Congenital Diaphragmatic Hernia and Eventration Flashcards

Question

What long-term morbidities can affect children born with CDH?

Answer 1

Respiratory – Long-term pulmonary dysfunction (50%, secondary to pulmonary hypo- plasia and prolonged ventilation). Digestive – Gastro-esophageal reflux (10–20% require fundoplication) – Failure to thrive (1/3 of survivors<5 percentile at one year of age, 20% requiring tube feeds). Musculo-skeletal – Chest wall or spinal deformities (1/3 of survivors has scoliosis, pectus excavatum, chest asymmetry). Neurodevelopmental – Impairment affects 25% survivors (neuromuscular hypotonia, hearing and visual impairment, neurobehavioral issues, and learning difficulties). To address CDH morbidities, a dedicated multidisciplinary (surgery, neonatology, pulmonology, gastroenterology, nutrition, neurology, audiology, orthopedics) follow-up is recommended.

Answer 2

Congenital: Due to poor muscularization (continuum with CDH with a sac) Acquired: Phrenic nerve injury from traumatic birth or cardiac surgery.

Answer 3

C. Hyperinflation of lung

Answer 4

D. Shifting of mediastinum to same side

Answer 5

In both Europe and the United States, the prevalence of CDH is estimated to be 2.3–2.4 per 10,000 live births, and has demonstrated a small but significant increase over time. A significant proportion of fetuses with CDH are either terminated or stillborn, often associated with other congenital anomalies. The overall incidence of CDH is likely underestimated, as around 25–35% of fetuses that are prenatally diagnosed with CDH result in pregnancy termination, in utero demise, or death shortly after birth. Thus, many infants with prenatally diagnosed CDH may never be seen or accounted for in a tertiary referral center. Presumed to be the most severe of all CDH infants, these patients contribute to the “hidden mortality” of CDH. [H&A] — CDH is estimated to occur in 1:2,000 to 1:4,000 live births. A significant hidden mortality exists due to pregnancy termination. CDH is still associated with 20%–30% mortality, one of the highest rates among the spectrum of common congenital anomalies treated by pediatric surgeons in high-resource settings. [Sherif]

Answer 6

CDH affects male infants more commonly, and the majority of posterolateral CDH are left sided (80%), with right sided (19%) and bilateral (1%) accounting for the rest. Ninety percent of all CDH cases are located at the posterolateral or “Bochdalek” location, and the remainder are located anteriorly, termed “Morgagni” hernias, along with defects of the central septum transversum. Bilateral diaphragmatic hernias are more commonly associated with other congenital anomalies, and portend a much worse prognosis. Recent epidemiologic studies have identified no association of CDH with maternal age.

Answer 7

Increasing evidence demonstrates CDH to have an intermittent association with genetic aberrations and concomitant anomalies, and it should certainly not be considered an isolated anomaly in many patients. Approximately 40% of CDH cases are nonisolated, having at least one additional anomaly. In up to one-third of patients with CDH, a causative genetic variation is detected. CDH has been associated with genomic aberrations on almost every chromosomal arm, and recurrences have prompted investigation into the locations of CDH-causing genes. The identification of a genetic association for an individual CDH patient provides important information about prognosis, management, and recurrence risk. Therefore, all cases of CDH warrant prenatal counseling with a discussion of options for chromosomal analysis, along with a postnatal chromosomal microarray and genetics consultation. CDH has also been associated with over 70 syndromes. In some cases, the diaphragmatic malformation is the predominant defect, as in Fryns and Donnai–Barrow syndromes. In other syndromes such as Simpson–Golabi–Behmel and Beckwith–Wiedemann syndromes, CDH only occurs in a small percentage, but still greater than in the general population. These syndromes can be carried by both autosomal and X-linked variants. Identifying the patterns of nonhernia-related anomalies associated with CDH and recognizing genetic syndromes help determine the prognosis, treatments, counseling, and outcomes.

Answer 8

Although approximately 60% of CDH cases are isolated, the others are associated with anomalies of the cardiovascular (27.5%), urogenital (17.7%), musculoskeletal (15.7%), and central nervous (9.8%) (CNS) systems. The impact of associated anomalies on prognosis and outcome cannot be overstated. Most infants with immediate neonatal demise have associated anomalies. In contrast, only approximately 10% of infants who survive preoperative stabilization and come to operative repair have major additional anomalies. Although defect size and the degree of CDH-PH are important contributors to overall survival, infants with isolated CDH demonstrate a significant survival advantage when compared with those with major concomitant cardiac, chromosomal, or associated structural anomalies (70–85% vs as low as 20%, depending on specific anomaly or anomalies). Due to the inferior outcomes of CDH when combined with significant anomalies, detailed and accurate prenatal diagnosis influences the prenatal counseling, delivery plan, perinatal management, and postnatal treatment of CDH. Postnatally diagnosed infants with CDH have significantly fewer associated anomalies and lower mortality, on average, than infants with a prenatal diagnosis, likely reflecting a decreased disease severity. However, this difference may be the result of lethal chromosomal anomalies leading to in utero demise, or may reflect parental decisions for termination in high-risk infants with anomalies that portend significant morbidity. Major congenital heart disease is a significant contributor to morbidity and mortality in newborns with CDH. Common cardiac defects associated with CDH include (in decreasing order of frequency): 1) ventricular septal defects (VSDs), 2) atrial septal defects (ASDs), and 3) other outflow tract anomalies (aortic coarctation, hypoplastic left heart syndrome, tetralogy of Fallot). In a review of 4268 infants with CDH, there was an 18% association with congenital heart disease. Major cardiac lesions (excluding patent foramen ovale, atrial septal defects, patient ductus arteriosus [PDA]) were found in 8%, and these infants had a much worse prognosis with an overall survival of 36% compared with infants with minor anomalies (67%) and those without cardiac defects (73%).

Answer 9

The financial burden of caring for the increased number of complex survivors of CDH has continued to rise. Data from the Kids’ Inpatient Database in 2011 projected the annual national costs of caring for infants with CDH to range between $264 and $400 million based on 60% overall survival. A significant contributor to this high cost over time is the utilization of ECMO, which was associated with a 2.4fold increase in expenditures from 1997 to 2006. Patients requiring ECMO support had the highest median cost and accounted for 28.5% of the total national costs for CDH.22 The magnitude of interhospital cost variation was recently assessed utilizing the Pediatric Health System database in 2014–2015. CDH cost a median of $154,730 but represented one of the diagnoses with the greatest cost variation at the hospital level (range $129,764–$173,712) compared with other pediatric surgical diagnoses, suggesting practice variation is an important driver of health care spending.

Answer 10

The development of the human diaphragm is a complex, multicellular, multitissue interaction that remains incompletely understood. 4th week AOG: Precursors to the diaphragm begin to form during the fourth week of gestation. Historically, the diaphragm was thought to develop from the fusion of four embryonic components: 1) anteriorly by the septum transversum, 2) dorsolaterally by the pleuroperitoneal folds (PPFs), 3) dorsally by the crura from the esophageal mesentery, and 4) posteriorly by the body wall mesoderm. According to this theory, as the embryo begins to form, the septum transversum migrates dorsally and separates the pleuropericardial cavity from the peritoneal cavity. At this point, the pleural and peritoneal cavities still communicate. The septum transversum interacts with the PPF and mesodermal tissue surrounding the developing esophagus and other foregut structures, resulting in the formation of primitive diaphragmatic structures. Bound by pericardial, pleural, and peritoneal folds, the paired PPFs now separate the pleuropericardial and peritoneal cavities. Eventually, the septum transversum develops into the central tendon. 6th week AOG: As the PPF develops during the sixth week of gestation, concurrently, the pleuroperitoneal membranes close and separate the pleural and abdominal cavities by the eighth week of gestation. Typically, the right side closes before the left. Ultimately, the phrenic axons and myogenic cells destined for neuromuscularization migrate to the PPF and form the mature diaphragm. The muscularization of the primitive diaphragm is a separate but inter-related process.

Answer 11

1) Failure of muscularization. Another theory for CDH development is a failure of muscularization of the future diaphragm prior to complete closure of the canal. Inadequate closure of the pleuroperitoneal canal allows the abdominal viscera to enter the thoracic cavity when they return from the extraembryonic coelom to herniate into the chest with the liver. As a result of the limited intrathoracic space, due to the visceral herniation, pulmonary hypoplasia develops. 2) Abnormal lung development. Although traditional theories suggest that the lung hypoplasia is secondary to the diaphragmatic malformation, others have postulated that the primary disturbance may be abnormal lung development that causes the diaphragmatic defect. According to this theory, disturbances in lung bud formation subsequently impair the posthepatic mesenchymal plate (PHMP) development and result in failure of diaphragm fusion/muscularization. 3) Early genetic mutations in a subset of PPF-derived muscle connective tissue More recently, the role of the PPF and, specifically, a subset of PPF-derived muscle connective tissue fibroblasts, in the development of CDH has been further elucidated. Through the use of mouse genetics, the PPFs were identified as the source of the central tendon, muscle connective tissue, and muscle connective tissue fibroblasts. The migration of these PPF cells has been found to control diaphragm morphogenesis. In this model, mice with mutated Gata4, strongly expressed in the PPFs, universally developed diaphragmatic hernias. Muscle connective tissue produced by mutated PPF fibroblasts was found to be phenotypically abnormal, allowing herniation of peritoneal contents into the thorax. The herniated tissue was shown to physically impede lung development (though mutations in Gata4 also have a primary effect on lung development). Therefore, this investigation identified a critical role of the PPF and muscle connective tissue fibroblasts in normal and abnormal diaphragmatic development. The nitrofen rodent model has led to improved understanding of abnormal pulmonary development in CDH. Nitrofen (2,4-dichloro-phenyl-p-nitrophenyl ether) is an environmental teratogen. If a specific dose is administered at a specific time during gestation, it can cause pulmonary, cardiac, skeletal, and diaphragmatic abnormalities, analogous to the human condition. Diaphragmatic defects resulting from the administration of nitrofen in mice are very similar to the diaphragmatic defects seen in babies with severe CDH in regard to size, location, and herniation of abdominal viscera. The side of the CDH depends on the time of nitrofen exposure during gestation. In nitrofen-exposed fetal mice, a defect is clearly seen in the posterolateral portions of the PPF. In addition, nitrofen exposure appears to affect muscularization of the PPF. Finally, the offspring will exhibit features of pulmonary vasculopathy including increased muscularization and pulmonary vessel hyporesponsiveness, as well as pulmonary hypoplasia, including reduced airway branching, decreased alveolarization, and surfactant deficiency, all leading to respiratory failure at birth. Other teratogens structurally similar to nitrofen have been shown to induce CDH in animal models as well. Although the exact etiology of CDH is unknown, these teratogens commonly affect the retinoic acid synthesis pathway by inhibiting retinol dehydrogenase-2 and causing similar diaphragmatic defects. Several clinical observations and molecular studies have supported the importance of the retinoic acid pathways in CDH development. Vitamin A–deficient rodents will produce offspring with CDH of variable severity. Retinoic acid receptor knockout mice produce fetuses with CDH. Failure to convert retinoic acid to retinaldehyde following administration of nitrofen produces posterolateral diaphragmatic defects in rats. Lower plasma levels of retinoic acid and retinol binding protein in infants with CDH have been found compared with controls.

Answer 12

Fetal lung development is divided into five overlapping stages. 1) Embryonic (3 - 6 weeks AOG): The embryonic stage begins during the third week of gestation as a caudal diverticulum from the laryngotracheal groove. The primary lung buds and trachea form from this diverticulum by the fourth week, and lobar structures are seen by the sixth week. (2) Pseudoglandular (5 - 17 weeks AOG): The pseudoglandular stage occurs between the 5th and 17th weeks of gestation with the formation of formal lung buds as well as the main and terminal bronchi. (3) Canalicular (16 - 25 weeks AOG): During the canalicular stage, the pulmonary vessels, respiratory bronchioles, and alveolar ducts develop between weeks 16 and 25 with the appearance of type 1 pneumocytes and type 2 pneumocyte precursors. At this stage, functional gas exchange is possible. (4) Saccular (24weeks - term) The saccular stage continues from 24 weeks to term with the maturation of alveolar sacs. Airway dimensions and surfactant synthesis capabilities continue to mature as well. (5) Alveolar (after birth): Finally, the alveolar stage begins after birth with a continued increase and development of functional alveoli. Concomitantly, fetal pulmonary vascular development occurs in concordance with the associated lung development and follows the pattern of airway and alveolar maturation. A functional unit known as the acinus consists of the alveolus, alveolar ducts, and respiratory bronchioles. The pulmonary vasculature develops as these acinar units multiply and evolve during the canalicular stage. The preacinar structures consist of the trachea, major bronchi, lobar bronchi, and terminal bronchioles. The pulmonary vascular development for the preacinus is typically completed by end of the pseudoglandular stage. In theory, any impedance to normal pulmonary development will concurrently hinder pulmonary vascular development (and the converse is likely also true).

Answer 13

Pulmonary hypoplasia is characterized by a decrease in bronchial divisions, bronchioles, and alveoli. The alveoli and terminal saccules exhibit abnormal septations that impair the air–capillary interface limiting gas exchange. At birth, the alveoli are thick-walled with intra-alveolar septations. These immature alveoli have increased glycogen content leading to thickened secretions that further limit gas exchange. Animal models of CDH have demonstrated pulmonary hypoplasia with decreased levels of total lung DNA and protein. In addition, the pulmonary vasculature has a diminished capacity for vasoreactivity, with abnormally thick-walled arteries and arterioles. Interestingly, the contralateral lung also exhibits the structural abnormalities of pulmonary hypoplasia. Preclinical treatments for pulmonary hypoplasia present interesting areas of research for nonsurgical therapies of infants with CDH. Previous therapies, including prenatal steroids and surfactant, have been shown to have no clinical benefit and are currently not recommended. Although multiple avenues of investigation are ongoing, several areas with potential include the retinoic acid pathway involving vitamin A, tracheal occlusion for pulmonary growth, and cell therapy approaches.

Answer 14

Normal fetal cardiopulmonary circulation transitions to its postnatal state rapidly with a 10-fold increase in pulmonary blood flow within hours following birth. Fetal pulmonary blood flow is characterized as a low-flow, high-resistance circuit due to medial and adventitial hypertrophy of the vasculature. Normally, the pulmonary vascular resistance (PVR) quickly decreases as the distal small pulmonary arteries and arterioles remodel over the first few months of life, resulting in a low-resistance, high-flow postnatal circulation. However, this process appears to be arrested in CDH newborns, and the fetal circulation persists resulting in CDH-PH. In fact, the abnormal fetal pulmonary circulation in CDH fetuses appears to originate and progress in early gestation. The pulmonary arteries exhibit a decrease in density per unit of lung parenchyma as well as an increase in muscularization that extends to the vasculature at the acinar level. In fetal lamb models of surgically created CDH as well as human fetuses with CDH, there is a relative decrease in lung parenchyma. This impaired lung growth and development has been speculated to be related to impaired vascular development. As a result, CDH-PH appears to develop in utero, which may cause a reduction in pulmonary artery growth, proper alveolar development, and normal lung growth. However, in contrast to a congenital pulmonary airway malformation (CPAM), another congenital malformation associated with pulmonary hypoplasia and severe pulmonary compression, pre- and postnatal pulmonary vascular pathology and remodeling was found to be worse in infants with CDH versus CPAM in one study, suggesting a multifactorial origin for CDH-PH. Finally, the timing of diaphragmatic and pulmonary development further supports the “two-hit hypothesis” of CDH development, wherein both defective early pulmonary development and subsequent defective diaphragmatic development contribute to the ultimate pulmonary pathogenesis. In a retrospective study, CDH infants who developed normal pulmonary artery pressures during the first 3 weeks of life were found to have a 100% survival rate. In this same study, an intermediate reduction in elevated pulmonary pressures after birth were seen in 34% of infants with a 75% survival. Mortality was 100% in CDH infants who had persistent, suprasystemic pulmonary pressures despite maximal therapy. Although contemporary outcomes for infants with pulmonary hypertension have improved, these data underscore the importance of CDH-PH.

Answer 15

Accurate prenatal diagnosis and prognostication of disease severity is an important adjunct to prenatal counseling, patient triage, and identification of high-risk infants with CDH. In obtaining an accurate diagnosis, it is important to differentiate CDH from other intrathoracic anomalies in which normal anatomy is otherwise undisturbed. These include CPAMs, bronchogenic cysts, bronchial atresia, or bronchopulmonary sequestrations, as well as mediastinal lesions, including enteric, neuroenteric, or thymic cysts. Diaphragm eventration must also be included in the differential diagnoses. Although it can be challenging to differentiate eventration from CDH, eventration carries a favorable prognosis with a different management algorithm. Eventrations are typically isolated lesions, but can be complicated with pleural and/or pericardial effusions. Approximately 50–70% of infants with CDH are identified during pregnancy, and the frequency of prenatal detection has substantially improved in the past two decades. The diagnosis of CDH is most often first made between the 18th and 22nd weeks of pregnancy on ultrasound (US) screening exams. Fetal US features include polyhydramnios, intrathoracic fluid-filled bowel loops, an echogenic chest mass, mediastinal shift, and/or an intrathoracic stomach. Left-sided CDHs are more frequently detected prenatally and feature mediastinal/cardiac shift to the right as well as herniation of the stomach, intestines, and/or spleen. The liver may herniate, but its echogenicity is often similar to the lung and may be more difficult to differentiate. In right-sided CDH, the right lobe of the liver is herniated, with a left-sided mediastinal shift. US of the fetal chest is best performed in the axial plane. The lung-to-head ratio (LHR) is a prenatal US assessment ratio, utilizing the contralateral lung area to the head circumference, which predicts CDH severity. Using the lung tracing method, fetal lung circumference is used to determine the LHR and is measured at the level of the four-chambered view of the heart. The fetal diaphragm can be seen as early as the first trimester as a thin hypoechogenic line in the sagittal view. Measurements of fetal lung circumference are most accurate after the first trimester, when the majority of the dynamic growth of the fetal thorax has stabilized, and the head-to-thorax ratio is less variable and generally remains 1:3. Although independent sonographic features of CDH have not been shown to be accurate predictors of postnatal severity, severe or advanced CDH can be identified by: 1) an intrathoracic liver (“liver up”), 2) mediastinal shift to the contralateral thoracic cavity, or 3) hydrops fetalis.

Answer 16

Two distinct US measurements have been utilized to risk stratify infants with CDH: (1) observed-to-expected (O/E) LHR (O/E normalizes for variation by gestational age) and (2) liver herniation into the hemithorax. A recent metaanalysis provides an up-to-date review of survival prediction with LHR and liver herniation. O/E LHR serves as one of the best US predictors of postnatal survival, with 25% serving as a reasonable discriminative threshold. The gestational age differential in thoracic growth compared with head growth can be ameliorated by using the LHR as a function of observed or measured to the expected or agebased norms of the same lung. Infants with O/E LHR <25% have predicted survival ranging from 12.5–30%, while survival for O/E LHR >35% ranges from 65–88%. Most studies that were evaluated also demonstrated significantly improved prognoses if the liver was not in the chest. Although fetal US is a highly reliable, inexpensive, readily accessible modality for prenatal prediction of prognosis, in CDH, its inconsistent utilization and inter-rater/interinstitutional variability has limited the generalizability of the technique.

Answer 17

If diaphragm pathology is suspected on fetal US, fetal magnetic resonance imaging (MRI) may add additional prognostic value. MRI offers improved tissue characterization and spatial resolution when compared with US. Moreover, MRI can further clarify liver position due to discernibly different signal intensities on MRI compared with US, accounting for the higher water content of fetal lungs on T2-weighted images. The percentage of liver herniation on fetal MRI correlates with pulmonary morbidity, with >20% liver herniation predicting more profound morbidity. In addition, fetal MRI is an excellent modality for morphologic and volumetric measurements of the fetal lung (total fetal lung volume [TFLV]). It is especially advantageous in patients with oligohydramnios and maternal obesity. Eight studies included in the recently published meta-analysis showed a statistically significant difference between the mean O/E TFLV of survivors compared with nonsurvivors with CDH. Survival rates with O/E TFLV <25% ranged from 0–25%, whereas for O/E TFLV >35%, survival ranged from 75–89%. [H&A] — Excellent imaging of the fetal lungs is often obtained on MRI, as the high water content of the lungs renders them quite bright on T2 sequences. While a fetal MRI is not essential to the evaluation, it does provide several pieces of important information, including a full anatomic evaluation of the fetus, accurate diagnosis of liver herniation and quantification of such herniation, if present, and calculation of total fetal lung volume (TFLV). In addition to LHR, the latter has also been found to have prognostic significance. [Sherif]

Answer 18

Newborns with CDH typically present with respiratory distress. Clinical scenarios at birth range from immediate, profound respiratory distress with concomitant respiratory acidosis and hemodynamic instability, to an initial stable period with delayed respiratory distress, to an asymptomatic newborn. Initial signs associated with respiratory distress include tachypnea, chest wall retractions, grunting, cyanosis, and/or pallor. On physical examination, infants will often have a scaphoid abdomen and may have a subtle increase in thoracic diameter. The point of maximal cardiac impulse is often displaced, a physical finding with mediastinal shift. Bowel sounds may be auscultated within the thoracic cavity with a decrease in breath sounds bilaterally. Chest excursion may be reduced, suggesting a lower tidal volume. The diagnosis of CDH is typically confirmed by a chest radiograph demonstrating intestinal loops within the hemithorax, cephalad displacement of the stomach/orogastric tube, and a mediastinal shift toward the contralateral hemithorax. The abdominal cavity may have minimal to no gas, particularly initially. Right-sided CDH can be challenging to diagnose. Salient features, such as intestinal and gastric herniation, may not be prominent, and the herniated right lobe of the liver can be mistaken for a right diaphragmatic elevation or eventration. Occasionally, features of lung compression may be the only radiographic sign, which can cause confusion with CPAMs, pulmonary sequestrations, bronchopulmonary cysts, neurogenic cysts, or cystic teratomas. Although most infants with CDH will be diagnosed within the first 24 hours of life, as many as 20% may present outside the neonatal period. These patients present with mild respiratory symptoms, chronic pulmonary infections, pleural effusions, pneumonias, feeding intolerance, or gastrointestinal pathology. As CDH is invariably associated with abnormal intestinal rotation and fixation, some children can present with intestinal obstruction or volvulus. Occasionally, CDH may be completely asymptomatic and is discovered only incidentally. Patients who present later in life have an excellent prognosis due to milder or absent associated complications, such as pulmonary hypoplasia and CDH-PH.

Answer 19

The prenatal diagnosis of CDH continues to improve with the increased use and refinement of fetal US examination and advanced fetal MRI. After initial screening, an advanced US helps to determine discordant size and dates, associated anomalies (cardiovascular, neurologic, other), as well as signs of fetal compromise (i.e., hydrops fetalis). Further, an accurate LHR can estimate the probable severity, allowing informed counseling and consideration for appropriate prenatal monitoring and/or intervention. Once diagnosed, chromosomal screening via amniocentesis for karyotyping and chromosome microarray analysis is recommended. Optimally, the mother and fetus should be referred to a tertiary perinatal center with protocolized fetal MRI and advanced maternal fetal medicine (a fetal center), neonatal, surgical, and critical care capabilities, including HFOV, ECMO, and pulmonary hypertension therapeutic expertise. A prenatal diagnosis enables informed counseling for the mother and family including treatment options and prognosis. PRENATAL MEDS In animal models, the hypoplastic lungs of CDH infants are structurally and functionally immature. Biochemical markers for lung maturity demonstrate decreased total lung DNA, total lung protein, and desaturated phosphatidylcholine in addition to a deficiency of surfactant. Some animal models demonstrate lung maturation and improved function as a result of prenatal administration of glucocorticoids. Initial results from small patient series seemed promising in that antenatal administration of glucocorticoids suggested improved lung function. However, other studies failed to demonstrate any benefit for CDH-associated pulmonary hypoplasia. As such, prenatal steroids are not currently recommended for CDH. Other agents targeting pulmonary morphology that rely on transplacental transport for delivery include vitamin A, glucagon-like peptide-1 agonists, phosphodiesterase (PDE) inhibitors, and tyrosine kinase inhibitors. Vitamin A compounds are critical in normal diaphragmatic and pulmonary development, and infants with CDH have been noted to have lower vitamin A levels. As such, vitamin A has been applied to the rat nitrofen model and rabbit model with mixed evidence for enhanced lung maturity and decreased pulmonary vessel thickness. However, to date, no human studies have examined the benefit of prenatal vitamin A, and there is evidence that excessive vitamin A can be teratogenic in human pregnancy. Animal studies have also examined the potential benefits of prenatal glucagon-like peptide-1 agonists and tyrosine kinase inhibitors with varied results. In addition, there are animal models that show promise in improving pulmonary vasculature remodeling prenatally with the administration of the PDE inhibitor sildenafil. Despite promising frontiers in research with prenatal medical and pharmacologic interventions for CDH, translation of these therapies via clinical trials remains elusive. At this point, there are no indications for any prenatal pharmacotherapy in CDH.

Answer 20

After confirming the diagnosis, initial postnatal therapy is targeted at resuscitation and stabilization of the infant in cardiopulmonary distress. A rapid overall assessment is important to determine hemodynamic stability and the severity of disease. In most cases, prompt endotracheal intubation (without bag mask ventilation) and initiation of conventional mechanical ventilatory support is required. A nasogastric tube should be inserted to avoid gastric and intestinal distention. Arterial and venous access is necessary for resuscitative maneuvers. Acid–base balance and oxygenation–ventilation status should be carefully monitored. Invasive monitoring is important in accurately assessing the infant’s overall perfusion and the severity of pulmonary hypertension and hypoplasia. Umbilical venous catheters may be helpful and, if possible, may be positioned in the right atrium to measure central venous pressures. In addition, an approximation of cerebral oxygenation and perfusion should be available using preductal oxygen content and/or saturation via either a right radial arterial catheter or a transcutaneous saturation probe. Targets for initial resuscitation include preductal arterial saturation (SaO2) between 80% and 90% with strictly limited positive airway pressures. In order to maintain lower peak inspiratory pressures (PIPs), a moderate level of hypercarbia (PaCO2, up to 70 mmHg) is accepted as long as it does not result in a profound compensatory acidosis. Occasionally, higher levels of PaCO2 are tolerated transiently as long as a pH > 7.2 is maintained. Failure to provide adequate tissue oxygenation can result in metabolic acidosis, which may exacerbate the pulmonary hypertension. PVR is increased by hypoxia and acidosis, which should be avoided or corrected. In the event of a pulmonary hypertensive crisis, including rapidly progressive hypoxia, hypercarbia, and/or severe ductal shunting, some centers use inhaled nitric oxide (iNO). However, there is mounting evidence that iNO does not reduce the need for ECMO nor improve survival in CDH. Alternative strategies including minimal environmental stimulation, fluid optimization, HFOV, milrinone, sildenafil and/or ECMO may be effective or necessary to stabilize clinical deterioration secondary to a pulmonary hypertensive crisis.

Answer 21

Depending on the degree of pulmonary hypertension and associated cardiac anomalies (both assessed by echocardiography within the first 6–12 hours of life), hemodynamic stability can be difficult to achieve. Pulmonary hypertension may be exhibited by a difference in pre- and postductal SaO2. However, echocardiography can better characterize the degree of pulmonary hypertension. Sonographic findings of pulmonary hypertension include: poor contractility of the right ventricle, flattening or bowing of the interventricular septum, enlarged right heart chambers, and tricuspid valve regurgitation (which can be used to estimate the right-ventricular systolic pressures). There may be right-to-left or bidirectional shunting across the ductus arteriosus or ASD/VSD. Almost all infants with CDH and severe pulmonary hypertension exhibit some left ventricular dysfunction and emerging evidence continues to suggest cardiac dysfunction plays a prominent role in the outcomes of patients with CDH. Vasopressor agents such as dopamine, dobutamine, epinephrine, and milrinone may be needed in hemodynamically unstable patients. These inotropic agents can augment left ventricular output and increase systemic pressures in order to ameliorate right-to-left ductal shunting.

Answer 22

Optimal mechanical ventilation is a critical component in the care of infants with respiratory failure secondary to CDH. However, the physiologic limits of the hypoplastic lung and the pathophysiologic, hyporesponsive pulmonary vasculature make mechanical ventilatory management a challenge. Hypoplastic lungs in CDH infants are characterized by a decreased number of airways and smaller alveolar airspaces. Also, the pulmonary vasculature exhibits decreased vascular branching as well as increased adventitia and medial wall thickness. This combination results in varying degrees of respiratory failure and CDH-PH. Fortunately, pulmonary and vascular development continues after birth and these pulmonary sequelae of CDH can improve. Because of this ongoing maturation, mechanical ventilation strategies have trended toward less aggressive approaches with the goal of maintaining oxygenation, while limiting the risks of ventilator-induced lung injury (VILI) and alveolar instability, major contributors to pulmonary morbidity and mortality. Conventional ventilation is the optimal initial mode of mechanical ventilation among infants with CDH. The optimal specific type of conventional mechanical ventilation remains individual clinician preference, though most cases of CDH can be managed using a pressure-controlled mode. A fractional inspired oxygen (FiO2) of 1.0 is initially utilized to maintain adequate SaO2 (>80–85%). Typically, higher respiratory rates and lower peak airway pressures (18–22 cmH2O) are employed while titrating the FiO2 to a preductal SaO2 > 80–85%, and a PaCO2 less than 70 mmHg (pH > 7.2). Maintaining an acceptable pH and PaCO2 are important in managing pulmonary hypertension. The ventilation strategy of induced respiratory alkalosis with hyperventilation to reduce ductal shunting has been abandoned. Initial conventional mechanical ventilation settings should include pressure-limited ventilation rates between 40 and 60 breaths per minute with PIP <25cmH2O to minimize volutrauma/barotrauma. The initial PIP can be weaned to minimal settings, but should be done with caution, using a gradual, methodical approach. While targeting a PaCO2 <70mmHg, rapid reduction in mechanical support may allow transient periods of stability, but may also produce potential refractory exacerbations of pulmonary hypertension. Spontaneous respirations are maintained by avoiding neuromuscular paralysis and minimal ventilation rates. This combination of 1) spontaneous respiration and 2) permissive hypercapnia has been a well-documented preoperative stabilization strategy in some centers with survival rates of almost 90% in selected patients with isolated CDH.

Answer 23

If conventional ventilation fails to reverse hypercapnia and hypoxemia, High-Frequency Oscillatory Ventilation (HFOV) strategies can be employed, in an attempt to avoid ventilatory-induced lung injury, by preserving end-expiratory lung volume without overdistending the lung parenchyma. As our understanding of the pulmonary anatomy and physiology in CDH continues to evolve, HFOV strategies have also changed. Initially used in a high-pressure, lung recruitment mode, this strategy has not demonstrated any benefit, likely due to the nonrecruitable nature of hypoplastic lungs. As the concept of preoperative stabilization became better defined, HFOV began to be used as means to avoid barotrauma early in the treatment course prior to refractory respiratory failure. In fact, some institutions have utilized HFOV as primary therapy.l A recent international, multicenter randomized trial evaluated the optimal initial mode of ventilation in infants with CDH. Compared with conventional ventilation, HFOV demonstrated no significant reduction in mortality or bronchopulmonary dysplasia (BPD) even after adjustment for severity (liver-up, prenatal LHR, side of defect). Secondary analyses found that patients who received conventional ventilation had a decreased length of ventilation, less ECMO support, less inhaled nitric oxide, sildenafil, and vasoactive medication use, and were less likely to fail the initial ventilator management strategy. Therefore, while the primary outcome variable in this study did not suggest a clear superiority of one ventilator mode when compared with another, secondary outcomes support conventional ventilation as the initial mode of ventilatory support for initial postnatal, preoperative stabilization. Regardless of modality, these strategies of preoperative stabilization and pressure-limited ventilation to minimize ventilator-induced lung injury, along with delayed operation, have resulted in improved survival. In order to achieve lower peak airway pressures, HFOV should be considered when PIP reaches 25cmH2O with conventional ventilation, and established targets are not being achieved. Initial HFOV settings include: 1) a mean airway pressure between 13 and 15 cmH2O (2cmH2O above conventional ventilation mean airway pressure (MAP)), 2) 10–12 Hz, amplitude between 30 and 50 cmH2O (optimizing chest vibration), and 3) inspiration to expiration ratio of 50%. The initial PaCO2 should be maintained in the range of 50–70mmHg and can be weaned by decreasing the amplitude. Eight-rib expansion of the contralateral hemithorax can be used as a guide to achieve optimal lung expansion without overdistention. Tidal volumes are directly related to the amplitude and inversely related to frequency. As such, significant increases in tidal volume can be seen when frequencies are below 10Hz. This can result in hyperinflation, which, in turn, can exacerbate VILI and adversely affect the pulmonary vasculature by impeding venous return. Constant assessment of acid–base status and end-organ perfusion is necessary as lung compliance can change before and after CDH repair.

Answer 24

Both experimental and animal studies of CDH have demonstrated variability of surfactant levels and composition. However, despite the lack of proven efficacy, exogenous surfactant therapy continues to be used, with unclear risks and benefits. Proponents of this therapy argue that the clinical evidence is based on a heterogeneous population of disease severity, and that the lack of clinical evidence to support its efficacy is due to its use in the most severe CDH infants. Clinical data from the CDH Study Group show no advantage to surfactant use in CDH, both in term and preterm infants. Given the current clinical evidence, surfactant therapy should only be used due to prematurity or in the setting of clinical research.

Answer 25

Pulmonary hypertension is a common and serious consequence among CDH infants. With increased PVR, these babies often display suprasystemic right ventricular pressures leading to right-to-left shunting in both the pre- and postductal circulations. This can result in progressive right heart dysfunction (and, ultimately, failure) with decreases in preductal saturation, narrowing of the pre- and postductal SaO2 , and, ultimately, systemic hypotension and decreased perfusion. In previously stable neonates, signs of poor perfusion may indicate closure of a PDA. In response, prostaglandin E1 (PGE1) can be instituted to reopen the ductus and improve right ventricle (RV) pressures. In infants that demonstrate significant pulmonary hypertension and RV dysfunction, left ventricular filling/function and overall perfusion may improve by off-loading the RV to improve the geometry of the interventricular septum. Preductal SaO2 > 80–85% should be maintained to ensure adequate cerebral perfusion. As the RV is unloaded, systolic blood pressure may decrease, especially in the setting of left ventricular dysfunction. Adequate preload should be maintained with volume loading or vasopressor support, such as epinephrine, to ensure ventricular function and coronary artery perfusion. Increasing the systemic pressure may decrease the degree of right-to-left shunting.

Answer 26

Inhaled nitric oxide (iNO) is a potent pulmonary vasodilator that has been shown to have tremendous benefit in the treatment of persistent pulmonary hypertension of the neonate (PPHN). Typically, iNO is utilized in the setting of echocardiographic evidence of right-to-left shunting and RV pressures greater than two-thirds systemic pressures. In clinical studies, iNO has been shown to improve oxygenation and decrease the need for ECMO in infants with respiratory failure secondary to PPHN. However, the efficacy of iNO as a rescue therapy for CDH-PH by either decreasing the need for ECMO or reducing mortality has not been shown. In the Neonatal Inhaled Nitric Oxide Study Group trial, the CDH subgroup had a greater likelihood for ECMO or death. The response to iNO is variable and unpredictable in infants with CDH. The initial improvement in oxygenation in CDH infants suggest that iNO could be utilized as a bridge for transport or until ECMO can be initiated. Some infants may demonstrate a rebound pulmonary hypertension that is more difficult to control than the initial disease. Also, the effect appears to be transient and does not obviate the need for ECMO. A recently published Cochrane review of iNO utilization for persistent PHTN did not show decreased mortality or need for ECMO in the subset of CDH infants, and recommended its use only in infants with hypoxic respiratory failure from etiologies other than CDH. [H&A] — Although inhaled NO can be a potent selective pulmonary vasodilator, several studies failed to show that it resulted in either a decreased requirement for ECMO or a decreased mortality. A recent analysis revealed that one-third of CDH patients treated with inhaled NO did not have evidence of significant pulmonary hypertension. The drug is most likely overused. Its expense represents a major resource burden in the treatment of this anomaly. Nevertheless, it can act as a useful adjunct in patients with supra-systemic pulmonary artery pressures. The role of echocardiography in the care of CDH patients has assumed increasing importance over the last several years. Some investigators have suggested that lack of response to inhaled NO may be due to poor ventricular function, which is seen in many patients with CDH. It is therefore prudent to base the initiation of NO on echocardiographic criteria of pulmonary hypertension without ventricular dysfunction. The only consensus regarding NO is to stop the drug if no response is seen. Otherwise, potential criteria for cessation of NO include ability to wean patient to FiO2 below 0.5, resolution of the right to left shunt as measured by saturation probes, resolution of supra-systemic pulmonary artery pressure on echocardiography, and after surgical repair. [Sherif]

Answer 27

PDE inhibitors are cyclic guanosine monophosphate (cGMP) modulators that target vascular remodeling by limiting smooth muscle cell proliferation. Type 5 PDEs (such as sildenafil) are the most active on visceral and vascular smooth muscle and have been utilized with iNO for the treatment of PH in patients with and without CDH. Sildenafil has been shown to improve oxygenation and decrease PVR when used independently or in combination with iNO. Sildenafil has been used in oral or intravenous forms for congenital heart disease and CDH-PH since its approval by the U.S. Food and Drug Administration (FDA) for use in adults. Utilization of sildenafil may have benefit in improving oxygenation and avoiding ECMO in the setting of pulmonary hypertension that is refractory to iNO therapy. The FDA has warned against using sildenafil for pediatric pulmonary hypertension between ages 1 and 17 years due to a potential increase in mortality during long-term therapy. However, there is an increasing body of research pointing toward a favorable safety profile with long-term sildenafil use in neonates and children. Current recommendations for use include following the European Medicines Agency guidelines with close follow-up. Other vasodilators including bosentan, an endothelin-1 receptor antagonist, have been utilized in infants with CDH, but the experience to date is limited.

Answer 28

In contrast to prior decades, CDH now accounts for the majority of infants who require ECMO for respiratory failure. ECMO utilization for CDH was first introduced as a rescue therapy for infants who had severe ventilator-associated lung injury and was associated with only a modest improvement in survival in high-risk CDH infants. However, ECMO has evolved as a treatment modality to prevent ventilator-induced barotrauma. In combination with other adjunctive treatments such as HFOV, ECMO is now routinely used for preoperative stabilization of infants with CDH. Although results are dependent on patient selection and disease severity, outcomes remain poor for CDH patients requiring ECMO, with multiple centers reporting between 30% and 50% survival. Without ECMO, the predicted mortality in this high-risk cohort reaches 80%. Despite these data, the benefits of ECMO for CDH are not universally accepted. Some authors report no survival advantage with ECMO, while others report as high as 80% survival without using ECMO. Hidden from these figures is a certain amount of patient variability regarding prenatal diagnosis and CDH severity. For example, centers with largely outborn populations of nonprenatally diagnosed CDH may have less severe disease, preventing accurate comparison without thorough risk stratification. Today, criteria for ECMO initiation mainly focus around a “failure to respond” to alternative therapies or failure to meet specified targets while remaining within prespecified ventilator limits. In efforts to maintain lung-protective ventilation, clinicians opt for ECMO rather than escalation of positive airway pressures. Either venoarterial or venovenous ECMO can be used as neither has shown superiority. Relative contraindications include: significant congenital anomalies, lethal chromosomal anomalies, intracranial hemorrhage, birth weight <2 kg, and gestational age <32–34 weeks. The duration of ECMO support has increased, with some centers opting for unlimited duration, though survivors after 4–5 weeks of ECMO support are rare. [H&A] — Current criteria for initiating ECMO include persistent poor oxygenation, poor ventilation, or poor perfusion despite maximal medical management with gentle ventilation techniques. The definition of each of these endpoints, and the extent of medical management before triggering ECMO, varies significantly between institutions. At the present time, it is likely that ECMO will continue to be used for the most severely affected CDH patients, who are highly unlikely to survive without this modality. Once a decision has been made to pursue ECMO, the next decision is whether to proceed with veno-venous (VV) or veno-arterial (VA) ECMO. VA ECMO allows for hemodynamic, as well as respiratory, support but carries the disadvantage of sacrificing the right carotid artery. It is often chosen when there is significant hemodynamic compromise, despite the assumption that better oxygenation may directly lead to improved cardiac function. Recent studies using the Extracorporeal Life Support Organization (ELSO) do not favor one mode over another. As echocardiographic evaluation becomes a more consistent part of patient evaluation, results may drive the choice of modality. Regardless of mode, escalation to ECMO should be discussed with the parents during prenatal consultation and during postnatal care. It should be remembered that survival after ECMO also comes with a price of increased long-term morbidities. Therefore, a decision by parents not to proceed to this most invasive treatment is reasonable and should be respected. [Sherif]

Answer 29

With an improved understanding of its pathophysiology, repair of CDH is no longer considered an emergency procedure. However, the optimal timing for repair remains unclear. Historically, early repair was thought to improve ventilation by reducing intrathoracic pressures after reduction of the herniated viscera. However, this strategy often led to urgent procedures being performed on unstable infants. A paradigm shift in management to delay the operative repair until the infant is stable became widely adopted in the early 1990s. The mid-1990s saw two randomized controlled trials of early (<12 hours) versus delayed (after 24 or 96 hours) repair, neither of which demonstrated a difference in mortality. A Cochrane review updated in 2002 echoed these findings. More recently, a CDHSG cohort of low-risk infants with CDH who did not require ECMO support was analyzed by timing of repair at three observed peak indices: day of life (DOL) 0–3, 4–7, or >8. When risk-adjusted for severity of illness (liver-up or down, birth weight, associated congenital heart disease, etc.), there was no difference in mortality amongst the three groups, implying that delayed operative repair does not impact survival. Another recent review of 268 consecutive patients with CDH who were risk-stratified by liver-up or down suggested that anatomically less severe CDH benefitted more from delayed repair, as those who were repaired earlier (within 48 hours) had an increased need for ECMO support. This work emphasizes the importance of risk stratification in CDH and perhaps lays a foundation for the development of risk-stratified treatment algorithms. While delayed repair in most patients with CDH has become standard, in higher risk infants with CDH who require ECMO support, timing of repair as it relates to initiation of ECMO therapy remains controversial. Recently, there have been data suggesting that earlier repair when supported on ECMO results in improved survival. Theories supporting early repair on ECMO include the avoidance of operating in the setting of tissue edema that can often occur with increased duration of ECMO, early optimization of pulmonary expansion and vasodilation, and possibly a trend toward decreased duration of ECMO support. Fallon et al. published similar findings in 2013 with a series of 29 patients repaired on ECMO, and those who were repaired early (within 72 hours) trended toward increased survival and demonstrated a shorter ECMO requirement with fewer circuit complications. In 2016, Kays et al. published a large series of high-risk (liver-up) CDH patients and demonstrated an increased survival when repaired early and before initiation of ECMO support, highlighting the potential benefits of early repair in this cohort of patients. However, this strategy of early repair when on ECMO is not universally accepted as other centers have demonstrated improved outcomes and decreased bleeding with delayed repair, particularly following decannulation. Risk stratification is paramount, though, as patients able to be decannulated prior to repair likely represent a less-severe cohort. Bleeding remains the most significant complication following CDH repair on ECMO, including both surgical site bleeding and intracranial hemorrhage. These risks may be minimized with early repair on ECMO prior to the development of a coagulopathy and significant edema, and after the pulmonary hypertension has stabilized, but prior to decannulation so as to allow reinstitution of ECMO if respiratory failure and/or pulmonary hypertension are exacerbated by the operative insult. Although rare, recurrent pulmonary hypertension can develop after CDH repair requiring a second ECMO run. In addition, use of aminocaproic acid (Amicar® ), a fibrinolysis inhibitor, may decrease bleeding complications during CDH repair on ECMO. Amicar® should be used prior to operation and for 36–72 hours following repair. Additional strategies include ECMO without heparinization, fresh ECMO circuits, minimal diaphragmatic muscular dissection, fibrin or thrombin sealants, and utilization of recombinant factor VII for uncontrolled bleeding. In summary, although more studies are needed to elucidate the optimal time to repair high-risk CDH patients who require ECMO support, early repair on ECMO may be associated with improved outcomes. [H&A] — The hernia should be repaired when oxygenation and perfusion are stabilized and pulmonary hypertension is well controlled. Signs that these criteria have been met include adequate urine output (>1 mL/kg/h), pre-ductal saturation consistently above 85%–90% on FiO 2 <0.5, a right to left saturation differential below 5%, consistently normal systemic blood pressure, and pulmonary artery pressure below systemic pressure on echocardiography. Delay in repair beyond 14 days of age is not warranted in most patients who were not placed on ECMO. The timing of repair in patients heading toward, or already on, EMCO has also been debated. Options include repair before going on ECMO, early in the ECMO run, before decannulation, and after decannulation. The latter has been considered the default option. The data on timing of repair for ECMO patients come mostly from single-institution studies, with good outcomes reported with most options. Early repair on ECMO may potentially improve ECMO outcomes and shorten the ECMO run, but hemorrhagic risks are high. Some protocols have emerged using epsilon-aminocaproic acid or tranexamic acid to decrease the bleeding risk. Repair prior to ECMO is not widely practiced, since cannulation often has to proceed urgently, not allowing time for repair in an unstable patient. Finally, some studies have shown an outcome disadvantage for surgical repair at any point during the ECMO run. Once again, each institution should establish clear criteria for repair in patients on ECMO. For example, it may be advantageous to repair the hernia early in a patient who does not show any progress during the first 3–4 days of the ECMO run, while repairing a patient who shows steady progress following decannulation. [Sherif]

Answer 30

Open repair of CDH can be performed using a thoracic or abdominal approach. Advantages to laparotomy include easier reduction of intrathoracic viscera, the ability to mobilize the posterior rim of diaphragm, easier management of intestinal rotational anomalies (if necessary), and avoidance of thoracotomy-associated musculoskeletal sequelae. The vast majority of open neonatal repairs for CDH are through a subcostal incision (>90%), with a few centers opting to use a midline laparotomy incision, and the rest being performed via thoracotomy. The herniated contents should be reduced from the hemithorax with careful attention to the spleen, which can be caught on the rudimentary rim of diaphragm, resulting in laceration. A true hernia sac, which is present less than 20% of the time, should be excised. The thoracic and abdominal cavities should be inspected for an associated pulmonary sequestration.

Answer 31

Despite this “gold standard” abdominal approach, the morbidity and respiratory sequelae of open CDH repair remain a concern. In addition to pulmonary hypoplasia and hypertension, respiratory compliance can be significantly reduced after open repair (despite the enlarged thoracic space created in the ipsilateral hemithorax). Mortality significantly increases when compliance decreases by >50%, which can occur as a result of a tight abdominal wall closure. Careful attention should be paid to the peak airway pressures as the abdominal fascia is closed. A large patch that bows into the hemithorax can minimize this risk. In the event that respiratory compromise ensues, the surgeon should consider a relaxed, temporary abdominal closure (fascial patch/prosthetic silo, vacuum-assisted closure, or skin-only closure), with planned delayed fascial closure, which is used in approximately 10% of cases. This approach is more often required for infants on ECMO and among those with right-sided CDH. Delayed closure, especially in those infants on ECMO, should be attempted after the generalized edema has resolved or the intra-abdominal domain has expanded.

Answer 32

In patients repaired off ECMO, the routine use of chest tubes after CDH repair to drain pleural fluid is generally considered obsolete. One of the considerations is that the chest tube can exacerbate ipsi- and/or contralateral hypoplastic lung injury secondary to rapid mediastinal shift, especially if connected to suction. In most situations, the thoracic space will eventually fill with fluid in the absence of a drain, and the lung will gradually grow. Recently, however, there has been a reassessment of this dogma, particularly with the growth of thoracoscopic approaches. Schlager et al. reviewed 174 patients who underwent CDH repair and found that chest tube placement was associated with fewer pleural complications than cases that required postoperative drain placement. The authors found that minimally invasive approaches more often needed drain placement for a pneumothorax, whereas open techniques often required drainage of an effusion. Traditionally, if a chest tube is placed, it is positioned in the thoracic cavity prior to final closure of the diaphragm. Chest tubes should be placed to water seal rather than suction. Symptomatic pleural fluid can be treated with repeated thoracentesis. If used, chest tubes should be removed expeditiously to avoid the potential for infectious complications. [H&A] — No, a chest tube is not required after CDH repair in the majority of patients. The mediastinal position will adjust naturally to the new anatomy. Fluid will gradually replace the air in the empty space, and resorb as the lung expands. One of the few indications for a chest tube is the development of a large, symptomatic chylothorax. However, this is a rare complication, seen in less than 5% of patients. [Sherif]

Answer 33

With advancing surgical techniques and optimization of perioperative respiratory care, many surgeons have adopted minimally invasive surgical (MIS) approaches to CDH repair in efforts to avoid the respiratory sequelae and other morbidity seen after open repair. Data from the CDHSG show that laparoscopic and thoracoscopic strategies are being used worldwide and have been utilized in 16% of all CDH repairs in the most recent era. MIS techniques have been used for primary repair as well as prosthetic patch closure with suggested advantages of less postoperative pain, shorter hospitalizations, avoidance of thoracotomy-associated complications, and an overall reduction of surgical stress. The sensitivity of CDH infants to hypercapnia and acidosis has drawn concerns regarding the utilization of MIS. The overall benefits of MIS are questioned because (1) CDH neonates may absorb the CO2 insufflation and (2) insufflation with CO2 can raise intrathoracic pressures that may limit venous return, end-organ perfusion, and tidal volume. The combination of CDH-related pulmonary hypoplasia, pulmonary hypertension, and labile pulmonary vascular reactivity may be detrimental during MIS operations. Although increases in CO2 absorption during MIS are generally well tolerated in infants, CDH neonates specifically demonstrate greater changes in end-tidal CO2 (ETCO2) and impaired elimination of CO2 during thoracoscopy and laparoscopy. Hypercapnia and the associated acidosis may result in increased pulmonary shunting. Patient selection is paramount for successful completion of an MIS repair as well as for minimizing operative morbidity. Historically, MIS was reserved for stable infants with anticipated small defects who did not require high mechanical ventilation settings or ECMO. Utilizing anatomic markers such as stomach herniation or clinical indicators of severity, surgeons have attempted to predict which defects might be most amenable to MIS repairs. Initially, the radiographic presence of the nasogastric tube within the abdomen and minimal respiratory compromise (PIP < 24 mmHg) were thought to predict a successful thoracoscopic repair. Many advocate for strict preoperative selection criteria for thoracoscopic repair, including minimal ventilatory support (PIP < 24mmHg), no clinical or sonographic evidence of PH, and an intra-abdominal stomach. On the other hand, even infants requiring preoperative ECMO have undergone successful repair with an MIS approach. Large defects that require patch repairs and right-sided defects are no longer absolute contraindications to MIS. With increasing experience in MIS techniques for CDH repair, we are beginning to better understand its advantages and disadvantages. In a recent CDHSG registry review, 3067 patients underwent open (84%) or MIS (16%) repair of CDH between 2007 and 2015. Patients undergoing open repair were higher risk, with 79% of MIS repair patients falling into the low risk (A or B defects) category. Advantages with MIS repair after risk-stratification with multivariable regression analysis demonstrated a significantly decreased hospital length of stay and rate of postoperative small bowel obstruction. A more rapid recovery with decreased adhesion formation and decreased incidence of bowel obstructions are consistent with the overall strengths of an MIS approach. However, though the rate of recurrence has decreased over time with experience and optimization of surgical techniques, MIS remains associated with higher incidences of recurrence when compared with open techniques despite risk stratification. Although the ability to perform MIS repair of CDH has been shown and the short-term outcomes are emerging (as noted previously), the long-term outcomes regarding the durability and long-term recurrence rates for an MIS approach remain unknown. Early on, the reported overall recurrence rates for MIS repair ranged from 5–23%, with early postoperative recurrences as high as 23–33%. Recent data, however, suggest that although the incidence of recurrence remains higher overall, only 6% of MIS repair patients have an early (in-hospital) recurrence compared with 3.2% in the open repair cohort. Factors associated with early recurrence after CDH repair in a large CDHSG registry review include larger defect size and an MIS approach on multivariable logistic regression analysis. There are no current guidelines regarding a standardized surgical MIS technique (patch vs primary repair, the use of extracorporeal/rib fixation sutures, an overlay or onlay patch, etc.). The totality of the risks and benefits of the MIS approach for CDH repair, including the impact of reoperations, remain unclear. Robotic CDH repair has also been demonstrated to be feasible and safe. Proponents of robotic CDH repair tout the increased degrees of freedom of the articulating instruments for suturing. Unfortunately, given the current daVinci ® Surgery System design and instrument size limitations, the current setup is suboptimal for small patients.

Answer 34

Irrespective of the operative approach, repair of large diaphragmatic defects remains a challenge, usually requiring diaphragmatic replacement with a prosthetic patch or autologous tissue. In large studies, around 50% of infants undergoing CDH repair require diaphragmatic replacement with a patch. Comparative studies between patch and primary repairs have consistently shown increased morbidity and mortality in the patch groups, most likely due to the large defect size and the associated severity of the pulmonary hypoplasia. In many studies, patch repair has been utilized as a surrogate for defect size and disease severity (i.e., larger defects = increased severity of disease). The CDHSG staging system has clearly shown that defect size is the factor that has the strongest association with morbidity and mortality.

Answer 35

Synthetic patches such as polytetrafluoroethylene (PTFE or Gore-Tex® ) or composite polypropylene (Marlex® ) represent the majority of the diaphragm replacements used in neonates with a large CDH. PTFE is a strong and soft polymer that is composed of monofilament yarns with inert reactivity and has shown good histologic integration with native diaphragm in animal models of CDH. Advantages to synthetic patches include (1) immediate availability; (2) minimal preparation time; (3) easily cut to fit the diaphragmatic defect; and (4) less tissue dissection, reducing the risk of hemorrhage, which is especially important during repair on ECMO. However, there are several disadvantages to synthetic patches for CDH repair. PTFE, anchored to the chest wall, can potentially produce a tethering point for creating a thoracic, sometimes pectus-type, deformity. There is an increased incidence of bowel obstruction, need for splenectomy, patch infections, and abdominal wall deformities. Although the overall recurrence rate for patch repair has been reported to be as high as 50%, more recent data suggest that the incidence of early (in-hospital) recurrence is approximately 6%. Early recurrences for defects requiring a patch are most likely due to lack of tissue adhesion or scarring and an incomplete muscular rim that then requires anchoring the patch to the ribs or esophagus. PTFE tends to scar and retract over time, which may contribute to the development of late recurrences in the growing child. More important than the type of patch utilized might be the shape of its construction. Several authors have supported the creation of a dome-shaped patch with minimal tension on the chest wall and ribs, allowing for additional intra-abdominal space and decreasing the potential for subsequent abdominal compartment syndrome. First described by Loff et al., implantation of a cone-shaped PTFE patch may be advantageous by providing a more physiologic shape and allowing increased abdominal domain.

Answer 36

Absorbable biosynthetic materials have been utilized as an alternative replacement to synthetic patches. They have been reported to decrease complications by offering a lower risk of infection and the ability of the patch to grow with the patient. Surgisis ® (SIS) is an acellular, bioengineered porcine intestinal submucosal matrix that consists of a type I collagen lattice with embedded growth factors. This noncross-linked biological matrix promotes fibroblast migration and cellular differentiation. First described for repair of incisional, inguinal, and paraesophageal hernias, SIS ® has also been utilized for CDH repair. A recent review and meta-analysis demonstrated no statistically significant difference in CDH recurrence, small bowel obstruction, or mortality when comparing SIS patch closure to PTFE. Despite the published evidence, the overall rate of SIS use is now approximately 6% (unpublished data, CDHSG 2016), likely due to concerns about recurrences. Permacol ® is an acellular porcine dermal collagen patch consisting of collagen fibers with cross-linked lysine and hydroxylysine. By promoting an inflammatory response in a manner similar to wound healing, the neodiaphragm is more pliable and, subsequently, less prone to recurrence. One group reported no recurrences observed with a median follow-up of 20 months, while recurrences were noted in 2% of patients with primary repair and 28% with PTFE. AlloDerm ® is an acellular human cadaveric dermal patch that is cross-linked for rapid revascularization. Animal studies have demonstrated revascularization and cell repopulation within one month. Surgimend ® is an acellular fetal bovine interwoven dermal collagen that promotes increased type III collagen. Because there is no cross-linking, there is increased collagen resistance leading to greater durability. Polylactic coglycolic acid (PLGA) is a collagen scaffold that promotes neovascularization and autologous tissue regeneration. Animal studies have demonstrated ingrowth of fibroblasts resulting in a thicker neodiaphragm. Despite the theoretical advantages, these absorbable biosynthetic patches remain imperfect as diaphragmatic substitutes. Thinning of the patch and incomplete muscular ingrowth, especially in large defects where native diaphragmatic muscle is absent, have been found. These biosynthetic patches are also prone to recurrences, similar to nonabsorbable patches. In addition, organ adherence may be required for neovascularization, and these organs often include the small bowel, spleen, or liver. Subsequently, biologic patches can be associated with adhesive bowel obstruction.

Answer 37

Complications with synthetic and biosynthetic patches have prompted some surgeons to advocate for primary or staged repair with autologous muscle flaps for large diaphragmatic defects. Muscle flaps offer the advantage of using a vascularized tissue that will grow with the infant and has a minimal inflammatory response. In 1962, Meeker and Snyder first described using the anterior abdominal wall for CDH repair. A few years later came the description of a split abdominal wall muscle flap used to repair a large defect in a newborn. Additional modern techniques include using a split abdominal muscle flap consisting of the internal oblique and transversus abdominis muscles, as well as a lower abdominal incision with transversus abdominis muscle repair, which can be done on ECMO. Due to the avascular dissection plane between the muscle layers, this approach may minimize the risk of bleeding while on ECMO. It is difficult to quantify the risk of recurrence with small case series, but a recent small, single-center report suggests a lower recurrence rate compared with patch repairs. Chest wall muscles, such as the latissimus dorsi muscle, have also been used as diaphragmatic substitutes. For very large defects, such as agenesis of the diaphragm, the combination of the latissimus dorsi and serratus anterior muscles has been described. The disadvantage with using local chest wall muscle flaps is the resulting body wall deformity, though this does not appear to be dramatically different when compared with patch repair of large CDH. Consequently, some pediatric surgeons reserve chest wall muscle flaps for patients with a recurrent CDH. Although autologous muscle flaps are vascularized and tend to grow with the child, these diaphragmatic reconstructions with latissimus dorsi/serratus muscle flaps have been shown to atrophy over time due to denervation of the graft. In addition, the lack of innervation prevents the natural physiologic movement of the diaphragm. As a result, the reverse latissimus dorsi flap with a microneural anastomosis of the phrenic nerve to the thoracodorsal nerve has been described to prevent muscle atrophy and allow physiologic muscle movement.

Answer 38

The ideal diaphragmatic replacement remains elusive in the operative treatment of CDH. Advances in regenerative medicine may provide the solution. Tissue-engineered muscle may provide a replacement for functional skeletal muscle that does not atrophy, with the added potential benefits of less risk for infection and dislodgement. Although the supporting three-dimensional scaffold is a key component of tissue engineering, skeletal muscle regeneration relies on a cell capable of in vitro proliferation and preserving biological activity. Satellite cells and mesenchymal stem cells have demonstrated success in rat models. Amniotic fluid is also an abundant source of stem cells with myogenic potential. Tissue engineering strategies could utilize amniotic stem cells collected at the time of amniocentesis to develop a muscular patch used during postnatal repair. Fauza and colleagues have developed a fetal tissuebased diaphragm engineered from mesenchymal amniocytes. In recent preclinical studies, these bioengineered diaphragms have demonstrated improved mechanical and functional outcomes when compared with acellular bioprosthetic patches.

Answer 39

In the late 1980s, open fetal repair before 24 weeks of gestation for left-sided CDH without liver and stomach herniation was conceptualized and performed. In a subsequent prospective study, fetuses undergoing in utero repair had a higher complication rate, including prematurity, without an improvement in survival. Surprisingly, better than expected survival was found in the standard postnatal management patients, and there were higher rates of complications in the fetal surgery group. Consequently, open fetal repair has been abandoned as a therapeutic option for CDH. The concept of tracheal occlusion originated from the observation that infants with congenital high airway obstruction developed hyperplastic lungs. Several groups have demonstrated increases in total lung protein and DNA, alveolar space, overall lung weight, and cross-sectional area of the pulmonary vasculature as well as better lung compliance following prenatally placed tracheal balloons in sheep. However, it has been noted that long-term tracheal occlusion decreases the number of type 2 pneumocytes and surfactant production. This finding has led to the concept of temporary in utero tracheal occlusion for the most severe cases of CDH. Current in utero techniques involve endoscopic insertion of an occlusive balloon into the fetal trachea without maternal laparotomy or general anesthesia. These balloons are inserted percutaneously with US guidance between 24 and 28 weeks of gestation and are deflated/removed at 34 weeks. This strategy of temporary tracheal occlusion avoids the need for an ex utero intrapartum treatment (EXIT) procedure at delivery, although emergent airway access may be needed at delivery for any patient who undergoes in utero tracheal occlusion and experiences premature labor prior to de-occlusion. [H&A] — In addition to diagnosis and generation of prognostic parameters, fetal care for CDH has also included a number of procedures, such as in utero repair, tracheal clipping, and tracheal balloon occlusion. In fact, these attempts to treat CDH in utero have directly led to the development of the ex-utero intrapartum treatment (EXIT) procedure now used for a variety of anomalies. Fetal treatment has also evolved from hysterotomy and open treatment to percutaneous techniques associated with decreased risk of premature delivery. A hiatus in fetal interventions occurred after early work could not prove a benefit over conventional care. However, there has been a renewed interest in fetal treatment. The TOTAL (tracheal occlusion to accelerate lung growth) trial is currently in progress. It is an international trial that includes European, North American, and Australian centers and is designed to assess the role of fetal tracheal occlusion (FETO). The trial has two separate arms, one comparing conventional management to FETO at 30–32 weeks of gestation in moderate cases and the other doing the same for severe cases at 27–30 weeks of gestation. In these trials, balloon removal is performed prior to birth. Results are awaited and will help determine if fetal therapy will once again have a role in treating CDH. [Sherif]

Answer 40

Multiple recent CDHSG-based studies have demonstrated that: 1) defect size, 2) presence of associated congenital heart disease, 3) associated anomalies, and 4) prematurity are the most significant predictors of outcome. Outcomes for CDH appear better in centers that treat a higher volume of CDH infants. Hidden from these survival data are patients with CDH who are not offered surgical repair. Among contributors to the CDHSG, rates of nonrepair vary widely (ranging from near zero to 66.7%) and do not correlate with patientdependent factors such as associated cardiac and chromosomal anomalies. This suggests that criteria for operative intervention are not uniform across centers and that patient selection may depend on institution-dependent experience and resources. Defect size, associated anomalies, concomitant major congenital heart disease, and prematurity impose the greatest influence on patient survival in CDH. Thus, any comparative study on morbidity or mortality must risk-stratify across these known risk factors. Stratification by defect size correlates with disease severity, and this association has prompted development of a universal grading system to define CDH defect size. Based on intraoperative findings, the four classifications range from small defects that could be repaired primarily to total diaphragmatic agenesis (see Fig. 24.10). Congenital heart defects occur in 6–18% of CDH infants. However, when categorized into major (hemodynamically significant) and minor lesions (such asymptomatic ASD, VSD, or PDA), survival varies from 36% (major) to 67% (minor). When compared with infants without structural cardiac anomalies, the risk of hospital mortality was 2.2-fold higher in infants with major cardiac disease. Defined as delivery <38 weeks of gestation, preterm birth occurs in approximately 23–30% of infants with CDH and the overall survival is approximately 50% for those born prematurely. Survival inversely correlates with prematurity. Infants born at <28 weeks of gestational age have been found to have a 32% chance of survival compared with 73.1% for those born at 37 weeks. After adjusting for comorbidities and disease severity, prematurity had an increased odds ratio of 1.68 for death. [H&A] — In addition to fetal prognostic parameters, several postnatal variables have been identified as predictors of overall prognosis. These variables include patient-defined ones that are identified at or shortly after birth, surgical findings, and variables identified during the trajectory of the patient’s care and progress. The size of the hernia defect has been consistently shown to correlate with mortality, as well as secondary outcomes, such as requirement for ECMO, hospital stay, and prolonged oxygen dependence. A standard staging system to describe defect size has been defined by the Congenital Diaphragmatic Hernia Study Group (CDHSG). The worse outcomes seen after patch repair and right-sided CDH are a function of defect size. For example, the most recent data from the CDHSG show a survival of 67% in right-sided hernias versus 72% in left-sided hernias. The lower survival in right CDH is not a function of side, but rather a function of a significantly higher proportion of C and D defects on the right side. Similarly, the presence of a hernia sac, a surrogate for smaller defects, has been associated with improved outcomes. [Sherif]

Answer 41

Although many survive to discharge, infants with CDH carry many sequelae and ongoing health needs that require longterm medical care. Disease-specific morbidities offer the opportunity for multiple specialties to align together and provide long-term follow-up and care for patients with CDH as well as opportunities for research. Pulmonary, neurologic, gastrointestinal, and musculoskeletal complications outlined in the text that follows are best served by a multidisciplinary team of surgical, medical, and developmental specialists with experience in caring for patients with CDH. In response to many single institution reports and increasing knowledge of long-term needs, the standard follow-up care algorithm for infants with CDH is being formulated, and its components are offered below.

Answer 42

Survivors of CDH may require long-term pulmonary support as a consequence of pulmonary hypertension, bronchopulmonary dysplasia, obstructive airway disease, or recurrent pneumonias. Although most improve over time, adult survivors are sometimes left with impairments on pulmonary function testing, supporting the need for specialized long-term follow-up and expertise. Specific pulmonary morbidities include asthma, reduced exercise capacity, airflow obstruction, persistent pulmonary hypertension, and recurrent infections. Patients with CDH may also exhibit a higher incidence of bronchopulmonary dysplasia as a consequence of VILI in the setting of pulmonary hypoplasia. In addition, abnormalities of ventilation/perfusion mismatch can persist beyond the first year of life, particularly if patch repair was required, demonstrating the persistent impact of pulmonary hypoplasia. Identifying neonates who may incur long-term pulmonary morbidity may begin as early as DOL 30, as those who require oxygen supplementation or ventilator support at this point are at significantly increased risk for morbidity at 1 and 5 years. In addition, up to 4% of survivors with CDH may require tracheostomy for long-term ventilator support. Respiratory infections appear to have a higher prevalence in children with CDH. Respiratory syncytial virus (RSV) is the most common pathogen seen in children <3 years of age, suggesting a need for RSV prophylaxis. Up to 7% of patients will have a pneumonia within the first year of life. A subset of patients can have recurrent lung infections up to 6–8 times per year, and these patients more commonly have undergone patch repair, required HFOV support, or prolonged ventilation. Obstructive pulmonary disease is commonly reported in surviving children with CDH. Asthma and general symptoms of bronchospasm and wheezing are well documented. Although symptoms appear to improve with age, most CDH children will exhibit some combination of obstructive and restrictive pulmonary function as well as increased reactivity to pharmacologic agents, even self-reported. This reduced pulmonary function is most likely due to lower functional volumes rather than primary obstruction of the airways.

Answer 43

Long-term neurodevelopmental impacts on survivors of CDH constitute a significant proportion of the data on overall morbidity. Though more difficult to detect, residual neurologic morbidities are increasingly recognized in long-term follow up studies. Worse neurodevelopmental outcomes have also been associated with increased severity of CDH, need for ECMO, and associated chromosomal anomalies. There is evidence of increasing pathologic lesions in CDH survivors such as periventricular leukomalacia (PVL), intracranial hemorrhage (IVH), or ventricular enlargement. The severity of PVL can be correlated with the degree of prematurity, but is also increased in patients with CDH compared with other premature infants.m Subtle cognitive problems in survivors of CDH are exhibited by a recent report that 20–40% need extra support in regular education. Several other studies have identified significantly more academic challenges among CDH survivors despite the fact their IQ scores appear to be similar to non-CDH patients. Motor function in all survivors of CDH is also impaired when compared with their peers, affecting 60% of 1-year-olds and 73% of 3-year-olds, and these issues can persist throughout childhood. In addition, when compared with controls, survivors of CDH also tend to have significantly more somatic, social, thought, and aggression problems at school. While disease severity and early neurologic dysfunction seem to be predictive, it is unclear whether or not somatic and social problems correlate with the need for ECMO. Long term, all survivors of CDH display a substantial risk for a formal diagnosis of a specific learning disability, attention-deficit/hyperactivity disorder, autism, developmental disability, or social difficulties. These challenges can become progressively more apparent as children increase in age, particularly as they demonstrate the need for placement in specialized classes. Interestingly, when the children themselves are queried, they report no decline in feelings of competence or emotional function. Hearing impairment is a recognized sequelae of CDH with an overall incidence reported up to 60% in some series that far exceeds those of other neonatal intensive care infants (1–3%) and the general population (0.002–0.006%). Factors known to be associated with sensorineural hearing loss (SNHL) in the CDH population include ototoxic drugs, hyperbilirubinemia, prolonged ventilation, HFOV, neuromuscular blockade, ECMO, and low birth weight. In contemporary retrospective cohort studies, however, the incidence of SNHL appears to be decreasing over time, from >50% to approximately 7%. When patients with SNHL were compared with those without, no significant differences were detected including defect size, birth weight, associated anomalies, or the need for ECMO. However, prolonged duration of aminoglycoside exposure independently increased the risk of SNHL, suggesting that postnatal treatments, less so than the CDH itself, contribute more to SNHL over time. Other series have identified an ECMO requirement, prolonged hospitalizations, and loop diuretic administration as associated risk factors for hearing loss. Therefore, most likely, SNHL is due to a combination of treatment and severity of disease. Because of the increased risk of SNHL in CDH children, audiologic testing is warranted as early as 6 months of age.

Answer 44

Gastrointestinal morbidity, including gastroesophageal reflux, need for supplemental enteral feeds, bowel obstructions, and constipation, is the most common morbidity, affecting more than two-thirds of CDH survivors. GERD or some variant of foregut dysmotility occurs in >50% of all CDH survivors. Certain anatomic alterations in the setting of CDH, more prevalent with larger defect sizes, render these patients particularly susceptible to GERD, including abnormal orientation of the esophageal hiatus, lack of an angle of His, shortening of the intraabdominal esophagus, and distortion of the stomach after herniation into the chest. Our understanding of the longterm morbidity of longstanding GERD in this surviving population is scarce but increasing. Recently there have been case reports of Barrett’s esophagus and even adenosquamous carcinoma in adult survivors of CDH, similar to the esophageal atresia population. Early predictors for GERD in the CDH population include the need for patch repair or an intrathoracic position of the stomach. However, no reliable predictors for later GERD (i.e., after age 6 years) have been identified yet, prompting recommendations for screening and long-term follow-up in survivors. Of particular concern is the fact that many survivors have no reported symptoms prior to endoscopic confirmation of reflux. Unfortunately, even operative attempts to correct reflux with fundoplication have been met with poor results, with failure to decrease the frequency of respiratory tract infections or improve growth. The ultimate decision to perform antireflux surgery in this complex population may depend upon identifiable long-term risk factors for severe GERD such as liver-up or prenatal intervention, and routine fundoplication is less utilized in contemporary practice.

Answer 45

Musculoskeletal development and chest wall deformities, such as pectus deformities, chest asymmetry, and scoliosis, are common in CDH children with a wide incidence between 21% and 80%. These deformities are more often associated with larger defects that require patch or muscle flap closure. Scoliosis can be severe and can progress into adulthood. These musculoskeletal abnormalities may be due to tension on the diaphragm after repair, or result from a thoracotomy without muscle sparing techniques, or result from a small hemithorax due to hypoplastic lungs. Most patients are asymptomatic and do not require operative intervention. However, these findings underscore the importance of long-term follow-up of these survivors to better understand their natural progression, functional impact, and amenability for treatment with corrective procedures or bracing.

Answer 46

An anterior diaphragmatic Morgagni hernia accounts for <2% of all CDH anomalies. The foramen of Morgagni hernia results from failure of fusion of the crural and sternal portions of the diaphragm. This can occur on either side at the junction of the septum transversum and thoracic wall where the superior epigastric artery (internal mammary artery, intrathoracically) traverses the diaphragm. These are usually large anterior midline defects. Typically, a hernia sac is present containing omentum, small intestine, and/or colon; rarely these hernias will contain liver and/or spleen. Morgagni hernias carry a high incidence of associated anomalies, namely congenital heart disease and Down syndrome. The majority of children with a Morgagni hernia are asymptomatic and are rarely diagnosed during the neonatal period. Symptoms, if present, typically include respiratory distress in infants, recurring lung infections, or general epigastric discomfort or vomiting due to intermittent obstruction. The chest radiograph may exhibit a well-defined air–fluid level in the midline of the chest and visceral herniation in the retrosternal space. Small hernias may require a contrast radiograph or CT scan to confirm the diagnosis. Operative repair usually entails reduction of the herniated viscera, excision of the hernia sac, and approximation of the diaphragm to the posterior rectus sheath at the costal margin. These repairs are increasingly performed via minimally invasive approaches. Although most defects can be repaired primarily, large defects may require patch closure. The long-term outcome regarding recurrence is yet to be defined. An anterior diaphragmatic hernia may be found in association with a pentalogy of Cantrell due to a failure in the development of the septum transversum. Pentalogy of Cantrell is a rare cluster of congenital anomalies that includes omphalocele, cardiac defects, ectopic cordis, and an anterior diaphragmatic defect extending into the pericardium. The cardiac defect is the most severe problem and is the main cause of mortality.

Answer 47

Eventration is an abnormal elevation of the diaphragm, which results in a paradoxical motion during respiration and interferes with normal pulmonary mechanics and function. Congenital eventration results from the incomplete development of the central tendon or muscular portion of the diaphragm. While commonly left-sided, bilateral congenital eventrations have been described. The diaphragm muscle is typically present, but does not move in a coordinated fashion. It is usually thin and may be indistinguishable from a hernia sac seen in CDH. Large eventrations can interfere with lung development due to the paradoxical motion and decreased thoracic space. Similar to CDH, congenital eventration can result in lung hypoplasia, although this is uncommon. Persistent fetal circulation and pulmonary hypertension are usually not seen with eventration but have been described. Acquired diaphragmatic eventration can occur due to paralysis of the phrenic nerve secondary to mediastinal tumors, congenital heart surgery, or birth trauma. Its incidence after congenital cardiac surgery has been reported to be approximately 5% with the highest proportion after Fontan and BlalockTaussig shunt procedures. Diaphragmatic eventration may present acutely with respiratory distress and tachypnea in the newborn, or may have a more indolent course with recurrent respiratory infections and wheezing. Neonates can have feeding intolerance due to discoordinated sucking and breathing. Older children may demonstrate exercise intolerance. Both lungs are usually affected by the paradoxical motion. With inspiration, the eventrated diaphragm rises, causing the mediastinum to shift and compress the contralateral lung. Eventration is typically suspected on a plain chest film showing an elevated hemidiaphragm. The diagnosis is subsequently confirmed by US or fluoroscopy. Motion studies demonstrate a paradoxical movement of the diaphragm and a mediastinal shift during respiration. Occasionally, a CT scan is required to distinguish eventration from pleural effusions, mediastinal tumors, bronchogenic cysts, or pulmonary sequestrations. Small eventrations may be observed as the child will eventually overcome and compensate for the abnormal diaphragmatic dynamics. When needed, initial treatment should include respiratory support, but mechanical ventilation is usually not necessary. However, larger defects that cause functional pulmonary impairment or promote recurring infections require repair. Acquired eventrations often require repair in order to be weaned from mechanical ventilation. Repair can be accomplished through the chest or abdomen. The eventrated diaphragm is plicated with a series of nonabsorbable sutures. Sutures should imbricate generous amounts of the diaphragmatic tissue without injuring the phrenic nerve. The edges of the diaphragm should overlap until the plicated muscle is taut. Subsequently, the diaphragm becomes immobilized, which results in an increased tidal volume and prevents mediastinal shift. Minimally invasive techniques have been well described using thoracoscopy or laparoscopy. — Diaphragmatic eventration can either be congenital due to poor muscularization (which is a continuum with CDH with a sac) or acquired due to phrenic nerve injury resulting from traumatic birth or cardiac surgery. Congenital eventration is often partial with an otherwise intact, mobile diaphragm. A significant association with gastric fixation anomalies is seen. Acquired eventration due to phrenic nerve palsy will affect the entire hemidiaphragm, resulting in paradoxical motion with variable degrees of respiratory compromise. In neonates and young infants, the typical consequence, if symptomatic, will be inability to wean from invasive or noninvasive ventilatory support. Older children, if symptomatic, will present with repeat respiratory infections. Thoracoscopic plication of the diaphragm carries low risk and can be performed by resection or imbrication of the redundant portions, preventing the diaphragm from paradoxical motion. A stapled technique has recently been described. Sherif

Answer 48

Target ventilation parameters of babies with CDH are the following: 1) pre-ductal oxygen saturation 85%–95% 2) PaCO2 45–60 mmHg, 3) pH 7.25–7.40, 4) PIP 20–25 cm H2O, and 5) PEEP 2–5 cm H2O.

Answer 49

The most important principle of medical management of babies with CDH is gentle ventilation, i.e., accepting less than normal oxygenation and ventilation values in order to avoid barotrauma and iatrogenic lung injury. Peak inspiratory pressures higher than 25 cmH2O should be avoided. Target ventilation parameters should be reached. Conventional ventilation is preferred if tolerated by the baby, but high frequency oscillatory or jet ventilation may be needed if peak inspiratory pressures above 25 cm H2O are required for adequate control of hypercapnia. Sedation should be provided to all ventilated babies, but neuromuscular blockade is not routinely required. Blood pressure should be maintained at normal for age. Hypotension and poor perfusion should be treated by judicious use of crystalloids, inotropic agents such as dopamine and epinephrine, and possibly hydrocortisone. Echocardiography should be used as an adjunct to assess pulmonary hypertension and ventricular function. Inhaled nitric oxide (NO) may be used for supra-systemic pulmonary arterial hypertension without left ventricular dysfunction. A number of agents, such as milrinone, sildenafil, and prostaglandin E may be selectively used in specific situations. TPN should be provided. [Sherif]

Answer 50

Postoperative management is a continuation of preoperative management. The respiratory insufficiency and pulmonary hypertension are progressively managed with the goal of weaning the patient from mechanical ventilation. Noninvasive respiratory support may be needed before discontinuation of supplemental oxygen. Enteral feedings should be started with attention to a high likelihood of potential gastroesophageal reflux and early institution of medical therapy. A pre-discharge echocardiogram should be performed to assess cardiac function and any persistence of pulmonary hypertension, in order to decide whether ongoing therapy for pulmonary hypertension may be required at discharge.

Answer 51

The two arms of CDH pathophysiology are pulmonary hypoplasia and pulmonary hypertension. The first occurs due to deficient lung development, resulting in a substantially decreased number of alveoli available for gas exchange after birth. The second occurs due to abnormal muscularization of the pulmonary arterial circulation, resulting in increased pulmonary vascular resistance and pulmonary hypertension. After birth, the pulmonary hypoplasia results in lower capacity to oxygenate the blood, while the persistent pulmonary hypertension produces a persistent fetal circulation with right to left shunting across the ductus arteriosus and foramen ovale. This shunt is clinically observed as a differential between higher pre-ductal and lower post-ductal oxygen saturations. However, in the absence of this clinical sign, right to left shunting may still be occurring predominantly through the foramen ovale. Simply stated, there are not enough lung units to oxygenate the blood, and even the available units do not see much of the circulating blood due to the right to left shunt. It is a perfect storm that leads to severe respiratory failure. This has led to our current understanding that CDH is not a surgical emergency, but rather a physiologic emergency. [Sherif]

Answer 52

B Central tendon of diaphragm develops from septum transversum, dorsolateral part develops from the pleuroperitoneal membrane, dorsal crura develops from the oesophageal mesenter and muscular portion develops from the thoracic intercostal muscle. Syed/MCQ

Answer 53

B Posterolaterally at junction of lumbar and costal muscle group, the fibrous lumbosacral trigon remains as small remnant of pleuroperitoneal membrane and relies on its strength of the fusion of two muscle group in the final stage of development. Delay or failure of muscle fusion leaves this area weak, perhaps predisposing to herniation. Syed/MCQ

Answer 54

D Umbilical hernia is the commonest congenital hernia. Syed/MCQ

Answer 55

B If the closure of the pleuroperitoneal canal has not occurred by the time of mid-gut return to abdomen during a gestational age 9–10 weeks, abdominal viscera herniate to thoracic cavity. Syed/MCQ

Answer 56

D At birth, symptoms depend on reactive pulmonary hypertension and pulmonary hypoplasia. Syed/MCQ

Answer 57

B Scaphoid abdomen is the feature of diaphragmatic hernia because the viscera are herniated to thorax. Syed/MCQ

Answer 58

B Fluoroscopy helps to differentiate Bochdalek hernia from eventration of diaphragm. In eventration, diaphragm moves paradoxically with respiratory motion. With inspiration, it goes up, and with expiration it goes down. Syed/MCQ

Answer 59

A Polyhydramnios is one of the anatomical prognostic factors. Syed/MCQ

Answer 60

C Plication is a procedure use for eventration of diaphragm. Syed/MCQ

Answer 61

D For right-sided eventration, thoracic approach is preferred, whether it is due to phrenic nerve injury or congenital cause. Eventration of the diaphragm is different from congenital variety as it has normal distribution of muscle and normal central tendinous area. It can be observed for a few weeks for return of function, and during operation, no portion of muscle needs to be excised. The muscular diaphragm may ultimately regain some function, and excision may only increase risk of injury to intradiaphragmatic portion of phrenic nerve. In congenital eventration, there is muscular aplasia or atrophy, and the thinned portion of diaphragm may be excised. Syed/MCQ

Answer 62

D 75 percent Syed/MCQ

Answer 63

B 2–5 percent of cases Syed/MCQ

Answer 64

B Trisomy 18. Syed/MCQ

Answer 65

C Non-inflation of lung is a long-term problem, which should be followed. Syed/MCQ

Answer 66

D Mediastinum shifts to opposite side. Syed/MCQ

Answer 67

C Lung development proceeds from initial lung bud formation through a series of branchings and alveolarisation. Embryonal phase is associated with lung bud formation, while pseudoglandular represents formation of the large bronchi. The canalicular phase of lung development generally occurs from week 16 to week 24 and it is this stage at which the terminal bronchioles are formed. Disruption at this stage results in ‘pruning’ of the pulmonary airways with large branching points but missing the small branches crucial for optimal gas exchange. Alveoli start forming in the fetal saccular stage and progress during the alveolar stage which continues postnatally. SPSE 1

Answer 68

A Prenatal diagnosis on ultrasound is the most common presentation of CDH in North America and in most developed nations. As routine antenatal sonography is generally performed between 18 and 20 weeks, the defect itself will be present at this time. occasionally the diagnosis of CDH is missed on this early ultrasound. liver and lung have similar echogenicity early on and liver herniated into the chest may be mistaken for lung. Bowel within the chest is less likely to be missed; however, occasionally when the defect is present the intestinal contents do not herniate into the chest. If prenatal ultrasound is not performed or the diagnosis is missed, the most common presentation of CDH is shortly after birth. Delivery itself is rarely complicated by the condition as the fetus is untroubled by pulmonary hypoplasia. late diagnoses and incidental findings of CDH are less common. SPSE 1

Answer 69

D At the present time, prenatal intervention for CDH is an experimental therapy undertaken on a small subset of high-risk patients. Repair itself is not pursued in fetal interventions but the trachea itself is plugged causing lung growth. The goal of the surgery is to salvage the small proportion of very high-risk infants. These infants will still require formal repair postnatally. Timing of surgical repair has shifted from its early conception as a surgical emergency to a repair that is undertaken once stability is achieved. Infants who die prior to surgical repair generally represent a subset for whom surgery does not change outcome. Ideally surgery is performed prior to extubation once the patient is stable on conventional ventilation and pulmonary arterial pressures are sub-systemic (ideally normalised). SPSE 1

Answer 70

D During development of pulmonary hypertension, pressures build up within the pulmonary arteries. There is increasing resistance to flow which results in shunting of blood from the pulmonary circulation to the systemic circulation via the ductus arteriosus. With worsening hypertension, pressure backs up into the ventricle causing the interventricular septum, which naturally curves into the right ventricle, to flatten and then bow into the left ventricle. The ventricular muscle also becomes hypertrophied and pressure may even force blood to regurgitate through the tricuspid valve. The velocity of this flow provides an indirect estimation of the degree of pulmonary hypertension. Ventricular hypertrophy is a late development in pulmonary hypertension and is not often seen in the first few days of life. SPSE 1

Answer 71

D The presence of a significant cardiac anomaly has grave repercussions for the fetus. Survival for infants with CDH complicated by complex heart disease has been estimated at 20%. other features that can be examined to help determine prognosis are often related to factors that provide some estimation of lung volume. liver within the chest is a strong predictor of poor lung volume and complications related to pulmonary hypoplasia. There is controversy as to the most sensitive predictor of pulmonary hypoplasia. Presence of liver in the chest (and the volume of liver as based on mRI) represents one measure that is predictive in most studies. There is less consistency in terms of direct measures of lung volumes. on ultrasound, this usually involves a two-dimensional measure of the contralateral lung at the level of the four-chamber view of the heart. The measurement of the lung is compared with some normal measure, often the fetal head. The lung-to-head ratio can be further normalised by comparing the lung-to-head ratio of the fetus with that of a fetus at similar gestational age without CDH (an observed-to-expected ratio). This is commonly performed in European centres to predict the most severely affected fetus. lung-to-head ratio less than 1.0 has been associated with worse outcomes in many but not all centres. mRI provides further information to enable a more precise estimate of lung volume. Right-sided CDH has poor outcome compared with left-sided CDH. one reason for this may be that small defects on the right side are not clinically apparent and it is only with large defects and liver herniation that right-sided CDH is diagnosed. mRI lung volumes currently show that survivors with CDH have lung volumes about 30% of expected, while fetuses that do not survive have lung volumes around 19%–20% of expected. SPSE 1

Answer 72

D Tracheomalacia is a complication typically associated with tracheooesophageal fistula and does not commonly present in CDH. Chest wall deformities are relatively common with CDH. long-term respiratory compromise has been demonstrated quantitatively with both obstructive and restrictive impairment in pulmonary function testing and is likewise clinically apparent with increase in bronchodilator use in this patient population. Gastro-oesophageal reflux is a common issue with these infants due to disruption of the anatomical relationship between the diaphragm and the distal oesophagus. SPSE 1

Answer 73

A Small extralobar pulmonary sequestrations are relatively common occurrences in conjunction with large diaphragmatic hernia and often are present at the border between the chest and the abdomen. SPSE 1

Answer 74

A Surfactant has not been associated with improved survival for infants with CDH. one of the crucial strategies for improving neonatal outcomes was the development of ‘gentle ventilation’ allowing for the accumulation of carbon dioxide or ‘permissive hypercapnia’ to minimise barotrauma. In infants with poor oxygenation, this strategy may involve using a high-frequency oscillator to delivery very small volume breaths. Although the indications for ECmo vary from centre to centre, it is a therapy that has a recognised role in the management of some high-risk patients with congenital diaphragmatic hernia. Inhaled nitric oxide may have some benefit in diminishing pulmonary hypertension in infants with diaphragmatic hernia. SPSE 1

Answer 75

B The frequency of diaphragmatic hernia in the general population is between 1 : 2500 and 1 : 5000 live births. Although uncommon, a future sibling will have between a 1% and a 2% chance of having a diaphragmatic hernia. SPSE 1

Answer 76

Type I, or sliding, hiatal hernias can be seen in patients with gastroesophageal reflux disease (GERD), but are rarely actually described on contrast imaging of the upper gastrointestinal tract in children. The most common etiology of a paraesophageal hernia in the pediatric population is a failed Nissen fundoplication. Types II, III, and IV congenital hiatal hernias, all considered paraesophageal hernias, are quite rare. These hernias are associated with GERD in approximately 50% of cases and other congenital anomalies in one-third of cases. The esophagus is often dilated. Diagnosis is often delayed due to lack of familiarity with this type of hernia on the part of pediatric clinicians. In contrast to Morgagni hernias, excision of the sac in this type of hernia is essential to delineation of hiatal anatomy and adequate repair. In infants, I prefer an open approach as the procedure is technically challenging. Laparoscopic repair is ideal in older children. Outcomes are generally quite favorable, unless severe chronic comorbidities exist. Sherif