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Congenital Diaphragmatic Hernia

  • Julia Zimmer
  • Prem PuriEmail author
Living reference work entry
  • 289 Downloads

Abstract

Congenital diaphragmatic hernia is a relatively common congenital malformation with a poorly understood etiology. On account of advances in technical equipment and operative and anesthetic treatment modalities, the surgical repair of the diaphragmatic defect either open or minimally invasive is nowadays often unproblematic. However, associated pulmonary hypoplasia and persistent pulmonary hypertension lead postnatally to severe respiratory distress and contribute to the high morbidity and mortality rates in this potential life-threatening condition. Therefore, optimal perioperative stabilization and management by an interdisciplinary team of pediatric surgeons, neonatologists, and anesthetists is crucial for these neonates. Nearly half of the CDH survivors beyond the neonatal period are able to lead a normal healthy and symptom free life. However, many survivors with complex medical and surgical needs require a multidisciplinary comprehensive care for their pulmonary, neurodevelopmental, and nutritive long-term outcome. Clinical and basic research continues to identify underlying gene and protein alterations and through this providing a potential for new treatment options for CDH.

Keywords

Congenital diaphragmatic hernia Pulmonary hypoplasia Pulmonary hypertension Diaphragmatic repair Animal models Nitrofen 

Introduction

Congenital diaphragmatic hernia (CDH) is a common and severe congenital malformation, characterized by a defect in the diaphragm through which the abdominal viscera migrate into the fetal thorax. The defect is located in the posterolateral diaphragm (Bochdalek hernia) in 90% of the cases and 9% occur as anteromedial defect (Morgagni hernia) (McHoney 2015). Total agenesis of the diaphragm is rare.

The overall prevalence o f CDH is reported to be between 1:2500 and 1:3000 live births (McHoney 2015; Morini et al. 2006). The CDH prevalence in Europe is 2.3 per 10,000 births for all cases and 1.6 per 10,000 births for isolated cases (McGivern et al. 2015). Approximately 80% of the CDH cases are left sided, 15% are right sided, and less than 5% are bilateral (Colvin et al. 2005; Gallot et al. 2007). The size of the defect varies from small (2 or 3 cm) to large ones, involving most of the hemidiaphragm. The international committee of the Congenital Diaphragmatic Hernia Study Group (CDH study group) created a standardized four grade (A to D) reporting system for CDH (Lally et al. 2013): Grade “A” defects are completely surrounded by muscle. “B” defects present with a small and “C” defects with a large portion of the chest wall devoid of diaphragm tissue. “D” defects are characterized by a complete or near complete absence of the diaphragm. Increasing diaphragmatic defect size and associated potential severe cardiac anomalies have been shown to worsen the outcome (Lally et al. 2013). Despite advances in technical equipment as well as resuscitation and intensive care treatment strategies, newborns with CDH continue to have high morbidity and mortality rates, which is mainly attributed to pulmonary hypoplasia and persistent pulmonary hypertension (Coughlin et al. 2016; Jeanty et al. 2014; Wynn et al. 2013b). Current survival rates in population-based studies vary between 55% and 80% (Boloker et al. 2002; Colvin et al. 2005; Gallot et al. 2007), with survival rates up to 90% in highly specialized centers (Wynn et al. 2013b). However, there is a noticeable hidden mortality due to increasing numbers of pregnancy termination (Burgos and Frenckner 2017).

Etiology

Embryogenesis

Despite ongoing research, the etiology of CDH is still not fully understood. Until now, more than 20 monogenetic disorders associated to CDH have been identified, but CDH usually occurs sporadically with unknown cause of origin (Wynn et al. 2014). CDH embryogenesis has been postulated as a failure of the pleuroperitoneal canals in the posterolateral part of the diaphragm to fuse during gestational week 8 (Sadler 2009). Thus, abdominal organs (typically liver, bowel, or stomach) migrate into the thorax, compressing the growing lungs and resulting in pulmonary hypoplasia. CDH associated pulmonary hypoplasia covers the whole lung, leading to less alveoli, thickened alveolar walls, increased interstitial tissue, and markedly diminished alveolar air space and gas-exchange area (Puri and Doi 2011; Sadler 2009, Fig. 1a, b). These alterations usually affect the ipsilateral lung most severely, but also extend to the contralateral lung. Similarly, the pulmonary vasculature develops abnormally with fewer vessels, adventitial and medial thickening, and peripheral extension of the muscle layer into the smaller intra-acinary arterioles (Levin 1978; Puri and Doi 2011).
Fig. 1

Histologic comparison of (a) normal lung vasculature. (b) Pulmonary vasculature in CDH. Note the increased pulmonary artery muscle thickness (red color)

Experimental studies have added new findings into this classical view of embryogenesis. The toxicological nitrofen CDH model presents pulmonary hypoplasia with abnormalities in both ipsilateral and contralateral lung even before the diaphragm starts to develop (Iritani 1984), which has been suggested to happen due to the so-called dual-hit hypothesis (Keijzer et al. 2000). This hypothesis proposes that the early retardation in lung development that occurs before the development of the diaphragmatic defect is caused by nitrofen , whereas the late-gestational increase in lung hypoplasia is caused by mechanical compression from herniated viscera (Puri and Doi 2011). It has been demonstrated that rat pleuroperitoneal canals are too narrow to allow herniation of bowel loops (Kluth et al. 1996). The nitrofen-induced CDH rat model is a widely used model to investigate gene and protein alterations not only for CDH etiology but also its associated complications of pulmonary hypoplasia and pulmonary hypertension (Takahashi et al. 2017; Zimmer et al. 2017b). One of these pathways, the retinoid signaling pathway with its components has been shown to be disrupted in animal models and CDH neonates likewise (Beurskens et al. 2010; Doi et al. 2010; Nakazawa et al. 2007; Sugimoto et al. 2008). Furthermore, prenatal retinoic acid (RA) treatment has been shown to upregulate pulmonary expression levels of genes involved in lung morphogenesis in the nitrofen-induced hypoplastic lung (Doi et al. 2009, 2010). Although prenatal use of RA has been controversial, these experimental data suggest that prenatal RA treatment may have a therapeutic potential to revert pulmonary hypoplasia associated with CDH.

Several knockout models have been developed for diaphragmatic hernia such as Wt-1/, Shh/, Slit3/, Gli2/Gl3/, Gata4/Gata6/, Fog2/, Pdgfrα/, COUP-TFII/, and RARs/ (Ackerman et al. 2005; Bleyl et al. 2007; Clugston et al. 2006; Jay et al. 2007; Mendelsohn et al. 1994; Molkentin 2000; Motoyama et al. 1998; Pepicelli et al. 1998; You et al. 2005; Yuan et al. 2003). However, only mutations of WT-1, Fog2, and recently COUP-TFII have been identified in human CDH patients so far (Bleyl et al. 2007; Devriendt et al. 1995; High et al. 2016; Scott et al. 2005). There is ongoing research to identify novel genes with predicted deleterious de novo variants potentially contributing to the pathogenesis of CDH and associated other anomalies (Yu et al. 2015).

Pathophysiology

The degree of pulmonary hypoplasia and pulmonary hypertension directly determine the outcome of a newborn diagnosed with CDH. The amount of abdominal viscera in the thorax and the associated degree of pulmonary hypoplasia affect onset and severity of symptoms. Respiratory distress with cyanosis, tachypnea, and sternal recession are the usual clinical signs in the newborn CDH patient. Pulmonary hypoplasia leads to hypoxia and hypercarbia, resulting in pulmonary vasoconstriction and hypertension. Consequently, reversal to right-to-left shunting through the ductus arteriosus and the foramen ovale occurs and the infant enters a harmful and self-perpetuating cycle (Puri and Doi 2011).

Characteristic alterations in CDH associated pulmonary vascular remodeling and pulmonary hypertension are abnormal vascular beds and increased arteriolar muscularization similarly to the changes seen in newborns with idiopathic persistent pulmonary hypertension (PPHN) (Levin 1978). Further features are dysfunctional endothelial cells, abnormal pulmonary smooth muscle cell proliferation and suppressed apoptosis, leading to arterial medial and adventitial thickening, increased pulmonary vascular resistance and venous hypertrophy (Guignabert et al. 2015; Kool et al. 2014, Fig. 1a, b).

Vasoactive substances such as endothelin-1 and endothelin A receptor are reported to be increased in infants and animal models with CDH and adversely affect vasoconstriction (Kobayashi and Puri 1994; Nobuhara and Wilson 1996). The transforming growth factor β (TGFβ) pathway is known to be altered in nitrofen-induced CDH pulmonary rat tissue (Burgos et al. 2010; Gosemann et al. 2013; Mahood et al. 2016; Oue et al. 2000; Zimmer et al. 2017a). Candilera et al. found decreased transforming growth factor β (TGFβ) levels in the amniotic fluid of human CDH pregnancies in comparison with normal pregnancies at amniocentesis (Candilera et al. 2016). Other authors, however, found conflicting results about the role of different TGF β factors in pulmonary vascular remodeling in human CDH lung tissue (Yamataka and Puri 1997).

There are also contradictory results about the immaturity of the surfactant system which may aggravate hypoxia and hypercarbia (Glick et al. 1992; Sullivan et al. 1994). It has therefore been suggested that the deceptive surfactant deficiency may be secondary to respiratory failure, rather than to a primary deficiency (IJsselstijn et al. 1998; Puri and Doi 2011). Fetal blood proinflammatory and chemotactic factors may also be involved in vascular changes resulting in pulmonary hypertension in CDH patients, as recently published (Fleck et al. 2013).

Diagnosis

With proper visualization of the diaphragm, CDH can be reliably diagnosed ultrasonographically at around 20 weeks of gestation. Abdominal viscera in the thorax and consequential compression of thoracic organs indicate its absence indirectly (Deprest et al. 2006a).

CDH must be distinguished from potential differential diagnosis such as diaphragmatic eventration, bronchopulmonary sequestration, congenital cystic adenomatoid malformation (CCAM), or bronchogenic cyst. Moreover, other anomalies such as cardiac malformations, neural tube defects, and chromosomal aberrations need to be excluded. Half of the CDH patients present with additional congenital disorders (Bojanic et al. 2015). Five percent to 30% of infants born with CDH have chromosomal abnormalities, among these, trisomy 21, 18, and 13 are the most common (McHoney 2015). CDH may also be part of a syndrome such as Pentalogy of Cantrell, Brachmann-Cornelia De Lange, Beckwith-Wiedemann, CHARGE, Goldenhar syndrome, Pierre Robin sequence, or VACTERL (Chandrasekharan et al. 2017), and patients must be examined accordingly.

The grade of lung hypoplasia needs to be determined as it is a crucial factor for postnatal survival. Thoracic liver herniation in left-sided CDH indicates severe pulmonary hypoplasia and can be assessed by umbilical vein and hepatic vessels Doppler (Deprest et al. 2006a; Metkus et al. 1996). Ultrasonographic lung-to-head ratio (LHR – the area of the right lung at the level of the four-chamber view divided by the head circumference) or MRI fetal lung volume measurement can predict the degree of pulmonary hypoplasia (Britto et al. 2015; Deprest et al. 2006b; Jeanty et al. 2014).

If not detected prenatally, CDH should be suspected postnatally in neonates with severe respiratory distress at birth or within the first hours of life. A scaphoid abdomen, an increased thoracic anteroposterior diameter, and a mediastinal shift are usually seen during physical assessment with absent breathing sounds on the affected side (Puri and Doi 2011). Associated congenital malformations may also be found. An X-ray of chest and abdomen with demonstration of thoracic air-filled bowel loops and a paucity of gas in the abdomen will bring the definite diagnosis (Fig. 2a, b). A mediastinal shift to the opposite side may be observed, and only a small portion of lung may be seen on the ipsilateral side (Puri and Doi 2011).
Fig. 2

(a) Left-sided CDH with viscera in the left chest, pulmonary hypoplasia, and significant mediastinal shift to the right. (b) Right-sided CDH with viscera visible in the right chest and mediastinal shift to the left side

Treatment Modalities

The optimal timing of delivery of an infant with CDH remains controversial. Early term birth (37–38 gestational weeks) has previously been shown to be associated with a less use of extracorporeal membrane oxygenation (ECMO) compared to term delivery for infants born via cesarean section (Chandrasekharan et al. 2017; Stevens et al. 2009). However, other studies postulated decreased mortality with advanced gestational age (40 weeks of gestation) (Chandrasekharan et al. 2017; Hutcheon et al. 2010).

Immediate postnatal endotracheal intubation and mechanical ventilation is recommended in order to maintain cardiopulmonary stability and delay the natural progression into severe hypoxemia and hypercapnia (McHoney 2015; Reiss et al. 2010). Mask ventilation and CPAP should be avoided as it will distend the stomach and further compromise respiratory status. A nasogastric tube deflates stomach and bowel. The usage of muscle relaxants should be avoided as part of the gentle ventilation strategy (Boloker et al. 2002; Reiss et al. 2010).

Previously, CDH was considered a surgical emergency, assuming that swift evacuation of abdominal thoracic viscera will allow expansion of the compressed lung tissue. Increasing knowledge of the pathophysiology of CDH has led to the modern approach of prolonged preoperative stabilization time, assuring cardiorespiratory and hemodynamic stability of the patient. However, several studies provided no strong advantage for a delayed (when stabilized) or early (within 24–48 h after birth) repair (Moyer et al. 2002; Okuyama et al. 2017).

Prenatal Treatment

Any prenatal intervention able to reverse or improve associated lung hypoplasia might theoretically improve prognosis and outcome of CDH patients. Fetal surgery with primary repair of the defect seemed to be a promising approach, but clinical application of anatomical fetal CDH repair was abandoned once it became clear that it was not possible in fetuses with liver herniation and that those without did not benefit from the intervention (Harrison et al. 1993, 1997; Puri and Doi 2011).

Experimental studies showed that tracheal occlusion triggers lung growth, leading to the approach of fetoscopic tracheal occlusion (FETO) in humans. The effect on lung growth by tracheal occlusion and retention of pulmonary fluid seems to be exerted by pulmonary stretch itself, which in turn causes upregulation of different growth factors (Liao et al. 2000; Muratore et al. 2000; Nobuhara et al. 1998; Puri and Doi 2011). Usually, the tracheal balloon is placed endoscopically in one-port technique (Deprest et al. 2006a; Harrison et al. 2003). If the balloon is deflated by repeated tracheoscopy at 34 weeks of gestation, vaginal delivery is permitted (Deprest et al. 2006a). A feared and frequent complication of FETO is preterm premature rupture of the membranes (PPROM), potentially caused iatrogenic and influencing the gestational age at delivery and balloon removal (Deprest et al. 2011). To deliver infants with FETO, the ex utero intrapartum treatment procedure (EXIT) has been developed. Cesarean section is performed with maximal uterine relaxation, and while keeping the infant on placental support, the upper airway can be instrumented (Puri and Doi 2011). However, currently there is only insufficient evidence to recommend in utero intervention for CDH fetuses as a routine clinical practice (Grivell et al. 2015). Controversially, FETO has been shown to improve survival in selected CDH cases but to also to increase morbidity including significantly longer durations of mechanical ventilation, supplementary oxygen, and hospital stay (Ali et al. 2016; Al-Maary et al. 2016). Presently, FETO is being evaluated in a large international randomized control trial (Oluyomi-Obi et al. 2017).

Various other medical strategies for lung hypoplasia such as steroid administration with or without thyrotropin releasing hormone, vitamins, or stem cell therapy have been tested in the last decades in different CDH animal models , but their impact on the human situation has yet to be addressed (Eastwood et al. 2015; Jeanty et al. 2014). Especially, regenerative medicine including stem cell therapy and tissue engineering seem to be a promising field for further treatment strategies in CDH as this may play an important role both in developing a myogenic patch capable of restoring muscle function as well as promoting the regeneration of hypoplastic lungs (De Coppi and Deprest 2012; DeKoninck et al. 2015; Shieh et al. 2017a; Yuniartha et al. 2014; De Coppi and Deprest 2017).

Preoperative Treatment

Any infant with respiratory distress requires endotracheal ventilatory support. Previously, aggressive hyperventilation strategies and hypocarbia often resulting in barotrauma were widely used, but gentle ventilation and permissive hypercarbia has been demonstrated to decrease mortality (Logan et al. 2007; Masumoto et al. 2009; Puligandla et al. 2015; Vitali and Arnold 2005). High-frequency oscillatory ventilation (HFOV) provides effective ventilation while decreasing barotrauma, but has not been shown to improve the mortality or morbidity rates in CDH (Puligandla et al. 2015; Snoek et al. 2016b). Any changes in HFOV settings must be monitored carefully, as high airway pressures may cause lung hyperinflation, with adverse effects on venous return, pulmonary vascular resistance, and ultimately in cardiac output (Logan et al. 2007). In a recent study, ventilation outcomes such as duration of ventilation time and the need for ECMO seem to favor conventional ventilation (Snoek et al. 2016b). A ventilation strategy tailored to the patient’s underlying physiology rather than the mode of ventilation is a crucial issue for clinicians treating CDH patients (Morini et al. 2017).

Following initial ventilation settings are recommended to achieve a target SaO2 of >85% preductally and a PCO2 of 45–60 mmHg (Puligandla et al. 2015; Reiss et al. 2010):

For pressure controlled ventilation, a peak inspiratory pressure (PIP) of 20–25 cm H2O, a positive end-expiratory pressure (PEEP) of 2–5 cm H2O, and a frequency (f) of 40–60/min is commended. For HFOV it is advised to maintain a mean airway pressure (MAP) of 13–17 cm H2O with a frequency of 10 Hz and a pressure delta (Δp) of 30–50 cm H2O, based on the extent of chest rise on the chest X-rays (Puligandla et al. 2015; Reiss et al. 2010).

Nitric oxide (NO) is a direct pulmonary vasodilator, but its relevance for CDH patients remains controversial (McHoney 2015; Putnam et al. 2016; Tiryaki et al. 2014). Short-term improvement in oxygenation in selected patients has been observed with positive effect on stabilizing the patient during transport or awaiting ECMO cannulation; however, inhaled NO does not reduce the need for ECMO itself (McHoney 2015; Oliveira et al. 2000; Harting 2017).

ECMO is a life support system used in the treatment of CDH when conventional mechanical ventilation fails, typically considered for infants with CDH ≥ 34 weeks’ gestation or with a birth weight > 2 kg and no associated other major lethal anomalies (Chandrasekharan et al. 2017). ECMO allows partial heart-lung bypass providing rest to the lungs for long time periods during which it is hoped that the lung and pulmonary vasculature will mature. Several centers advocate the use of ECMO only in patients with evidence of a “honeymoon period,” i.e., patients with adequate gas exchange for a period preceding the deterioration in respiratory status (Puri and Doi 2011). Others use preductal blood gases, where only patients with a period of normal preductal pO2 and pCO2 will be considered for ECMO (Logan et al. 2007; Puri and Doi 2011). Optimal patient selection for ECMO in CDH requires refinement of non-ECMO support techniques so that this higher risk but higher potential reward modality is focused primarily on those patients with more severe CDH as defined by smaller lungs, worse birth physiology, anatomy, and larger defects (Kays 2017). Although widely used, a Cochrane review found that the ECMO benefit remains unclear (Mugford et al. 2008).

Additionally to conventional mechanical ventilation or ECMO, surfactant replacement has been experimentally used but beside its risky administration its benefit is unproven (Chandrasekharan et al. 2017; Logan et al. 2007). Data from the CDH Study Group showed no significant advantage of surfactant use, both in term and preterm infants with CDH (Morini et al. 2017).

Recently, the efficacy of Perflubron-induced lung growth (PILG) has been studied in CDH patients requiring ECMO (Mychaliska et al. 2015). PILG doubled the total lung size but had no positive effect on persistent pulmonary hypertension (Mychaliska et al. 2015).

CDH patients need to be carefully managed by intensive care physicians. Appropriate fluid and catecholamine management, adequate sedation, and analgesia are crucial in these infants. Routine administration of pre- or postnatal glucocorticoids is not recommended (Puligandla et al. 2015).

Alternative strategies for NO-resistant pulmonary hypertension are PDE inhibitors. The PDE 5 inhibitor sildenafil enhances NO-mediated vasodilatation, improving oxygenation and outcome (Bialkowski et al. 2015; McHoney 2015). The PDE 3 inhibitor Milrinone has also been shown to be effective in the management of NO resistant PH in CDH infants (Chandrasekharan et al. 2017; Hagadorn et al. 2015). The endothelin receptor blocker Bosentan has been used with limited experience as adjunctive therapy for PPHN (Chandrasekharan et al. 2017; Steinhorn et al. 2016). Other agents with proposed benefit are prostaglandins or novel agents like L-citrulline; Rho-kinase inhibitors or proliferator-activated receptor-γ agonists are currently under investigation (Lakshminrusimha et al. 2016).

Operative Repair

For the surgical repair of the diaphragmatic defect one can choose between open (laparotomy or thoracotomy) or minimally invasive (laparoscopic or thoracoscopic) technique; however, the optimal approach is still a matter of discussion among surgeons (Terui et al. 2015). The abdominal approach is commonly preferred as the exposure is usually excellent and abdominal viscera can be easily reduced as well as associated gastrointestinal anomalies corrected (Fig. 3). When reducing abdominal organs, small intestine and the colon should first be reduced on the right side and the liver is withdrawn last (Fig. 4). After reduction of hernia an attempt is made to visualize the ipsilateral lung. Most diaphragmatic defects can be sutured by direct sutures after refreshing the defect edges (Figs. 5 and 6a, b). Although the anterior rim of the diaphragm is usually quite evident, the posterior rim may not be immediately apparent and may require dissection for delineation. There is usually a layer of peritoneum running from the retroperitoneum over the lower edge of the defect. Division of this tissue usually allows visualization of the posterior edge of the diaphragm. The defect is closed by interrupted nonabsorbable suture (Puri and Doi 2011).
Fig. 3

Operative repair of CDH. A subcostal transverse muscle cutting incision is made on the side of the hernia (Image from Puri and Höllwarth, Pediatric Surgery (Springer Surgery Atlas Series), 2006, Springer)

Fig. 4

Gentle manual reduction of viscera into the abdomen (Image from Puri and Höllwarth, Pediatric Surgery (Springer Surgery Atlas Series), 2006, Springer)

Fig. 5

After inspecting diaphragmatic defect, posterior rim of the diaphragm is mobilized by incising the overlying peritoneum (Image from Puri and Höllwarth, Pediatric Surgery (Springer Surgery Atlas Series), 2006, Springer)

Fig. 6

(a, b) Primary closure of the diaphragmatic defect by interrupted nonabsorbable sutures (Image from Puri and Höllwarth, Pediatric Surgery (Springer Surgery Atlas Series), 2006, Springer)

If the posterior rim is absent altogether, the anterior rim of the diaphragm is sutured to the lower ribs with either periosteal or pericostal sutures. If the defect is too large for primary closure, prosthetic material should be placed (Fig. 7). Numerous types of patches are commercially available (natural vs. synthetic, absorbable vs. nonabsorbable), but the ideal material has yet to be identified (Zani et al. 2014). Right-sided CDH has been found to require patch repair more commonly than left-sided CDH due to larger defect size or complete agenesis (Collin et al. 2016).
Fig. 7

Patch placement for large diaphragmatic defects (Image from Puri and Höllwarth, Pediatric Surgery (Springer Surgery Atlas Series), 2006, Springer)

An alternative is a muscle flap taken from the transversus abdominus, leaving the outer abdominal muscle layers intact. Due to the risk of hemorrhage, this technique should not be performed in patients with ECMO or in risk of ECMO treatment. Furthermore, operations involving muscle flaps are too long and complex for critically ill patients and may lead to chest deformities. The insertion of a chest drain prior to closure is controversial as it may increase the transpulmonary pressure gradient (Puri and Doi 2011).

Reduced trauma and physiological disturbance through surgery as well as better cosmetically outcome are the main advantages of minimal invasive CDH repair. However, although survival and patch usage has been found to be similar to open surgery, neonatal thoracoscopic CDH repair is associated with greater recurrence rates, operative times and severe intraoperative acidosis and hypercapnia (Bishay et al. 2013; Lansdale et al. 2010; Pierro 2015; Weaver et al. 2016; Zhu et al. 2016).

Postoperative Treatment

Postoperatively, patients need to be monitored as closely and careful as preoperatively, with special attention on fluid management, ventilator support, and hemodynamic monitoring (Puri and Nakazawa 2009). Some infants may show improvement in oxygenation in the so-called honeymoon period but will usually deteriorate 6–24 h later, which is due to pulmonary hypertension and persistent fetal circulation with increased pulmonary artery resistance, high pulmonary artery pressure, and right-to-left ductal and preductal shunting leading to hypoxemia (Puri and Doi 2011). Postoperative pulmonary hypertension is probably caused by various factors, such as limited diaphragmatic excursion and increased abdominal pressure with impaired visceral and peripheral perfusion. Overdistended alveoli of the hypoplastic lungs with diminished alveolar-capillary blood flow, release of vasoactive cytokines, and deterioration of pulmonary compliance may contribute as well. A sudden deterioration in the patient’s oxygenation status should always raise the suspicion of pneumothorax. Also, infections including pneumonia and septicemia are not uncommon.

Prognosis

Certain factors can influence and predict CDH associated pre- and perinatal mortality, with important impact on any potential prenatal intervention and the information given to the parents (Daodu and Brindle 2017). Chromosomal aberrations and other lethal malformations should be identified. Intrathoracic herniation of stomach and/or liver has been shown to be associated to a higher mortality (Jeanty et al. 2014; Mann et al. 2012; Sananes et al. 2016). The lung-to-head ratio (LHR) is a crucial indicator for CDH outcome, and values <1 have been found to relate to a high risk of death, ECMO, and pulmonary hypertension at 1 month of age (Garcia et al. 2013; Jeanty et al. 2014). The observed-to expected LHR (O/E LHR) is usually associated with death if the values is less than ~20% (Ruano et al. 2012).

The observed-to-expected total fetal lung volume (O/E TLV), percent predicted lung volumes (PPLV) and percent liver herniation, need for ECMO, and development of chronic lung disease in MRI studies were predictors of mortality (Jeanty et al. 2014; Ruano et al. 2014; Walleyo et al. 2013; Oluyomi-Obi et al. 2017).

The CDH study group created a logistic equation using birth weight and 5-minute Apgar score to distinguish between high, intermediate, and low risk of death (Congenital Diaphragmatic Hernia Study Group 2001). Later, the fetal risk was further stratified by the factors absent or low 5-minute Apgar score, presence of chromosomal or major cardiac anomalies, very low birth weight, and suprasystemic pulmonary hypertension (Brindle et al. 2014). Only recently, the CDH group developed the Score for Neonatal Acute Physiology-II to predict not only mortality but also need for ECMO in CDH patients on the first day of life by analyzing a multivariable logistic regression adjusted for hernia side, gestational age, liver position, Center, ventilation mode, and observed-to-expected lung-to-head-ratio (Snoek et al. 2016a). Furthermore, low birth weight, patch repair, and need for ECMO correlate with more severe pulmonary hypertension at 1 month of age (Wynn et al. 2013b).

Golden et al. demonstrated that infants undergoing CDH repair post ECMO-decannulation have better outcomes. In their study group, survival rate was 54% in infants undergoing extracorporeal life support (ECLS), 65% in those who underwent repair, 36% in those repaired during ECLS, and 85% in those who were decannulated prior to repair (Golden et al. 2017).

Exit-to-ECMO strategy neither increased survival nor long-term morbidity in severe CDH patients (Shieh et al. 2017b).

CDH survivors have lower initial PaCO2 at 30 days than nonsurvivors (Abbas et al. 2015; McHoney 2015). Additionally, neonates with continuous hypercarbia have a worse prognosis than those who are stabilized to a normal PaCO2 (Abbas et al. 2015). Further biomarkers to predict the outcome of CDH patients are the best oxygenation index on day 1 (Goonasekera et al. 2016; Ruttenstock et al. 2015) and a simplified formula of postnatal blood gas (PaO2–PaCO2) to calculate need for ECMO or death (Park et al. 2013).

Outcome

Improvement in treatment strategies for neonates born with CDH has increased the survival rate of more severely affected infants. Long-term follow-up of those patients has led to the recognition of pulmonary and extrapulmonary morbidities which were not previously recognized. The most common problem in CDH infants surviving beyond the neonatal period is pulmonary morbidity, which is even more distinct in patients treated with ECMO or requiring patch repair (Burgos et al. 2017; Jaillard et al. 2003; Puri and Doi 2011; Hollinger et al. 2017). BPD rate is up to 41% in CDH neonates who survived the first month of life (van den Hout et al. 2010). Furthermore, CDH survivors with chronic lung disease may require prolonged ventilator support and tracheostomy and/or suffer from recurrent respiratory tract infections (Bagolan et al. 2004; Jaillard et al. 2003; Tracy and Chen 2014). Therefore, some authors recommend palivizumab (Synagis®) vaccination for CDH infants in fall and winter (Gaboli et al. 2014; Masumoto et al. 2008; Resch 2014).

Neurodevelopmental outcome has been intensively studied in CDH survivors. Developmental delay; motor, behavioral, and cognitive disorders; as well as impaired language and neurocognitive skills are reported frequently among these patients (Danzer et al. 2010; Danzer and Hedrick 2011; Friedman et al. 2008; Tracy and Chen 2014; Wynn et al. 2013a; Hollinger et al. 2017). Interestingly, there were no significant differences found in neurodevelopmental outcome between right-sided and left-sided CDH survivors, with both groups exhibiting normal median GQ scores at 1 year of age (Collin et al. 2016).

Ototoxic medications and prolonged mechanical ventilation s with high oxygen tensions may contribute to sensorineural hearing loss (SNHL), which is found frequently in CDH survivors treated with and without ECMO, suggesting that the use of ECMO is not the only predisposing factor for SNHL (Robertson et al. 2002; Tracy and Chen 2014). However, several retrospective studies found an SNHL rate of 2.3–7.5% in both ECMO and non-ECMO CDH survivors (Dennett et al. 2014; Partridge et al. 2014; Wilson et al. 2013), which is equivalent to the SNHL rate of all neonatal intensive care unit patients (Hille et al. 2007; Tracy and Chen 2014).

Many CDH survivors present with gastrointestinal symptoms such as gastroesophageal reflux (GER), failure to thrive (defined as weight <25th or 5th centile), and late bowel obstruction (Burgos et al. 2017; Puri and Doi 2011; Rais-Bahrami et al. 1995; Sigalet et al. 1994). One-third of the patients require gastrostomy tubes due to nutritional morbidity (Chiu et al. 2006; Muratore et al. 2001; Tracy and Chen 2014). Treatment for GERD comprises H2-blockers, but if clinical problems like pulmonary infections or choking persist, fundoplication must be discussed (Bagolan and Morini 2007; Tracy and Chen 2014). The most frequently reported predictor for antireflux surgery is the need of diaphragmatic patch repair (Jaillard et al. 2003; Muratore et al. 2001), and recurrence is more common in patients repaired with a prosthetic patch. Moreover, patients with patch repair have a higher risk for developing musculoskeletal deformities such as scoliosis or pectus excavatum (Jancelewicz et al. 2010).

Most CDH survivors beyond the neonatal period are able to lead a normal life; however, the children with CDH should have a multidisciplinary follow-up and assessed regularly for their pulmonary, neurodevelopmental, and nutritive outcome until adulthood.

Congenital Eventration of the Diaphragm (CDE)

Eventration of the diaphragm is characterized by an atypically high or deviated position of all or parts of the hemidiaphragm, which can occur congenitally or acquired as a result of phrenic nerve palsy. Congenital CDE is a developmental abnormality in muscular aplasia of the diaphragm, which primarily has fully developed musculature, and becomes atrophic secondary to phrenic nerve damage and disuse. CDE occurs in 1 per 1400 patients with higher prevalence in males (Wu et al. 2015).

Clinical Features

Clinical characteristics may vary widely from being asymptomatic to severe respiratory distress, pneumonia, bronchitis, or bronchiectasis. Gastrointestinal symptoms such as vomiting or epigastric discomfort have also been reported. Patients with phrenic nerve palsy may have a history of difficult delivery, exhibiting tachypnea, respiratory distress, or cyanosis. Breathing sounds may be reduced on the affected side during physical examination and a mediastinal shift during inspiration and a scaphoid abdomen may be observed. Occasionally, CDE patients exhibit associated malformations like hypoplastic lung, congenital heart disease, or cryptorchidism (Wu et al. 2015).

Diagnosis

A chest X-ray reveals an elevated diaphragm with a smooth, unbroken outline on frontal and lateral chest (Fig. 8a, b). Fluoroscopy is useful to distinguish a complete eventration from a hernia. Complete eventration can lead to paradoxical diaphragmatic movements. Ultrasound helps to identify abnormal organs underneath the eventration. Other study modalities such as pneumoperitonography, contrast peritonography, radioisotope scanning, CT, or MRI scans are rarely required.
Fig. 8

(a) Right-sided CDE with liver visible in the right chest and mediastinal shift to the left. (b) Lateral X-ray image of right CDE

Management

Asymptomatic patients without crucial pulmonary abnormalities can be treated conservatively. Same applies for patients with incomplete phrenic nerve palsy without paradoxical movement as normal function usually returns. In contrast, symptomatic patients, especially those with respiratory distress, need prompt respiratory support and ventilation with humidified oxygen to minimize the diaphragmatic excursions. A nasogastric tube should be placed to decompress the stomach. Surgery is undertaken once the patient’s condition is stabilized.

Operative Repair

Diaphragmatic plication is the method of choice, increasing both tidal volume and maximal breathing capacity (Fig. 9a, b). For left-sided CDE, an abdominal approach through a subcostal incision is usually chosen, whereas a thoracic approach with a posterolateral incision in the sixth space may be used for right-sided CDE. A transabdominal approach facilitates good visualization of the complete diaphragm and easier mobilization of abdominal contents. Plication via laparoscopic or thoracoscopic approach is also safe repair method (Fujishiro et al. 2016).
Fig. 9

(a, b) Plication repair of diaphragmatic eventration (Image from Puri and Höllwarth, Pediatric Surgery (Springer Surgery Atlas Series), 2006, Springer)

Outcome

Mortality of CDE is usually related to pulmonary hypoplasia, but patients without underlying pulmonary hypoplasia commonly have an excellent prognosis. Timely precise diagnosis and management of symptomatic CDE effectively prevents respiratory morbidity and reduces complications such as recurrence, pneumonia, pleural effusions, or renal insufficiency (Wu et al. 2015).

Conclusions and Future Directions

CDH remains a therapeutical challenge due to its associated comorbidities lung hypoplasia and pulmonary hypertension. Advances in neonatal resuscitation, intensive care treatment, and technical equipment have improved the overall survival rate up to 90% in highly specialized centers. Ongoing basic research on the genetic and molecular pathomechanisms aims to identify crucial parts in the diaphragmatic, pulmonary, and vascular development for further treatment strategies. Currently, CDH management focuses mainly on postnatal surgical and medical care; however, promising studies on stem cells and tissue engineering may open opportunities for prenatal treatment on diaphragmatic and lung development likewise. Infants born with CDH need to be managed carefully and interdisciplinary by obstetrician, neonatologists, anesthetist, and pediatric surgeons to assure optimal outcome of these patients. Although most CDH survivors beyond the neonatal period are able to lead a normal life, they should have multidisciplinary follow-up and assessed regularly for their pulmonary, neurodevelopmental, and nutritive outcome until adulthood.

Cross-References

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.National Children’s Research CentreOur Lady’s Children’s HospitalDublinIreland
  2. 2.Department of Pediatric SurgeryHannover Medical SchoolHannoverGermany
  3. 3.School of Medicine and Medical Science and Conway Institute of Biomedical ResearchUniversity College DublinDublinIreland

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