Pathophysiology
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 dysfunction 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.
Frequency
International
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/Morbidity
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 and early pneumothorax.
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.
Clinical
History
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, requiring aggressive resuscitative measures.
Physical
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, pneumothorax signs (poor air entry, poor perfusion) may also be found.
Causes
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. Congenital diaphragmatic hernia can be induced in rat models with administration of the 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.
The herniation of viscera in congenital diaphragmatic hernia usually occurs 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 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.
Treatment
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.
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.7
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.
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.
Alkalinization is sometimes used 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.8
Inhaled nitric oxide has revolutionized the treatment of PPHN but its use in the infant with congenital diaphragmatic hernia is controversial. Nitric oxide has not been shown to reduce mortality or the need for ECMO in infants with congenital diaphragmatic hernia, although it may immediately stabilize infants with critical hypoxemia. 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.
Surgical Care
Fetal surgery
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.9
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.10 Currently, fetal intervention is not indicated in congenital diaphragmatic hernia.
Postnatal surgical care
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. Herniated viscera in the chest does not appear to exacerbate the pathophysiology as long as bowel decompression with a nasogastric tube is continuous.
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 placement: Chest tube drainage is necessary when a tension pneumothorax is present; however, whether routine chest drainage 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.
Lung transplantation: 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 problems associated with donor lung availability and immunosuppression.
Medication
Medical therapy in congenital diaphragmatic hernia (CDH) is directed toward stabilizing blood pressure and circulating volume, pulmonary distress, and hypoxemia.
Vasoactive agents
Judicious use of vasoactive agents may increase cardiac output without affecting systemic or pulmonary vascular resistance.
Differential Diagnoses
Cystic Adenomatoid Malformation
Disorders of the Thoracic Cavity and Pleura
Pneumothorax
Pulmonary Hypertension, Persistent-Newborn
موضوع: Congenital Diaphragmatic Hernia 
