose and ionized calcium concentrations within reference range. If necessary, support blood pressure using volume expansion and inotropic agents. An adequate circulating volume is necessary to maintain right ventricular filling and cardiac output; however, once circulating volume is normalized, repeated boluses of crystalloid solutions, colloid solutions, or both do not provide additional benefit. Inotropic support with dopamine, dobutamine, or milrinone may be helpful in maintaining adequate systemic blood pressure; dobutamine and milrinone may be particularly helpful if myocardial dysfunction is present. Epinephrine infusions may be necessary in severe cases; low-dose epinephrine (< 0.2 mcg/kg/min) may help to promote pulmonary blood flow and improve cardiac output. The appropriate targets for PaO2 and PaCO2 are controversial. PaO2 concentrations greater than 50 mm Hg typically provide for adequate oxygen delivery at the tissue level. Aiming for higher PaO2 concentrations may lead to increased ventilator support and barotrauma. Similarly, infants with congenital diaphragmatic hernia often have hypercarbia because of pulmonary hypoplasia. Whether to maintain a low PaCO2 for pulmonary vasodilation, to allow permissive hypercapnia, or to maintain normocarbia remains controversial. No reliable controlled studies are known, and debate continues in the medical literature. Retrospective studies suggest that gentle ventilation and allowing chronic mild hypercarbia may be associated with improved survival. Alkalinization was frequently used in the past because of its ability to produce a rapid pulmonary vasodilation. Forced alkalosis can be accomplished either by using hyperventilation to induce hypocarbia or by alkali infusions. However, benefits of alkalosis have never been demonstrated

in any prospective clinical trial, and these therapies are considered controversial. In addition, alkalosis may result in undesirable side effects. For instance, hypocarbia constricts the cerebral vasculature and reduces cerebral blood flow. Extreme alkalosis and hypocarbia are strongly associated with later neurodevelopmental deficits, including a high rate of sensorineural hearing loss. Previous studies by Walsh-Sukys and colleagues indicates that the use of alkali infusions may be associated with increased use of ECMO and an increased use of oxygen at age 28 days.[12] Inhaled nitric oxide has revolutionized the treatment of PPHN but its benefit in the infant with congenital diaphragmatic hernia remains controversial. Nitric oxide does not reduce mortality or the need for ECMO in infants with congenital diaphragmatic hernia, although it may immediately stabilize infants with critical hypoxemia and reduce the chances of cardiopulmonary arrest.[13] Inhaled nitric oxide should be used with caution if ECMO is not immediately available. New studies indicate a potential role for long-term low-dose inhaled nitric oxide therapy in the treatment of late or recurrent pulmonary hypertension. Sedation is an important adjunctive therapy, but the use of paralytic agents remains highly controversial. Although diminished swallowing may be beneficial, paralysis may promote both atelectasis of dependent lung regions and ventilation-perfusion mismatch, as well as generalized edema and decreased chest wall compliance.

Surgical Care
Theoretically, fetal surgery for congenital diaphragmatic hernia provides an elegant solution to the difficult problem of congenital diaphragmatic hernia. Unfortunately, this is far from reality. Harrison et al reported the first human fetal surgery for congenital diaphragmatic hernia in 1990. However, a randomized trial published in 1998 showed that in utero repair did not improve survival compared with standard therapy.[14] Subsequent trials of fetal intervention focused on occluding the fetal trachea. The fetal lung secretes fluid by active ion transport through gestation, and this lung fluid provides a template for lung growth. Occlusion of the fetal trachea traps this fluid and stimulates lung growth, either by retention of growth factors within the lung or stimulation of local growth factors by the gentle distension provided by the fluid. Unfortunately, a randomized trial in humans found that fetal tracheal occlusion did not improve outcome compared with standard treatment.[15] Currently, fetal intervention is not indicated in congenital diaphragmatic hernia, although some groups continue to offer it on an experimental basis. Until recently, specialists believed that reduction of the herniated viscera and closure of the diaphragmatic defect should be emergently performed following birth. However, a delayed surgical approach that enables preoperative stabilization decreases morbidity and mortality. This change in protocol is due to the recent understanding that the medical problems of pulmonary hypoplasia and PPHN are largely responsible for the outcome of congenital diaphragmatic hernia and that the severity of these pathophysiologies is largely predetermined in utero.[16] Herniated viscera in the chest does not appear to exacerbate the pathophysiology as long as bowel decompression with a nasogastric tube is adequate.

Several reports indicate that circulatory stability, respiratory mechanics, and gas exchange deteriorate after surgical repair. The ideal time to repair a congenital diaphragmatic hernia is unknown. Some suggest that repair 24 hours after stabilization is ideal, but delays of up to 7-10 days are typically well tolerated, and many surgeons now adopt this approach. Some surgeons prefer to operate on these neonates when normal pulmonary artery pressure is maintained for at least 24-48 hours based on echocardiography. Chest tube drainage is necessary when a tension pneumothorax is present; however, whether routine chest drainage following surgical repair has a role is controversial. Some clinicians report improved survival when chest drainage is not used. Others think that balanced intrathoracic drainage, in which a closed gated pressure system is used to maintain intrathoracic pressure within the normal physiologic range, may minimize risk of pulmonary injury and improve respiratory mechanics. Transplantation of a single lung has been reported in one case. Lung transplantation may allow the remaining hypoplastic lung to grow and to recover from injury while still allowing adequate oxygenation and ventilation. However, this approach has not been widely used because of the substantial probleMedical therapy in congenital diaphragmatic hernia (CDH) is directed toward stabilizing blood pressure and circulating volume, pulmonary distress, and hypoxemia. ms associated with donor lung availability and immunosuppression.

Further Inpatient Care

Pulmonary care in congenital diaphragmatic hernia (CDH)

Severely affected infants have chronic lung disease. These infants may require prolonged therapy with supplemental oxygen and diuretics, an approach similar to that for bronchopulmonary dysplasia. The use of steroids, particularly high doses for prolonged periods, is controversial and may hinder appropriate lung and brain development. Late pulmonary hypertension has been successfully treated with low-dose inhaled nitric oxide. This therapy can be delivered via nasal cannula following extubation. In this setting, the delivered dose is diluted because of entrainment of room air. In a recent report, the median duration of treatment using inhaled nitric oxide delivered via nasal cannula was 17 days. Case reports are now emerging regarding the use of other pulmonary vasodilators, such as sildenafil and endothelin receptor antagonists. Systemic study is required to assess the sustained benefit.

Neurologic evaluation
Following recovery, a neurologist or developmental pediatrician should perform an examination that includes an evaluation for CNS injury using head CT scanning or MRI.

The incidence of hearing loss appears to be particularly high in patients with congenital diaphragmatic hernia (approximately 40% of infants). An automated hearing test should be performed prior to discharge.

Gastroesophageal reflux
The incidence of significant gastroesophageal reflux is very high in patients who survive congenital diaphragmatic hernia, and studies document an incidence of 45-85%. The need for a diaphragmatic patch may be a significant predictor of gastroesophageal reflux. Severe reflux may result in chronic aspiration and is, therefore, aggressively treated. Although most infants can be medically treated with H2-blockers or proton pump inhibitors in combination with a motility agent such as metoclopramide, surgical intervention is sometimes required.

Further Outpatient Care

Failure to thrive is common, and, in some studies, more than 50% of patients are below the 25th percentile for height and weight during the first year of life. In one study, one third of infants required gastrostomy tube placement to improve caloric intake. The need for supplemental oxygen at the time of discharge is a significant predictor for subsequent growth failure. Possible causes include increased caloric requirements due to chronic lung disease, oral aversion after prolonged intubation, poor oral feeding due to neurologic delays, and gastroesophageal reflux. Because of the risk for CNS insult and sensorineural hearing loss, infants should be closely monitored for the first 3 years of life,[17] preferably in a specialty follow-up clinic. These risks are particularly high in infants who are discharged home on supplemental oxygen. Reassess hearing at age 6 months (and later if indicated) because late sensorineural hearing loss occurs in approximately 40% of patients. Even if a child has no major neurodevelopmental delays, he or she should be evaluated prior to entering school to determine if any subtle deficits may predispose the child to learning disabilities.

Prognosis
Overall reported survival varies among institutions. Remember that a single institution's results may look better than those provided by population-based studies because of case-selection biases. When all resources, including ECMO, are provided, reported survival rates range from 40-90%. The ELSO registry reports the ECMO survival rate at 52%. As noted, survivors are at risk for significant long-term morbidity, including chronic lung disease, growth failure, gastroesophageal reflux, hearing loss, and neurodevelopmental delay. The risk appears to be highest in infants with severe lung disease (need for long term

supplemental oxygen), need for patch closure of the diaphragm, and need for gastrostomy tube feeding.