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Congenital Diaphragmatic Hernia

Julia Zimmer and Prem Puri

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Embryogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Treatment Modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Prenatal Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Preoperative Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Operative Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Postoperative Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Congenital Eventration of the Diaphragm (CDE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Operative Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

J. ZimmerNational Children’s Research Centre, Our Lady’sChildren’s Hospital, Dublin, Ireland

Department of Pediatric Surgery, Hannover MedicalSchool, Hannover, Germanye-mail: [email protected]

P. Puri (*)National Children’s Research Centre, Our Lady’sChildren’s Hospital, Dublin, Ireland

School of Medicine and Medical Science and ConwayInstitute of Biomedical Research, University CollegeDublin, Dublin, Irelande-mail: [email protected]

# Springer-Verlag GmbH Germany 2017P. Puri (ed.), Pediatric Surgery,https://doi.org/10.1007/978-3-642-38482-0_57-1

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mailto:[email protected]

mailto:[email protected]

https://doi.org/10.1007/978-3-642-38482-0_57-1

Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

AbstractCongenital diaphragmatic hernia is a relativelycommon congenital malformation with apoorly understood etiology. On account ofadvances in technical equipment and operativeand anesthetic treatment modalities, the surgi-cal repair of the diaphragmatic defect eitheropen or minimally invasive is nowadays oftenunproblematic. However, associated pulmo-nary hypoplasia and persistent pulmonaryhypertension lead postnatally to severe respi-ratory distress and contribute to the high mor-bidity and mortality rates in this potential life-threatening condition. Therefore, optimal peri-operative stabilization and management by aninterdisciplinary team of pediatric surgeons,neonatologists, and anesthetists is crucial forthese neonates. Nearly half of the CDH survi-vors beyond the neonatal period are able tolead a normal healthy and symptom free life.However, many survivors with complex med-ical and surgical needs require a multi-disciplinary comprehensive care for theirpulmonary, neurodevelopmental, and nutritivelong-term outcome. Clinical and basic researchcontinues to identify underlying gene and pro-tein alterations and through this providing apotential for new treatment options for CDH.

KeywordsCongenital diaphragmatic hernia � Pulmonaryhypoplasia � Pulmonary hypertension �Diaphragmatic repair � Animal models �Nitrofen

Introduction

Congenital diaphragmatic hernia (CDH) is a com-mon and severe congenital malformation, charac-terized by a defect in the diaphragm through

which the abdominal viscera migrate into thefetal thorax. The defect is located in the postero-lateral diaphragm (Bochdalek hernia) in 90% ofthe cases and 9% occur as anteromedial defect(Morgagni hernia) (McHoney 2015). Total agen-esis of the diaphragm is rare.

The overall prevalence of CDH is reported tobe between 1:2500 and 1:3000 live births(McHoney 2015; Morini et al. 2006). The CDHprevalence in Europe is 2.3 per 10,000 births forall cases and 1.6 per 10,000 births for isolatedcases (McGivern et al. 2015). Approximately80% of the CDH cases are left sided, 15% areright sided, and less than 5% are bilateral (Colvinet al. 2005; Gallot et al. 2007). The size of thedefect varies from small (2 or 3 cm) to large ones,involving most of the hemidiaphragm. The inter-national committee of the Congenital Diaphrag-matic 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 bymuscle. “B” defects present with a small and “C”defects with a large portion of the chest walldevoid of diaphragm tissue. “D” defects are char-acterized by a complete or near complete absenceof the diaphragm. Increasing diaphragmaticdefect size and associated potential severe cardiacanomalies have been shown to worsen the out-come (Lally et al. 2013). Despite advances intechnical equipment as well as resuscitation andintensive care treatment strategies, newborns withCDH continue to have high morbidity and mor-tality rates, which is mainly attributed to pulmo-nary hypoplasia and persistent pulmonaryhypertension (Coughlin et al. 2016; Jeanty et al.2014; Wynn et al. 2013b). Current survival ratesin population-based studies vary between 55%and 80% (Boloker et al. 2002; Colvin et al.2005; Gallot et al. 2007), with survival rates upto 90% in highly specialized centers (Wynn et al.2013b). However, there is a noticeable hidden

2 J. Zimmer and P. Puri

mortality due to increasing numbers of pregnancytermination (Burgos and Frenckner 2017).

Etiology

Embryogenesis

Despite ongoing research, the etiology of CDH isstill not fully understood. Until now, more than20 monogenetic disorders associated to CDHhave been identified, but CDH usually occurssporadically with unknown cause of origin(Wynn et al. 2014). CDH embryogenesis hasbeen postulated as a failure of the pleuroperitonealcanals in the posterolateral part of the diaphragmto fuse during gestational week 8 (Sadler 2009).Thus, abdominal organs (typically liver, bowel, orstomach) migrate into the thorax, compressing thegrowing lungs and resulting in pulmonary hypo-plasia. CDH associated pulmonary hypoplasiacovers the whole lung, leading to less alveoli,thickened alveolar walls, increased interstitial tis-sue, and markedly diminished alveolar air spaceand gas-exchange area (Puri and Doi 2011; Sadler2009, Fig. 1a, b). These alterations usually affectthe ipsilateral lung most severely, but also extendto the contralateral lung. Similarly, the pulmonaryvasculature develops abnormally with fewer ves-sels, adventitial and medial thickening, andperipheral extension of the muscle layer into thesmaller intra-acinary arterioles (Levin 1978; Puriand Doi 2011).

Experimental studies have added new findingsinto this classical view of embryogenesis. Thetoxicological nitrofen CDH model presents pul-monary hypoplasia with abnormalities in bothipsilateral and contralateral lung even before thediaphragm starts to develop (Iritani 1984), whichhas been suggested to happen due to the so-calleddual-hit hypothesis (Keijzer et al. 2000). Thishypothesis proposes that the early retardation inlung development that occurs before the develop-ment of the diaphragmatic defect is caused bynitrofen, whereas the late-gestational increase inlung hypoplasia is caused by mechanical com-pression from herniated viscera (Puri and Doi2011). It has been demonstrated that ratpleuroperitoneal canals are too narrow to allowherniation of bowel loops (Kluth et al. 1996). Thenitrofen-induced CDH rat model is a widely usedmodel to investigate gene and protein alterationsnot only for CDH etiology but also its associatedcomplications of pulmonary hypoplasia and pul-monary hypertension (Takahashi et al. 2017;Zimmer et al. 2017b). One of these pathways,the retinoid signaling pathway with its compo-nents has been shown to be disrupted in animalmodels and CDH neonates likewise (Beurskenset al. 2010; Doi et al. 2010; Nakazawa et al. 2007;Sugimoto et al. 2008). Furthermore, prenatalretinoic acid (RA) treatment has been shown toupregulate pulmonary expression levels of genesinvolved in lung morphogenesis in the nitrofen-induced hypoplastic lung (Doi et al. 2009, 2010).Although prenatal use of RA has been

Fig. 1 Histologic comparison of (a) normal lung vasculature. (b) Pulmonary vasculature in CDH. Note the increasedpulmonary artery muscle thickness (red color)

Congenital Diaphragmatic Hernia 3

controversial, these experimental data suggestthat prenatal RA treatment may have a therapeuticpotential to revert pulmonary hypoplasia associ-ated with CDH.

Several knockout models have been developedfor diaphragmatic hernia such as Wt-1�/�,Shh�/�, Slit3�/�, Gli2/Gl3�/�, Gata4/Gata6�/�,Fog2�/�, Pdgfrα�/�, COUP-TFII�/�, andRARs�/� (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; Youet al. 2005; Yuan et al. 2003). However, onlymutations of WT-1, Fog2, and recently COUP-TFII have been identified in human CDH patientsso far (Bleyl et al. 2007; Devriendt et al. 1995;High et al. 2016; Scott et al. 2005). There isongoing research to identify novel genes withpredicted deleterious de novo variants potentiallycontributing to the pathogenesis of CDH andassociated other anomalies (Yu et al. 2015).

Pathophysiology

The degree of pulmonary hypoplasia and pulmo-nary hypertension directly determine the outcomeof a newborn diagnosed with CDH. The amountof abdominal viscera in the thorax and the associ-ated degree of pulmonary hypoplasia affect onsetand severity of symptoms. Respiratory distresswith cyanosis, tachypnea, and sternal recessionare the usual clinical signs in the newborn CDHpatient. Pulmonary hypoplasia leads to hypoxiaand hypercarbia, resulting in pulmonary vasocon-striction and hypertension. Consequently, reversalto right-to-left shunting through the ductusarteriosus and the foramen ovale occurs and theinfant enters a harmful and self-perpetuating cycle(Puri and Doi 2011).

Characteristic alterations in CDH associatedpulmonary vascular remodeling and pulmonaryhypertension are abnormal vascular beds andincreased arteriolar muscularization similarly tothe changes seen in newborns with idiopathicpersistent pulmonary hypertension (PPHN)(Levin 1978). Further features are dysfunctionalendothelial cells, abnormal pulmonary smooth

muscle cell proliferation and suppressed apopto-sis, leading to arterial medial and adventitialthickening, increased pulmonary vascular resis-tance and venous hypertrophy (Guignabert et al.2015; Kool et al. 2014, Fig. 1a, b).

Vasoactive substances such as endothelin-1and endothelin A receptor are reported to beincreased in infants and animal models withCDH and adversely affect vasoconstriction(Kobayashi and Puri 1994; Nobuhara and Wilson1996). 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). Candileraet al. found decreased transforming growth factorβ (TGFβ) levels in the amniotic fluid of humanCDH pregnancies in comparison with normalpregnancies at amniocentesis (Candilera et al.2016). Other authors, however, found conflictingresults about the role of different TGF β factors inpulmonary vascular remodeling in human CDHlung tissue (Yamataka and Puri 1997).

There are also contradictory results about theimmaturity of the surfactant system which mayaggravate hypoxia and hypercarbia (Glick et al.1992; Sullivan et al. 1994). It has therefore beensuggested that the deceptive surfactant deficiencymay be secondary to respiratory failure, ratherthan to a primary deficiency (IJsselstijn et al.1998; Puri and Doi 2011). Fetal blood pro-inflammatory and chemotactic factors may alsobe involved in vascular changes resulting in pul-monary hypertension in CDH patients, as recentlypublished (Fleck et al. 2013).

Diagnosis

With proper visualization of the diaphragm, CDHcan be reliably diagnosed ultrasonographically ataround 20 weeks of gestation. Abdominal viscerain the thorax and consequential compression ofthoracic organs indicate its absence indirectly(Deprest et al. 2006a).

CDH must be distinguished from potential dif-ferential diagnosis such as diaphragmaticeventration, bronchopulmonary sequestration,


congenital cystic adenomatoid malformation(CCAM), or bronchogenic cyst. Moreover, otheranomalies such as cardiac malformations, neuraltube defects, and chromosomal aberrations needto be excluded. Half of the CDH patients presentwith additional congenital disorders (Bojanicet al. 2015). Five percent to 30% of infants bornwith CDH have chromosomal abnormalities,among these, trisomy 21, 18, and 13 are themost common (McHoney 2015). CDH may alsobe part of a syndrome such as Pentalogy ofCantrell, Brachmann-Cornelia De Lange,Beckwith-Wiedemann, CHARGE, Goldenharsyndrome, Pierre Robin sequence, or VACTERL(Chandrasekharan et al. 2017), and patients mustbe examined accordingly.

The grade of lung hypoplasia needs to be deter-mined as it is a crucial factor for postnatal sur-vival. Thoracic liver herniation in left-sided CDHindicates severe pulmonary hypoplasia and can beassessed by umbilical vein and hepatic vesselsDoppler (Deprest et al. 2006a; Metkus et al.1996). Ultrasonographic lung-to-head ratio(LHR – the area of the right lung at the level ofthe four-chamber view divided by the head cir-cumference) or MRI fetal lung volume measure-ment can predict the degree of pulmonaryhypoplasia (Britto et al. 2015; Deprest et al.2006b; Jeanty et al. 2014).

If not detected prenatally, CDH should besuspected postnatally in neonates with severerespiratory distress at birth or within the first

hours of life. A scaphoid abdomen, an increasedthoracic anteroposterior diameter, and a mediasti-nal shift are usually seen during physical assess-ment with absent breathing sounds on the affectedside (Puri and Doi 2011). Associated congenitalmalformations may also be found. An X-ray ofchest and abdomen with demonstration of tho-racic air-filled bowel loops and a paucity of gasin the abdomen will bring the definite diagnosis(Fig. 2a, b). A mediastinal shift to the oppositeside may be observed, and only a small portion oflung may be seen on the ipsilateral side (Puri andDoi 2011).

Treatment Modalities

The optimal timing of delivery of an infant withCDH remains controversial. Early term birth(37–38 gestational weeks) has previously beenshown to be associated with a less use of extra-corporeal membrane oxygenation (ECMO) com-pared to term delivery for infants born viacesarean section (Chandrasekharan et al. 2017;Stevens et al. 2009). However, other studies pos-tulated decreased mortality with advanced gesta-tional age (40 weeks of gestation)(Chandrasekharan et al. 2017; Hutcheon et al.2010).

Immediate postnatal endotracheal intubationand mechanical ventilation is recommended inorder to maintain cardiopulmonary stability and

Fig. 2 (a) Left-sided CDHwith viscera in the left chest,pulmonary hypoplasia, andsignificant mediastinal shiftto the right. (b) Right-sidedCDH with viscera visible inthe right chest andmediastinal shift to the leftside


delay the natural progression into severe hypox-emia and hypercapnia (McHoney 2015; Reisset al. 2010). Mask ventilation and CPAP shouldbe avoided as it will distend the stomach andfurther compromise respiratory status. A nasogas-tric tube deflates stomach and bowel. The usage ofmuscle relaxants should be avoided as part of thegentle ventilation strategy (Boloker et al. 2002;Reiss et al. 2010).

Previously, CDH was considered a surgicalemergency, assuming that swift evacuation ofabdominal thoracic viscera will allow expansionof the compressed lung tissue. Increasing knowl-edge of the pathophysiology of CDH has led tothe modern approach of prolonged preoperativestabilization time, assuring cardiorespiratory andhemodynamic stability of the patient. However,several studies provided no strong advantage for adelayed (when stabilized) or early (within 24–48 hafter birth) repair (Moyer et al. 2002; Okuyamaet al. 2017).

Prenatal Treatment

Any prenatal intervention able to reverse orimprove associated lung hypoplasia might theo-retically improve prognosis and outcome of CDHpatients. Fetal surgery with primary repair of thedefect seemed to be a promising approach, butclinical application of anatomical fetal CDHrepair was abandoned once it became clear that itwas not possible in fetuses with liver herniationand that those without did not benefit from theintervention (Harrison et al. 1993, 1997; Puri andDoi 2011).

Experimental studies showed that trachealocclusion triggers lung growth, leading to theapproach of fetoscopic tracheal occlusion(FETO) in humans. The effect on lung growthby tracheal occlusion and retention of pulmonaryfluid seems to be exerted by pulmonary stretchitself, which in turn causes upregulation of differ-ent growth factors (Liao et al. 2000; Muratoreet al. 2000; Nobuhara et al. 1998; Puri and Doi2011). Usually, the tracheal balloon is placedendoscopically in one-port technique (Deprestet al. 2006a; Harrison et al. 2003). If the balloon

is deflated by repeated tracheoscopy at 34 weeksof gestation, vaginal delivery is permitted(Deprest et al. 2006a). A feared and frequentcomplication of FETO is preterm premature rup-ture of the membranes (PPROM), potentiallycaused iatrogenic and influencing the gestationalage at delivery and balloon removal (Deprest et al.2011). To deliver infants with FETO, the ex uterointrapartum treatment procedure (EXIT) has beendeveloped. Cesarean section is performed withmaximal uterine relaxation, and while keepingthe infant on placental support, the upper airwaycan be instrumented (Puri and Doi 2011). How-ever, currently there is only insufficient evidenceto recommend in utero intervention for CDHfetuses as a routine clinical practice (Grivellet al. 2015). Controversially, FETO has beenshown to improve survival in selected CDHcases but to also to increase morbidity includingsignificantly longer durations of mechanical ven-tilation, supplementary oxygen, and hospital stay(Ali et al. 2016; Al-Maary et al. 2016). Presently,FETO is being evaluated in a large internationalrandomized control trial (Oluyomi-Obi et al.2017).

Various other medical strategies for lung hypo-plasia such as steroid administration with or with-out thyrotropin releasing hormone, vitamins, orstem cell therapy have been tested in the lastdecades in different CDH animal models, buttheir impact on the human situation has yet to beaddressed (Eastwood et al. 2015; Jeanty et al.2014). Especially, regenerative medicine includ-ing stem cell therapy and tissue engineering seemto be a promising field for further treatment strat-egies in CDH as this may play an important roleboth in developing a myogenic patch capable ofrestoring muscle function as well as promoting theregeneration of hypoplastic lungs (De Coppi andDeprest 2012; DeKoninck et al. 2015; Shieh et al.2017a; Yuniartha et al. 2014; De Coppi andDeprest 2017).

Preoperative Treatment

Any infant with respiratory distress requires endo-tracheal ventilatory support. Previously,


aggressive hyperventilation strategies and hypo-carbia often resulting in barotrauma were widelyused, but gentle ventilation and permissive hyper-carbia has been demonstrated to decrease mortal-ity (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 decreasingbarotrauma, but has not been shown to improvethe mortality or morbidity rates in CDH(Puligandla et al. 2015; Snoek et al. 2016b). Anychanges in HFOV settings must be monitoredcarefully, as high airway pressures may causelung hyperinflation, with adverse effects onvenous return, pulmonary vascular resistance,and ultimately in cardiac output (Logan et al.2007). In a recent study, ventilation outcomessuch as duration of ventilation time and the needfor ECMO seem to favor conventional ventilation(Snoek et al. 2016b). A ventilation strategy tai-lored to the patient’s underlying physiology ratherthan the mode of ventilation is a crucial issue forclinicians treating CDH patients (Morini et al.2017).

Following initial ventilation settings arerecommended 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 peakinspiratory pressure (PIP) of 20–25 cm H2O, apositive end-expiratory pressure (PEEP) of2–5 cm H2O, and a frequency (f) of 40–60/minis commended. For HFOV it is advised to main-tain a mean airway pressure (MAP) of 13–17 cmH2O with a frequency of 10 Hz and a pressuredelta (Δp) of 30–50 cm H2O, based on the extentof chest rise on the chest X-rays (Puligandla et al.2015; Reiss et al. 2010).

Nitric oxide (NO) is a direct pulmonary vaso-dilator, but its relevance for CDH patients remainscontroversial (McHoney 2015; Putnam et al.2016; Tiryaki et al. 2014). Short-term improve-ment in oxygenation in selected patients has beenobserved with positive effect on stabilizing thepatient during transport or awaiting ECMO can-nulation; however, inhaled NO does not reducethe need for ECMO itself (McHoney 2015;Oliveira et al. 2000; Harting 2017).

ECMO is a life support system used in thetreatment of CDH when conventional mechanicalventilation fails, typically considered for infantswith CDH � 34 weeks’ gestation or with a birthweight > 2 kg and no associated other majorlethal anomalies (Chandrasekharan et al. 2017).ECMO allows partial heart-lung bypass providingrest to the lungs for long time periods duringwhich it is hoped that the lung and pulmonaryvasculature will mature. Several centers advocatethe use of ECMO only in patients with evidence ofa “honeymoon period,” i.e., patients with ade-quate gas exchange for a period preceding thedeterioration in respiratory status (Puri and Doi2011). Others use preductal blood gases, whereonly patients with a period of normal preductalpO2 and pCO2 will be considered for ECMO(Logan et al. 2007; Puri and Doi 2011). Optimalpatient selection for ECMO in CDH requiresrefinement of non-ECMO support techniques sothat this higher risk but higher potential rewardmodality is focused primarily on those patientswith more severe CDH as defined by smallerlungs, worse birth physiology, anatomy, andlarger defects (Kays 2017). Although widelyused, a Cochrane review found that the ECMObenefit remains unclear (Mugford et al. 2008).

Additionally to conventional mechanical ven-tilation or ECMO, surfactant replacement hasbeen experimentally used but beside its riskyadministration its benefit is unproven(Chandrasekharan et al. 2017; Logan et al.2007). Data from the CDH Study Group showedno significant advantage of surfactant use, both interm and preterm infants with CDH (Morini et al.2017).

Recently, the efficacy of Perflubron-inducedlung growth (PILG) has been studied in CDHpatients requiring ECMO (Mychaliska et al.2015). PILG doubled the total lung size but hadno positive effect on persistent pulmonary hyper-tension (Mychaliska et al. 2015).

CDH patients need to be carefully managed byintensive care physicians. Appropriate fluid andcatecholamine management, adequate sedation,and analgesia are crucial in these infants. Routineadministration of pre- or postnatal glucocorticoidsis not recommended (Puligandla et al. 2015).


Alternative strategies for NO-resistant pulmo-nary hypertension are PDE inhibitors. The PDE5 inhibitor sildenafil enhances NO-mediatedvasodilatation, improving oxygenation and out-come (Bialkowski et al. 2015; McHoney 2015).The PDE 3 inhibitor Milrinone has also beenshown to be effective in the management of NOresistant PH in CDH infants (Chandrasekharanet al. 2017; Hagadorn et al. 2015). The endothelinreceptor blocker Bosentan has been used withlimited experience as adjunctive therapy forPPHN (Chandrasekharan et al. 2017; Steinhornet al. 2016). Other agents with proposed benefitare prostaglandins or novel agents likeL-citrulline; Rho-kinase inhibitors orproliferator-activated receptor-γ agonists are cur-rently under investigation (Lakshminrusimhaet al. 2016).

Operative Repair

For the surgical repair of the diaphragmatic defectone can choose between open (laparotomy orthoracotomy) or minimally invasive (laparoscopicor thoracoscopic) technique; however, the optimalapproach is still a matter of discussion amongsurgeons (Terui et al. 2015). The abdominalapproach is commonly preferred as the exposureis usually excellent and abdominal viscera can beeasily reduced as well as associated gastrointesti-nal anomalies corrected (Fig. 3). When reducingabdominal organs, small intestine and the colonshould first be reduced on the right side and theliver is withdrawn last (Fig. 4). After reduction ofhernia an attempt is made to visualize the ipsilat-eral lung. Most diaphragmatic defects can besutured by direct sutures after refreshing thedefect edges (Figs. 5 and 6a, b). Although theanterior rim of the diaphragm is usually quiteevident, the posterior rim may not be immediatelyapparent and may require dissection for delinea-tion. There is usually a layer of peritoneum run-ning from the retroperitoneum over the loweredge of the defect. Division of this tissue usuallyallows visualization of the posterior edge of thediaphragm. The defect is closed by interruptednonabsorbable suture (Puri and Doi 2011).

If the posterior rim is absent altogether, theanterior rim of the diaphragm is sutured to thelower ribs with either periosteal or pericostalsutures. If the defect is too large for primaryclosure, prosthetic material should be placed(Fig. 7). Numerous types of patches are commer-cially available (natural vs. synthetic, absorbablevs. nonabsorbable), but the ideal material has yetto be identified (Zani et al. 2014). Right-sidedCDH has been found to require patch repairmore commonly than left-sided CDH due to largerdefect size or complete agenesis (Collin et al.2016).

An alternative is a muscle flap taken from thetransversus abdominus, leaving the outer abdom-inal muscle layers intact. Due to the risk of hem-orrhage, this technique should not be performed inpatients with ECMO or in risk of ECMO treat-ment. Furthermore, operations involving muscleflaps are too long and complex for critically illpatients and may lead to chest deformities. Theinsertion of a chest drain prior to closure is con-troversial as it may increase the transpulmonarypressure gradient (Puri and Doi 2011).

Reduced trauma and physiological disturbancethrough surgery as well as better cosmeticallyoutcome are the main advantages of minimalinvasive CDH repair. However, although survivaland patch usage has been found to be similar toopen surgery, neonatal thoracoscopic CDH repairis associated with greater recurrence rates, opera-tive times and severe intraoperative acidosis andhypercapnia (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 asclosely and careful as preoperatively, with specialattention on fluid management, ventilator support,and hemodynamic monitoring (Puri andNakazawa 2009). Some infants may showimprovement in oxygenation in the so-called hon-eymoon period but will usually deteriorate 6–24 hlater, which is due to pulmonary hypertension andpersistent fetal circulation with increased


pulmonary artery resistance, high pulmonaryartery pressure, and right-to-left ductal and pre-ductal shunting leading to hypoxemia (Puri andDoi 2011). Postoperative pulmonary hypertensionis probably caused by various factors, such aslimited diaphragmatic excursion and increasedabdominal pressure with impaired visceral andperipheral perfusion. Overdistended alveoli ofthe hypoplastic lungs with diminished alveolar-capillary blood flow, release of vasoactive cyto-kines, and deterioration of pulmonary compliancemay contribute as well. A sudden deterioration inthe patient’s oxygenation status should alwaysraise the suspicion of pneumothorax. Also, infec-tions including pneumonia and septicemia are notuncommon.

Prognosis

Certain factors can influence and predict CDHassociated pre- and perinatal mortality, withimportant impact on any potential prenatal

Fig. 3 Operative repair of CDH. A subcostal transversemuscle 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 abdo-men (Image from Puri and Höllwarth, Pediatric Surgery(Springer Surgery Atlas Series), 2006, Springer)

Fig. 5 After inspecting diaphragmatic defect, posteriorrim of the diaphragm is mobilized by incising the overlyingperitoneum (Image from Puri and Höllwarth, PediatricSurgery (Springer Surgery Atlas Series), 2006, Springer)


intervention and the information given to the par-ents (Daodu and Brindle 2017). Chromosomalaberrations and other lethal malformations shouldbe identified. Intrathoracic herniation of stomachand/or liver has been shown to be associated to ahigher 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 highrisk of death, ECMO, and pulmonary hyperten-sion at 1 month of age (Garcia et al. 2013; Jeantyet al. 2014). The observed-to expected LHR (O/ELHR) is usually associated with death if the valuesis less than ~20% (Ruano et al. 2012).

The observed-to-expected total fetal lung vol-ume (O/E TLV), percent predicted lung volumes(PPLV) and percent liver herniation, need forECMO, and development of chronic lung diseasein MRI studies were predictors of mortality(Jeanty et al. 2014; Ruano et al. 2014; Walleyoet al. 2013; Oluyomi-Obi et al. 2017).

The CDH study group created a logistic equa-tion using birth weight and 5-minute Apgar scoreto distinguish between high, intermediate, andlow risk of death (Congenital Diaphragmatic Her-nia Study Group 2001). Later, the fetal risk wasfurther stratified by the factors absent or low5-minute Apgar score, presence of chromosomalor major cardiac anomalies, very low birth weight,and suprasystemic pulmonary hypertension (Brin-dle et al. 2014). Only recently, the CDH groupdeveloped the Score for Neonatal AcutePhysiology-II to predict not only mortality butalso need for ECMO in CDH patients on the firstday of life by analyzing a multivariable logisticregression adjusted for hernia side, gestationalage, liver position, Center, ventilation mode, andobserved-to-expected lung-to-head-ratio (Snoeket al. 2016a). Furthermore, low birth weight,patch repair, and need for ECMO correlate withmore severe pulmonary hypertension at 1 monthof age (Wynn et al. 2013b).

Golden et al. demonstrated that infants under-going CDH repair post ECMO-decannulationhave better outcomes. In their study group, sur-vival rate was 54% in infants undergoing extra-corporeal life support (ECLS), 65% in those whounderwent repair, 36% in those repaired during

Fig. 6 (a, b) Primaryclosure of thediaphragmatic defect byinterrupted nonabsorbablesutures (Image from Puriand Höllwarth, PediatricSurgery (Springer SurgeryAtlas Series), 2006,Springer)

Fig. 7 Patch placement for large diaphragmatic defects(Image from Puri and Höllwarth, Pediatric Surgery(Springer Surgery Atlas Series), 2006, Springer)


ECLS, and 85% in those who were decannulatedprior to repair (Golden et al. 2017).

Exit-to-ECMO strategy neither increased sur-vival nor long-term morbidity in severe CDHpatients (Shieh et al. 2017b).

CDH survivors have lower initial PaCO2 at30 days than nonsurvivors (Abbas et al. 2015;McHoney 2015). Additionally, neonates withcontinuous hypercarbia have a worse prognosisthan those who are stabilized to a normal PaCO2(Abbas et al. 2015). Further biomarkers to predictthe outcome of CDH patients are the best oxygen-ation index on day 1 (Goonasekera et al. 2016;Ruttenstock et al. 2015) and a simplified formulaof postnatal blood gas (PaO2–PaCO2) to calculateneed for ECMO or death (Park et al. 2013).

Outcome

Improvement in treatment strategies for neonatesborn with CDH has increased the survival rate ofmore severely affected infants. Long-term follow-up of those patients has led to the recognition ofpulmonary and extrapulmonary morbiditieswhich were not previously recognized. The mostcommon problem in CDH infants survivingbeyond the neonatal period is pulmonary morbid-ity, which is even more distinct in patients treatedwith ECMO or requiring patch repair (Burgoset al. 2017; Jaillard et al. 2003; Puri and Doi2011; Hollinger et al. 2017). BPD rate is up to41% in CDH neonates who survived the firstmonth of life (van den Hout et al. 2010). Further-more, CDH survivors with chronic lung diseasemay require prolonged ventilator support and tra-cheostomy and/or suffer from recurrent respira-tory tract infections (Bagolan et al. 2004; Jaillardet al. 2003; Tracy and Chen 2014). Therefore,some authors recommend palivizumab (Syn-agis®) vaccination for CDH infants in fall andwinter (Gaboli et al. 2014; Masumoto et al.2008; Resch 2014).

Neurodevelopmental outcome has been inten-sively studied in CDH survivors. Developmentaldelay; 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). Inter-estingly, there were no significant differencesfound in neurodevelopmental outcome betweenright-sided and left-sided CDH survivors, withboth groups exhibiting normal median GQ scoresat 1 year of age (Collin et al. 2016).

Ototoxic medications and prolonged mechani-cal ventilations with high oxygen tensions maycontribute to sensorineural hearing loss (SNHL),which is found frequently in CDH survivorstreated with and without ECMO, suggesting thatthe use of ECMO is not the only predisposingfactor for SNHL (Robertson et al. 2002; Tracyand Chen 2014). However, several retrospectivestudies found an SNHL rate of 2.3–7.5% in bothECMO and non-ECMO CDH survivors (Dennettet al. 2014; Partridge et al. 2014; Wilson et al.2013), which is equivalent to the SNHL rate of allneonatal intensive care unit patients (Hille et al.2007; Tracy and Chen 2014).

Many CDH survivors present with gastrointes-tinal symptoms such as gastroesophageal reflux(GER), failure to thrive (defined as weight <25thor 5th centile), and late bowel obstruction (Burgoset al. 2017; Puri and Doi 2011; Rais-Bahrami et al.1995; Sigalet et al. 1994). One-third of thepatients require gastrostomy tubes due to nutri-tional morbidity (Chiu et al. 2006; Muratore et al.2001; Tracy and Chen 2014). Treatment forGERD comprises H2-blockers, but if clinicalproblems like pulmonary infections or chokingpersist, fundoplication must be discussed(Bagolan and Morini 2007; Tracy and Chen2014). The most frequently reported predictorfor antireflux surgery is the need of diaphragmaticpatch repair (Jaillard et al. 2003; Muratore et al.2001), and recurrence is more common in patientsrepaired with a prosthetic patch. Moreover,patients with patch repair have a higher risk fordeveloping musculoskeletal deformities such asscoliosis or pectus excavatum (Jancelewicz et al.2010).

Most CDH survivors beyond the neonatalperiod are able to lead a normal life; however,


the children with CDH should have a multi-disciplinary follow-up and assessed regularly fortheir pulmonary, neurodevelopmental, and nutri-tive outcome until adulthood.

Congenital Eventrationof the Diaphragm (CDE)

Eventration of the diaphragm is characterized byan atypically high or deviated position of all orparts of the hemidiaphragm, which can occur con-genitally or acquired as a result of phrenic nervepalsy. Congenital CDE is a developmental abnor-mality in muscular aplasia of the diaphragm,which primarily has fully developed musculature,and becomes atrophic secondary to phrenic nervedamage and disuse. CDE occurs in 1 per 1400patients with higher prevalence in males (Wu et al.2015).

Clinical Features

Clinical characteristics may vary widely frombeing asymptomatic to severe respiratory distress,pneumonia, bronchitis, or bronchiectasis. Gastro-intestinal symptoms such as vomiting or epigas-tric discomfort have also been reported. Patientswith phrenic nerve palsy may have a history ofdifficult delivery, exhibiting tachypnea, respira-tory distress, or cyanosis. Breathing sounds may

be reduced on the affected side during physicalexamination and a mediastinal shift during inspi-ration and a scaphoid abdomen may be observed.Occasionally, CDE patients exhibit associatedmalformations like hypoplastic lung, congenitalheart disease, or cryptorchidism (Wu et al. 2015).

Diagnosis

A chest X-ray reveals an elevated diaphragm witha smooth, unbroken outline on frontal and lateralchest (Fig. 8a, b). Fluoroscopy is useful to distin-guish a complete eventration from a hernia. Com-plete eventration can lead to paradoxicaldiaphragmatic movements. Ultrasound helps toidentify abnormal organs underneath theeventration. Other study modalities such aspneumoperitonography, contrast peritonography,radioisotope scanning, CT, or MRI scans arerarely required.

Management

Asymptomatic patients without crucial pulmo-nary abnormalities can be treated conservatively.Same applies for patients with incomplete phrenicnerve palsy without paradoxical movement asnormal function usually returns. In contrast,symptomatic patients, especially those with respi-ratory distress, need prompt respiratory support

Fig. 8 (a) Right-sidedCDE with liver visible inthe right chest andmediastinal shift to the left.(b) Lateral X-ray image ofright CDE


and ventilation with humidified oxygen to mini-mize the diaphragmatic excursions. A nasogastrictube should be placed to decompress the stomach.Surgery is undertaken once the patient’s conditionis stabilized.

Operative Repair

Diaphragmatic plication is the method of choice,increasing both tidal volume and maximal breath-ing capacity (Fig. 9a, b). For left-sided CDE, anabdominal approach through a subcostal incisionis usually chosen, whereas a thoracic approachwith a posterolateral incision in the sixth spacemay be used for right-sided CDE. A trans-abdominal approach facilitates good visualizationof the complete diaphragm and easier mobiliza-tion of abdominal contents. Plication via laparo-scopic or thoracoscopic approach is also saferepair method (Fujishiro et al. 2016).

Outcome

Mortality of CDE is usually related to pulmonaryhypoplasia, but patients without underlying pul-monary hypoplasia commonly have an excellentprognosis. Timely precise diagnosis and

management of symptomatic CDE effectivelyprevents respiratory morbidity and reduces com-plications such as recurrence, pneumonia, pleuraleffusions, or renal insufficiency (Wu et al. 2015).

Conclusions and Future Directions

CDH remains a therapeutical challenge due to itsassociated comorbidities lung hypoplasia and pul-monary hypertension. Advances in neonatalresuscitation, intensive care treatment, and tech-nical equipment have improved the overall sur-vival rate up to 90% in highly specialized centers.Ongoing basic research on the genetic and molec-ular pathomechanisms aims to identify crucialparts in the diaphragmatic, pulmonary, and vascu-lar development for further treatment strategies.Currently, CDH management focuses mainly onpostnatal surgical and medical care; however,promising studies on stem cells and tissue engi-neering may open opportunities for prenatal treat-ment on diaphragmatic and lung developmentlikewise. Infants born with CDH need to be man-aged carefully and interdisciplinary by obstetri-cian, neonatologists, anesthetist, and pediatricsurgeons to assure optimal outcome of thesepatients. Although most CDH survivors beyondthe neonatal period are able to lead a normal life,

Fig. 9 (a, b) Plication repair of diaphragmatic eventration (Image from Puri and Höllwarth, Pediatric Surgery (SpringerSurgery Atlas Series), 2006, Springer)


they should have multidisciplinary follow-up andassessed regularly for their pulmonary,neurodevelopmental, and nutritive outcome untiladulthood.

Cross-References

▶Airway Malformations▶Cardiovascular Physiology▶Chylothorax and Other Pleural Effusions inNeonates

▶Clinical Genetics▶Embryology of Congenital Malformations▶Epidemiology of Birth Defects▶Extracorporeal Membrane Oxygenation▶ Fetal Surgery▶Long-Term Outcomes in Newborn Surgery▶Metabolism▶ Prenatal Diagnosis for CongenitalMalformations

▶ Preoperative Assessment▶ Principles of Minimally Invasive Surgery▶Respiratory Physiology

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