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PEDIATRIC SURGERY ISBN: 978-0-323-07255-7Volume 1 9996085473Volume 2 9996085538

Copyright # 2012, 2006 by Saunders, an imprint of Elsevier Inc.

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Practitioners and researchers must always rely on their own experience and knowledge in evaluating andusing any information, methods, compounds, or experiments described herein. In using such information ormethods they should be mindful of their own safety and the safety of others, including parties for whom theyhave a professional responsibility.

With respect to any drug or pharmaceutical products identified, readers are advised to check the mostcurrent information provided (i) on procedures featured or (ii) by the manufacturer of each product to beadministered, to verify the recommended dose or formula, the method and duration of administration,and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledgeof their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient,and to take all appropriate safety precautions.

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Library of Congress Cataloging-in-Publication Data

Pediatric surgery. 7th ed. / editor in chief, Arnold G. Coran ; associate editors, N.Scott Adzick . . . [et al.].

p. ; cm.Includes bibliographical references and index.ISBN 978-0-323-07255-7 (2 vol. set : hardcover : alk. paper)I. Coran, Arnold G., 1938- II. Adzick, N. Scott.[DNLM: 1. Surgical Procedures, Operative. 2. Child. 3. Infant. WO 925]

617.98dc23

2011045740

Editor: Judith FletcherDevelopmental Editor: Lisa BarnesPublishing Services Manager: Patricia TannianSenior Project Manager: Claire KramerDesigner: Ellen Zanolle

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

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CHAPTER 63

CongenitalDiaphragmaticHernia andEventrationCharles J. H. Stolar and Peter W. Dillon

History

The earliest English language description of the gross anatomyand pathophysiology associated with congenital diaphrag-matic hernia (CDH) in a newborn was by McCauley, an asso-ciate of Hunter, as reported in the Proceedings of the RoyalCollege of Physicans, 17541:

The child was born in the lying-in-hospital in Brownlow Street onthe 24th of August, 1752: and was a fully grown boy, remarkablyfat and fleshy. He was the fifth child of a healthy young womanwho was well during her pregnancy. The child, when first born,started and shuddered; so that the nurse apprehended his goinginto fits. He breathed also with difficulty and it was some time be-fore he could cry; which when he did, there was something pecu-liar in its note. He seemed to revive a little in about half an hourand breathed more freely: but soon relapsed and died before hewas quite an hour and a half old. Being informed of these partic-ulars by the mother, the matron, and the nurse, I was desirous ofexamining the body. . . .? I laid open the abdomen and found none

of the intestines were contained in that cavity except part of thecolon which was distended with meconium. Before I proceededfurther with the dissection I sent to acquaint my ingenious friend,Dr. Hunter. We together dissected and examined this curious sub-ject: and at the same time committed to writing the most remark-able appearances.

When the sternum was raised, the stomach with thegreatest part of the intestines, with the spleen, and part of thepancreas were found in the left cavity of the thorax; having beenprotruded through a discontinuation, or rather an aperture ofthe diaphragm, about an inch from the natural passage of theesophagus.

From the extraordinary bulk of the parts contained in theleft side of the thorax, the mediastinum, the heart, the esopha-gus, and the descending aorta were forced a considerable wayto the right side of the thorax; because there was not the leastmark of rupture or inflammation about the edges of the chasm:and because it is probable that the diminished size of the leftlobes of the lungs, and the heart and mediastinum being pushedto the right side, were gradually affected by the bulk and increaseof the viscera.

As the esophagus was pushed to the right side by the stomachand the bowels, in the cavity of the thorax it kept the same courseand pierced the diaphragm not in the usual place, but consider-ably further to the right side: and the aperture through whichit passed was backwards and to the right side with respect tothat for the vena cava.

I have preserved the heart and lungs to show the dispropor-tioned sizes of the lobes. And I have dried and prepared thediaphragm with its connections to the vertebrae and sternum toshow the preternatural aperture through which the bowels passedinto the thorax; as also the passage of the esophagus to the rightside of the diaphragm. These preparations were at the same timeshown to the Society.

Cooper,2 in 1827, and Laennec,3 in 1834, not onlyreported clinical descriptions and gross pathology of CDHbut also suggested that laparotomy might be the proper ap-proach for reduction and correction of the hernia. Bowditch,4

in 1847, was the first to make the bedside diagnosis of CDHand further emphasized the clinical criteria for diagnosis.Although Bochdaleks understanding of the embryologywas incorrect, this congenital defect continues to carry hisname.5 He speculated that the hernia resulted from a pos-terolateral rupture of the membrane separating the pleuro-peritoneal canal into two cavities. He also incorrectlyspeculated that the best way to repair the defect was throughthe bed of the 12th rib. The record is not clear as to whetherthis was actually attempted. The earliest, although unsuccess-ful, efforts to repair CDHs were by Nauman,6 in 1888, andODwyer, in 1890.7 The first reports of successful repairs werein an adult by Aue,8 in 1901, and a child by Heidenhain,9

in 1905.The groundwork for treating CDH in the newborn period

was laid by Hedblom,10 whose review of the reported casesas of 1925 showed that 75% of 44 infants diagnosed in thenewborn period died. He suggested that earlier interventionmight improve survival. Successful repair of CDH remainedrare until 1940, when Ladd and Gross11 reported 9 of 16patients surviving operative repair, the youngest being40 hours old. It was not until 1946 that Gross12 reportedsurvival of the first infant younger than 24 hours old afteroperative repair of the defect. Until the 1980s, the standardof care remained immediate neonatal surgery followed bypostoperative resuscitative therapy (Fig. 63-1).

809

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Epidemiology and Genetics

The reported incidence of CDH is estimated to be between 1 in2000 to 5000 births. In the United States, approximately 1000infants per year are affected with this condition, and ina recent study from Atlanta the birth prevalence was foundto be 2.4 per 10,000 births.17 The incidence in stillbornsis less well documented. Approximately one third of infantswith CDH are stillborn, but these deaths are usually theresult of associated fatal congenital anomalies.1820 Whenstillborns are counted with live births, females appear to bemore commonly afflicted than males.13,21,22

Defects are more common on the left side, with approxi-mately 80% being left sided and 20% right sided. BilateralCDH defects are rare and have a high incidence of associatedanomalies.103 Infants with isolated CDH are more likely to bepremature, macrosomic, and male; and about one third ofaffected infants may have associated major defects.24,25

Womenwho are thin or underweight for their height may havean increased risk of having an infant with an isolated CDH.26

CDH is thought to represent a sporadic developmentalanomaly, although a number of familial cases have been

reported.13,2731 The expected recurrence risk in a first-degreerelative has been estimated to be 1 in 45, or approximately2%.30 Structural chromosomal abnormalities have beenidentified in 9% to 34% of CDH infants and include triso-mies, deletions, and translocations.32 Specific chromosomeswith deleted or translocated genes may be candidate locifor CDH development.33,34 The combination of CDH andan abnormal karyotype has been associated with a pooroutcome.32,35,36

The cause of CDH is unknown. As with other embryopa-thies, there is increasing evidence that CDH may be due tothe exposure of genetically predisposed or susceptible indi-viduals to environmental factors. Exposure to a number ofpharmacologic agents and environmental hazards has beenimplicated in its development. These include insecticidesand drugs, such as phenmetrazine, thalidomide, quinine,cadmium, lead, and nitrofen.3740 The clinical findings ofvitamin A deficiency in CDH infants and the effects of vitaminA administration in nitrofen-induced pulmonary hypoplasiahave strengthened the evolving hypothesis that alterationsin retinoid-regulated target genes may be responsible forCDH development.41

Associated Anomalies

Any newborn with a major congenital anomaly, includinginfants with CDH, has an increased incidence of an additionalmalformation compared with the general population. Al-though previously thought to be low, the incidence of associ-ated malformations in infants with a CDH ranges from 10% to50%.4246 Skeletal defects have been noted in as many as 32%of CDH infants and include limb reduction and costovertebraldefects.44,45,47 Cardiac anomalies have been found in 24% ofinfants.48 Cardiac hypoplasia involving the left ventricle andoften associated with hypoplasia of the aortic arch is fre-quently described and can be confused with hypoplastic heartsyndromes. However, the clinical significance is limited. Mostcardiovascular malformations involve the cardiac outflowtract, such as ventricular septal defects, tetralogy of Fallot,transposition of the great vessels, double outlet right ventricle,and aortic coarctation.25,28,4851 Anatomic anomalies of thetracheobronchial tree have been found in 18% of patients withCDH and include congenital tracheal stenosis, tracheal bron-chus, and trifurcated trachea.45 The incidence of associatedmalformations in stillborn infants with CDH is even higher.In one study, 100% of stillborn infants with CDH had asso-ciated lethal anomalies.16,22 Abnormalities noted in this still-born group were predominantly neural tube defects andincluded anencephaly, myelomeningocele, hydrocephalus,and encephaloceles. Even in infants who survive to birthbut die shortly thereafter, neural tube defects were the mostcommon malformations noted. Cardiac defects were the sec-ond most common group and included ventriculoseptaldefects, vascular rings, and coarctation of the aorta.51 Othermidline developmental anomalies have also been reportedand include esophageal atresia, omphalocele, and cleft palate.A number of syndromes have a CDH as a pathologic finding.These include trisomy 21, 18, and 13, and syndromes suchas Frey, Beckwith-Wiedemann,Goldenhar, Coffin-Siris, Fryns,Meacham, and Kabuki.23,35,50,5355

FIGURE 63-1 Chest radiograph of an infant with a right-sided congenitaldiaphragmatic hernia demonstrating air-filled loops of intestine in theright hemithorax with contralateral displacement of the mediastinum.The infant has been cannulated for venoarterial extracorporeal membraneoxygenation.

810 PART VI THORAX

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Embryology

DIAPHRAGMATIC DEVELOPMENT

The embryologic development of the diaphragm remainsincompletely understood and involves multiple, complexcellular and tissue interactions. The fully developed dia-phragm is derived from four distinct components: (1) theanterior central tendon forms from the septum transversum,(2) the dorsolateral portions form from the pleuroperitonealmembranes, (3) the dorsal crura evolve from the esophagealmesentery, and (4) the muscular portion of the diaphragmdevelops from the thoracic intercostal muscle groups. Theprecursors of diaphragmatic structure begin to form duringthe fourth week of gestation with the appearance of the peri-toneal fold from the lateral mesenchymal tissue. At the sametime, the septum transversum forms from the inferior portionof the pericardial cavity. The septum transversum serves toseparate the thoracic from the abdominal cavities and eventu-ally forms the central tendinous area of the fully developeddiaphragm. It defines the rudimentary pleuroperitoneal canalsand allows for the establishment of mesenchymal tissue withinthese canals that ultimately results in pulmonary parenchymaldevelopment.56

Closure of the pleuroperitoneal canals with the formationof a pleuroperitoneal membrane occurs during the eighthweek of gestation. Several theories have been proposed toexplain the formation of this membrane and the subsequentdevelopment of a diaphragmatic structure. Progressive growthof the pleuroperitoneal membrane has been one mechanismproposed for canal closure.5759 Other researchers have pos-tulated that concurrent hepatic and adrenal organogenesis iscrucial to this process.7a,59,60,71 The involvement of a posthe-patic mesenchymal plate in diaphragmatic formation has beenproposed.61

The pleuroperitoneal folds extend from the lateral bodywall and grow medially and ventrally until they fuse withthe septum transversum and dorsal mesentery of the esopha-gus during gestational week 6. Complete closure of the canaltakes place during week 8 of gestation. Anatomically, the rightside closes before the left.56Muscularization of the diaphragmappears to develop from the innermost muscle layer of thethoracic cavity, although it has been proposed that the posthe-patic mesenchymal plate is a possible source of muscular tis-sue.60,61 Posterolaterally, at the junction of the lumbar andcostal muscle groups, the fibrous lumbocostal trigone remainsas a small remnant of the pleuroperitoneal membrane andrelies on the fusion of the two muscle groups in the final stagesof development for its strength. Delay or failure of muscularfusion leaves this area weak, perhaps predisposing to hernia-tion. Bochdalek first described this area of the posterolateraldiaphragm in 1848, and it is for this reason that the mostcommon site for CDH bears his name.

LUNG DEVELOPMENT

Fetal lung development is divided into five stages: embryonic,pseudoglandular, canalicular, saccular, and alveolar.63 Embry-onic lung development begins during the third week ofgestation as a derivative of the foregut and is marked by theformation of a diverticulum off of the caudal end of the laryn-gotracheal groove.64 The trachea and the two primary lung

buds form from this diverticulum by the fourth week of ges-tation. At 6 weeks, these lung buds have further developedinto defined lobar structures. The pseudoglandular phase oflung development takes place during the 7th to 16th weeksof gestation and involves airway differentiation. It is duringthis period that all bronchial airways develop. From the16th to the 24th weeks of gestation, fetal lung developmententers the canalicular phase of growth. During this period,airspace development occurs, as crude alveolar air sacs beginto take shape. Type 1 pneumocytes begin to differentiate, andthe precursors of type 2 pneumocytes ultimately responsiblefor surfactant production begin to appear. Gas exchangebecomes functionally possible at this stage.

Continued maturation of the crude alveolar airspaces takesplace during the saccular phase of development that extendsfrom 24 weeks gestation to term. During this time period,there is continued remodeling of the airspace dimensionsand a maturation of surfactant synthesis capabilities.201

Mature, adult-like alveoli begin to appear shortly afterbirth.66,67 Extensive alveolar maturation and multiplicationthen takes place from birth until approximately 8 years ofage, with a 10-fold increase in the number of functioningalveoli.6871 Some investigators have proposed that alveolarformation may be completed by 2 years of age.72

Pulmonary vascular development follows the stages of air-way and alveolar growth and can be divided into two ana-tomic units based on associated airway structure. The termacinus describes the functional unit of the lung that includesthe respiratory bronchioli, alveolar ducts, and alveoliallstructures that evolve during or after the canalicular phaseof lung development. Vascular development in this regionproceeds concurrently with alveolar growth and multiplica-tion. The preacinar structures include the trachea, majorbronchi, and lobar bronchi up to the terminal bronchioles.Preacinar vascular development is completed by 16 weeksgestational age.7376

It is now recognized that pulmonary development ismarked by a series of programmed events regulated by mastergenes, such as the homeobox genes, nuclear transcription fac-tors, hormones, and growth factors. These processes involvegenes regulating epithelial and endothelial interactions as wellas temporal and spatial interactions of several hormones andgrowth factors. Early developmental transcription factors,such as hepatocyte nuclear factor-3b and thyroid transcriptionfactor-1, regulate pulmonary development from the foregutmesenchyme. Additional stimuli of pulmonary developmentinvolve the transforming growth factor-b pathway, SonicHedgehog pathway, Notch-delta pathway, Wingless-Int path-way, and cytokine receptor pathways. Subsequent signaltransduction control of organogenesis includes the apoptoticpathways, nuclear receptor pathways, and interleukin path-ways. The angiopoietins and isoforms of vascular endothelialgrowth factor are involved in pulmonary angiogenesis andvascular development.77,78 Hormones such as the glucocorti-coids, thyroid hormone, and retinoic acid have been shown toregulate several of the crucial cellular interactions required forproper pulmonary organogenesis and differentiation.

Very little is known about the alterations in gene expres-sion, growth factor interactions, and hormone levels asso-ciated with airway and vascular development in thehypoplastic CDH lung. A number of factors have been foundto be elevated in CDH lung specimens, including epidermal

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growth factor, transforming growth factor-a, vascularendothelial growth factor, insulin-like growth factor, tumornecrosis factor-a, angiopoietin-2, and glucocorticoid receptorgene expression.41,77,7983 Decreased expression of SonicHedgehog, heme-oxygenase-1, and endothelial nitric oxidesynthase levels has been found in CDH specimens.8486

Abnormal levels of factors that contribute to the regulationof pulmonary vascular tone have also been reported. Highplasma concentrations of endothelin-1, a powerful vasocon-strictor, have been found in association with increased expres-sion of its pulmonary artery receptors in CDH infants.87,88

Advances in understanding potential mechanisms respon-sible for the alterations in pulmonary development associatedwith a congenital diaphragmatic hernia have been limited bythe lack of a completely acceptable experimental animalmodel. Currently, three model systems exist for studyingpulmonary maldevelopment: a surgical model of a diaphrag-matic defect, a nitrofen model of pulmonary and diaphrag-matic hypoplasia, and various gene knockout mice modelsof pulmonary hypoplasia.89 Elegant models by de Lorimierand Harrison, in which diaphragmatic defects were surgicallycreated in fetal sheep, showed that long-term compression ofabdominal contents into the thoracic cavity resulted in pulmo-nary maldevelopment and lung hypoplasia.90,91 The disad-vantage of this surgical model is that the defect is createdlate in the time course of fetal development and may notaddress early developmental mechanisms. The nitrofen modelof experimental CDH coincides with the theory that manydevelopmental defects, including CDH, are embryopathiescaused by toxin exposure. Nitrofen is an herbicide withknown teratogenic effects. Its administration to pregnant miceresults in offspring with pulmonary hypoplasia, diaphrag-matic defects, reduced airway branching, excessive muscular-ization of pulmonary vessels, surfactant deficiency, andrespiratory failure at birth. The pulmonary hypoplasia result-ing from nitrofen administration has been associated withalterations in a number of growth factors and developmentalpathways in embryonic mice.92 Finally, investigations usingspecific knockout mice have contributed to the understandingof the role of various factors and pathways in pulmonary anddiaphragmatic development.89

A number of physical factors may also affect pulmonarygrowth and development.63 Adequate intrathoracic space isa prerequisite for normal pulmonary growth. Any intratho-racic or extrathoracic process that results in a decrease ofthe intrathoracic space and pulmonary parenchymal compres-sion can lead to the development of structurally immaturelungs.9096 Other physical factors important in lung growthinclude the maintenance of normal fetal lung liquid andamniotic fluid dynamics.93,95,98,99,101

Pathology

Although the cause of CDH is uncertain, its consequences onpulmonary development and function are well documented.During the early development of the diaphragm, the midgutis herniated into the yolk sac. If closure of the pleuroperitonealcanal has not occurred by the time the midgut returns to theabdomen during gestational weeks 9 and 10, the abdominalviscera herniate through the lumbocostal trigone into the

ipsilateral thoracic cavity. The resulting abnormal positionof the bowel prevents its normal counterclockwise rotationand fixation. No hernia sac is present if the event occurs beforecomplete closure of the pleuroperitoneal canal, but a nonmus-cularizedmembrane forms a hernia sac in 10% to 15% of CDHpatients.100 Although some claim the herniation can occur latein gestation or be intermittently present as a dynamic process,in most cases the defect is established by gestational week12.100a The subsequent postnatal problems relate to the effectsof the herniated viscera on the developing heart and lungs.

The classical left-sided CDH features a 2.0- to 4.0-cmposterolateral defect in the diaphragm through which theabdominal viscera have been translocated into the hemithorax(Fig. 63-2). Herniated contents often include the left lobe ofthe liver, the spleen, and almost the entire gastrointestinaltract. The stomach is frequently in the chest, which resultsin some degree of obstruction at the gastroesophageal junc-tion. This obstruction, in turn, causes dilation and ectasia ofthe esophagus. Occasionally, the kidney may be in the chesttethered by the renal vessels. In instances of a right-sideddefect, the large right lobe of the liver can occupy much ofthe hemithorax in addition to other abdominal viscera. Thehepatic veins may drain ectopically into the right atrium,and fibrous fusion between the liver and the lung has beenreported. Both of these anatomic findings can significantlycomplicate attempted surgical repair of the diaphragmaticdefect.89,102

The diaphragmatic defect usually features a completelyopen space between the chest and abdomen, although someinfants have a membrane of parietal pleura and peritoneumacting as a hernia sac. This finding is to be distinguished from

FIGURE 63-2 Schematic illustration of a left congenital diaphragmatichernia showing translocation of abdominal viscera through a posterolat-eral aperture into the chest. (From Spitz L, Coran AG [eds]: Rob & SmithsPediatric Surgery. London, Chapman & Hall, 1996.)

812 PART VI THORAX

an eventration of the diaphragm, which results from phrenicnerve or anterior horn cell degeneration. The muscle fibers ofthe diaphragm are usually present.

Bilateral CDH is anunusual occurrence and is almost alwaysfatal because of bilateral lung growth arrest (Fig. 63-3).103

Unilateral visceral herniation affects both ipsilateral andcontralateral pulmonary development, although hypoplasiais predictably more severe on the ipsilateral side. This is con-firmed by an analysis of lung volumes and weights in humanautopsy specimens and animal models.90,96,104,105 Becausethe process of CDH herniation occurs at the time of bronchialsubdivision, it is at this stage that lung development becomescompromised. Although all major bronchial buds are presentin a CDH lung, the number of bronchial branches in theaffected lung is greatly reduced. This finding was noted inboth ipsilateral and contralateral pulmonary specimens.104

Alveolar development is severely affected, and it has beenreported that few normal alveoli exist in the lungs at term.106

In addition, the changes in airway structure are quite variable.Infants requiring low ventilatory assistance during treatmenthad the same airway muscle mass as controls, whereas infantswith prolonged ventilatory support had significantly greatermuscle thickness throughout the conducting airways.107

The pulmonary vascular bed is distinctly abnormal in lungsfrom patients with CDH. A reduction in the total number ofarterial branches in both the ipsilateral and the contralateralpulmonary parenchyma has been reported.108,109 Structur-ally, significant adventitial and medial wall thickening hasbeen noted in pulmonary arteries of all sizes in CDH lungsin association with abnormal muscularization of the smallpreacinar and intraacinar arterioles.110112 The physiologicconsequence of this abnormal arterial muscularization maybe an increased susceptibility to the development of fixedand intractable pulmonary hypertension. No significantchanges in pulmonary venous structure have been identifiedresulting from CDH development. Increased adventitialthickness of pulmonary veins has been noted in CDH infants

but appears to be postnatally derived, perhaps as a resultof treatment or secondary to the pathology of pulmonaryhypertension.28,113

Pulmonary blood flow accounts for only 7% of cardiacoutput during normal fetal development, and pulmonaryvascular resistance remains high. The fetus preferentiallyshunts oxygenated blood from the placenta through the fora-men ovale and ductus arteriosus in a right-to-left directioninto the systemic circulation. At birth, a number of hemody-namic changes take place that dramatically alter this circula-tory profile. With the institution of breathing, pulmonaryvascular resistance falls, as does pulmonary artery pressureallowing for an increase in pulmonary blood flow. Systemicvascular resistance and left atrial pressure rise, causing theforamen ovale to close. Increased arterial oxygen tension in-duces spontaneous closure of the ductus arteriosus. Transitionfrom a fetal to an adult-type circulatory pattern is accom-plished. Persistent fetal circulation may develop if this processis interrupted. After birth and interruption of placentalcirculatory support, persistently elevated pulmonary vascularresistance results in increased pulmonary artery pressures anddecreased pulmonary vascular blood flow. The increased vas-cular resistance results in right-to-left shunting of blood ateither the atrial or the ductal levels with the delivery of unsat-urated blood into the systemic circulation. As the blood flowin the shunt increases, the oxygen saturation in the systemiccirculation falls and the mixed venous blood returning tothe right side of the heart becomes progressively desaturated.The resulting hypoxia further increases pulmonary vascularresistance and compromises pulmonary blood flow whileincreasing the right-to-left shunt flow. Severe and progressiverespiratory failure ensues.

Factors that contribute to the persistence of high pulmo-nary vascular resistance in CDH lungs are thought to be thestructural changes in decreased total arteriolar cross-sectionalarea in the involved lungs and the increased muscularizationof the arterial structures that are present. In the postnatalperiod, there is failure of the normal arterial remodeling pro-cess, further maintaining the abnormal vascular resistancethat may be only partly reversed by treatment interven-tions.114 Additional exacerbations of pulmonary vascularresistance may be induced by the known stimulators ofpulmonary hypertension, including hypoxia, acidosis, hypo-thermia, and stress.115 Alterations in the levels of variousprostaglandins, leukotrienes, catecholamines, and the renin-angiotensin system have been implicated as mediators of thiscomplex process.116118 It can only be surmised at this timewhether there is an exaggerated response to these stimuli bythe abnormal vascular structures of CDH lungs.113

DIAGNOSIS

The diagnosis of a CDH is often made on a prenatal ultrasound(US) examination and is accurate in 40% to 90%of cases.119,119a

Although considerable variation in detection rates have beenreported, the mean gestational age at discovery is 24 weeksand has been reported as early as 11 weeks.120 The US maybe obtained for routine obstetric care or because of suspicionconcerning the presence of polyhydramnios. Polyhydramnioshas been reported present in up to 80% of pregnancies withassociated CDH.99a The mechanism of polyhydramnios isthought to be due to kinking of the gastroesophageal junction

FIGURE 63-3 Operative photograph of a left congenital diaphragmatichernia created in a fetal lamb. The posterolateral defect can be seenlooking from the abdomen into the chest. (From Spitz L, Coran AG[eds]: Rob & Smiths Pediatric Surgery. London, Chapman & Hall, 1996.)

813CHAPTER 63 CONGENITAL DIAPHRAGMATIC HERNIA AND EVENTRATION

by translocation of the stomach into the thorax with resultantforegut obstruction. The US diagnosis of a CDH is most oftensuggested by observing the stomach in the fetal thorax at thesame cross-sectional level as the heart (Fig. 63-4). AdditionalUS findings suggestive of a CDH include the absence of thestomach in the abdomen and the presence of the liver or othersolid viscera in the thorax. The stomachmay be small because ofinterference with fetal swallowing. If the diaphragmatic defect ison the right side, the liver can tamponade the hernia site andobscure the diagnosis. The diagnosis of CDHmay bemissed be-cause intermittent herniation of abdominal viscera into the tho-racic cavity has been reported.99a Furthermore, when thestomach is in a normal abdominal position, herniated smallbowel loops are not easily distinguishable from lung paren-chyma. Themisinterpretation of the fetal US scan can be causedby other diagnoses, such as esophageal atresia and cystic lunganomalies. Functional information concerning fetal breathingcan be obtained by duplex Doppler examination of amnioticflow at the fetal nares at the time of fetal US. A fetal tidal vol-ume/minute ventilation canbedetermined thatmayhave a bear-ing on prognosis.121

In addition to diagnosis, prenatal US may also be of benefitin predicting outcome by using quantitative techniques toestimate the severity of pulmonary hypoplasia of the fetalCDH lung. Three-dimensional estimation of the fetal lung vol-ume, calculation of the right lung area to thoracic area ratio,and calculation of the lung to thoracic circumference ratioare three different measurements that may correlate with neo-natal outcome,122125 but the lung-to-head ratio has been themost widely used prognostic indicator.126 US can be limitedby the poor acoustic contrast between fetal lung and herniatedviscera, position of the fetus, and operator experience. As a re-sult, prenatal magnetic resonance imaging (MRI) evaluation isbeing used with increasing frequency when obstetric sonogra-phy has detected a complex fetal anomaly and is ideally suitedfor fetuses with a diaphragmatic hernia.127129 MRI can read-ily determine liver position in relation to the diaphragm anddetect herniated liver into either hemithorax. It may also beused to more accurately assess lung volume and perhaps cor-relation with outcome.130132

After birth, the spectrum of respiratory symptoms in an in-fant with a CDH is determined by the degree of pulmonaryhypoplasia and reactive pulmonary hypertension. The mostseverely affected infants develop respiratory distress at birth,whereas a majority demonstrate respiratory symptoms withinthe first 24 hours of life. Classically, these infants have a scaph-oid abdomen and an asymmetric distended chest. The chestmay become more distended as swallowed air passes intothe stomach and intestines. Gastrointestinal distention furthercompresses pulmonary parenchyma and affects ventilatorycharacteristics. It may lead to additional mediastinal compres-sion with impairment of the contralateral lung. Because of thesmall size of the neonates chest, breath soundsmay ormay notbe present on the side of the defect. Mediastinal compressionwith shift into the contralateral thorax may cause deviation ofthe trachea away from the side of the hernia and also result inobstruction to venous return with the hemodynamic conse-quences of hypotension and inadequate peripheral perfusion.The signs of respiratory distress may include cyanosis, gasp-ing, sternal retractions, and poor respiratory effort. In babieswith a left CDH, heart sounds will be heard best over the rightchest; dextrocardia accompanied by respiratory distress is aCDH until proven otherwise.

The diagnosis of a CDH can be confirmed by a plain chestradiograph that demonstrates loops of intestine in the chest.The location of the gastric bubble should also be noted, andits position can be confirmed by placement of an orogastrictube. Rarely, a contrast study of the upper gastrointestinal tractis required. The chest radiograph shows angulation of the me-diastinum and a shifting of the cardiac silhouette into the con-tralateral thorax. Although minimal aeration of the ipsilateralparenchyma may be noted, chest radiographs are unreliablefor estimating the degree of pulmonary hypoplasia.58,133135

Once the diagnosis of a CDH is confirmed, additionalradiographic and US examinations should be carried out tosearch for associated anomalies. Echocardiography and bothrenal and cranial US scans should be obtained.

Although most CDHs present in the first 24 hours of life,10% to 20% of the infants with this defect present later.136,137

These latter infants present with recurrent mild respiratory

A B

FIGURE 63-4 A, Ultrasound examination of a 28-week gestation fetus (twin B) in cross section demonstrating the fetal heart (FH) and stomach (ST) in thesame plane. B, Ultrasound examination of the same fetus but in a sagittal plane, demonstrating relationship of the stomach, liver, and heart.

814 PART VI THORAX

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illnesses, chronic pulmonary disease, pneumonia, effusion,empyema, or gastric volvulus. Occasionally, neonatal strepto-coccal pneumonia may mask a delayed-onset right CDH.138

Differential Diagnosis

The diagnosis of a CDH can be confused with a number ofother congenital thoracic conditions, including eventrationof the diaphragm, anterior diaphragmatic hernia of Morgagni,congenital esophageal hiatal hernia, congenital cystic diseaseof the lung, and primary agenesis of the lung. Diaphragmaticeventration has many causes but is seen in the newborn withbirth trauma or Werdnig-Hoffmann disease. The eventrateddiaphragm can rise as high as the third intercostal spaceand have the same physiologic consequences as CDH. Itcan also be completely asymptomatic. The diagnosis is madeby fluoroscopy or real-time US with the demonstration ofparadoxic movement of the diaphragm. MRI is also usefulin determining diaphragmatic structure. Morgagni herniasoccur at the hiatus for the internal mammary arteries andare much less common than Bochdalek hernias. Most arediagnosed incidentally on plain radiographs, but someMorgagni hernias can present as a gastrointestinal crisisbecause of incarceration or volvulus of the colon or smallbowel and require immediate operative intervention.

Prognostic Factors

The search to determine clinically relevant prognostic factorsthat predict the outcome of infants with CDH has been frus-tratingly complex, contradictory, and for the most part unsuc-cessful. Many studies have attempted to examine both anatomicand physiologic parameters that relate to survival, but eachhas been hampered by its retrospective analysis in the presenceof the continuing evolution of new therapies.139,139a Whereasconsideration of multiple factors may influence ones clinicalimpression regarding the survival potential of an infant withCDH, such an impression cannot be derived from onemeasure-ment alone.

ANATOMIC FACTORS

With the ability to establish the diagnosis of CDH in utero as aresult of the increased use of prenatal US, studies suggestedthat the antenatal diagnosis of a CDH before 24 weeks gesta-tional age was associated with a high mortality. Others haveshown that antenatal diagnosis, regardless of timing, of anisolated CDH without other associated anomalies is not anindicator of outcome,140 but more recent reports confirm thatantenatal diagnosis is associated with a worse prognosis.A CDH associated with another significant anomaly still hasa dismal prognosis. If a CDH is not detected by prenatal USbut is subsequently diagnosed after birth, survival rates maybe excellent.122 The Canadian Pediatric Surgery Network(CAPSNet) collected 347 CDH cases between May 2005 andMay 2010 (www.capsnetwork.org/resources/annual report2010); of the 269 patients admitted alive to a pediatric centerand with a completed record, 68% had a prenatal diagnosis,with a 74% survival, while the 32% without a prenatal

diagnosis had a 96% survival (this drops to 86% when thebabies who died in transport are included). Preselection biasprior to transport was not reported.

Antenatal diagnosis and antenatal referral to a full-servicechildrens facility, especially those with maternal/fetalmedicine/lying-in services, has removed much of the postna-tal/pretransfer bias and selection. It was also reported thatthe presence of polyhydramnios was indicative of poor sur-vival.141 A number of studies, however, have refuted thisobservation and have shown that the presence of polyhy-dramnios has no predictive value on the eventual outcomeof an infant with CDH.142,143 The anatomic position of theliver has not been consistently shown to be a reliable predictorof mortality in CDH.120,126,131,144146 Nevertheless, there arereports suggesting the presence of liver herniation may be pre-dictive of the need for extracorporeal membrane oxygenation(ECMO) as well as a requirement for prosthetic patch repairfor diaphragmatic repair.15,126,147

The position of the stomach has been proposed as a prog-nostic indicator by a number of investigators. Survival rates ofinfants with CDH with the stomach properly located belowthe diaphragm at the time of diagnosis have been reportedto be as high as 100% but is only 30% when the stomachhad herniated into the chest.148,149 Other studies have shownno predictive value of such positioning.150 The side of the di-aphragmatic defect may be somewhat predictive of outcome.It has been reported that patients with right-sided defects havea worse prognosis than those with left-sided defects.14,151

A recent study reported no differences in outcomes betweenthe two sides.152 However, right-sided defects may notbecome evident in the newborn period and may present withvery mild respiratory symptoms at a later age.153

A number of different imaging parameters have beenreported in an attempt to predict the presence of pulmonaryhypoplasia and serve as a prognostic indicator of survival. Theseinclude measurements of the fetal thorax and lung, fetal breath-ing movements, and various calculated blood flow measure-ments within the pulmonary arteries.154 The lunghead ratio(LHR) has been the most extensively studied. The LHR is mea-sured using ultrasonography and is the ratio of the area ofthe contralateral lung (opposite the hernia defect) to the fetalhead circumference. The lung area is calculated from perpen-dicular transverse measurements determined at the plane ofthe four-chamber view of the fetal heart. This measurementhas been suggested to predict prognosis and guide manage-ment.126,155,156 However, there is no consensus as to whatvalue of LHR should serve as a determinant of prognosis orwhen during gestation that measurement should be made.157

Because LHR has been proposed to determine the timing ofexperimental fetal intervention, most studies report LHR mea-surements before 32 weeks gestational age.158 Current data in-dicate that the strength of association with survival is strongestfor those fetuses with LHR greater than 1.0 compared with LHRless than 1.0.159 A recent report by Aspelund and colleagues ofa single-institution experience of all inborn CDH infants man-aged with a consistent treatment algorithm had significant sta-tistical power to support an LHR less than 0.85 as reliablypredicting 100% mortality.160

Because LHR changes with gestational age, use of theobserved-to-expected LHR (O/E-LHR) has been reported.158,161

A severe left CDH has been characterized by an O/E-LHR ofless than 25%.

815CHAPTER 63 CONGENITAL DIAPHRAGMATIC HERNIA AND EVENTRATION

Prenatal magnetic resonance imaging is being investigatedextensively as a method for improving prognostic predictivecapability by more accurately determining lung volumes inCDH patients.162 Measured indices include lung to head ratioas well as relative and absolute fetal lung volumes. The prog-nostic accuracy appears to be slightly better than sonographicdeterminations.146 Signal intensity analysis of fetal lung tissueas part of MRI imaging studies may be a future application ofthis modality, although a recent report found that lungvolumes was a better predictor.162,163

The sophisticated analysis of cardiopulmonary structureand function in either the prenatal or postnatal period mayalso be of prognostic importance.142,164166 A number ofindices have been reported, including the calculation of thecardioventricular index (left ventricle/right ventricle), thecardiovascular index (Ao/PA), pulmonary artery diameters,the McGoon index (MGI), and pulmonary artery index(PAI).166170 The McGoon and pulmonary artery indices aredetermined shortly after birth by the following formula:

MGI RPA diameter LPA diameter =Descending aorta diameter

PAI RPA area LPA area =BSA

(RPA and LPA right and left pulmonary artery, respectively;BSA body surface area)

MGI scores less than 1.31 have been found to be highlypredictive of mortality, while the same has been found forPAI scores less than 90. An analysis of left ventricular masscombined with the simultaneous determination of fractionalshortening has also been used to predict outcome, with anindex of 1.2 associated with nonsurvival.171 Advanced echo-cardiographic measurements with interesting clinical promiseinclude the determination of lung tissue perfusion with theanalysis of fractional moving blood volume (FMBV) and theuse of pulsed Doppler measurements in the proximal branchof the pulmonary artery to determine the pulsatility index (PI)and the peak end-diastolic reversed flow (PEDRF).172174

These measurements may have increasing importance inthe search for suitable prenatal predictors of survivability inthe setting of fetal therapy.175

PHYSIOLOGIC PARAMETERS

Unfortunately, there are few physiologic parameters that canbe measured in the neonate to assess pulmonary functionother than PO2, PCO2, and pH. Thus arterial blood gas analysishas been the cornerstone for attempting to establish clinicalpredictive criteria. Early studies showed differences in pHand PCO2 between survivors and nonsurvivors in responseto therapeutic interventions available at that time.176178

Infants with a low PCO2 and a PO2 that was initially normalor improved with mechanical ventilation had an excellentoutcome, whereas those infants who had high PCO2 levelsunresponsive to mechanical ventilation did poorly. These au-thors noted the importance of measuring both preductal andpostductal blood gases to assess the degree of right-to-leftshunting. The report by Stolar and colleagues179 advocatedpreductal oximetry values in the setting of maximal con-ventional care to identify potential ECMO candidates. In theabsence of preductal SaO2 greater than 90%, overwhelmingpulmonary hypoplasia was inferred, and ECMO was not

offered. This represented less than 5% of all patients, forwhich there was 100% mortality.

Since these initial reports, investigators have deriveda number of formulas using various blood gas components topredict outcome. The most basic concept is the alveolararterial oxygen gradient (AaDO2). It is calculated by the formula

AaDO2 f713& FiO2 ' PaCO2g=0:8) ' PaO2

Although initially used to determine entry criteria forECMO, its use has been superseded by the development ofother indices.

Using blood gas analysis and PCO2 levels in combinationwith ventilatory data, parameters were determined to predictoutcome in CDH infants managed with conventional ventila-tory techniques.110,180182 To do this, a ventilatory index (VI)was calculated:

VI RR & PIP' PEEP

(PEEP positive end-respiratory pressure; PIP peakinspiratory pressure; RR respiratory rate)

When thePCO2 couldbe reduced to less than40mmHgwitha ventilatory index less than 1000, all patients survived. Amod-ified ventilatory index (MVI) was calculated by using peakinspiratory pressure rather than mean airway pressure (MAP):

MVI RR & PIP& PaCO2=1000

In infants with an MVI less than 40, the survival rate was96% using conventional therapy. All infants died if the MVIwas greater than 80.183

The most commonly used calculation is the oxygenationindex (OI). It is calculated by the formula

OI MAP& FiO2 & 100=PaO2

This formula should be calculated using the preductal PaO2,because the postductal one varies tremendously with theamount of shunting.

A 1994 report showed that with conventional ventilatorytherapy, an OI less than 6 had a survival rate of 98%, whereasan OI greater than 17.5 had no survivors.183 The predictivepowers of these factors with such therapies as ECMO, high-frequency oscillation (HFO), surfactant, and nitric oxide(NO) have not been determined. Simple preoperative lungfunction measurements are difficult to obtain but may be ofsome interest.184

In summary, efforts to reliably predict mortality for the fetusor live-born infant with isolated CDH have been fraught withuncertainty. Although a calculated LHR less than 0.85 (or anobserved/expected LHR less than 20% to 25%) may have highpredictability for mortality, better understanding of prognosisawaits functional evaluation of the fetus. This might includetidal amniotic fluid breathing/lung volumes or response tomaternal hyperoxia. Postnatal use of theMcGoon index, also be-cause of its functional nature, holds promise.184a In the absenceof substantiated, reproducible information regarding prognosis,treatment continues to be guided by best clinical judgment.

PULMONARY FUNCTION TESTS

The analysis of preoperative and postoperative pulmonaryfunction tests has been reported to have predictive value inidentifying infants who might require ECMO therapy as wellas identifying survivors.184 Initial studies of respiratory

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function in infants with CDH uncovered the detrimentalchanges in compliance measurements resulting from surgicalrepair and helped support the hypothesis of medical stabi-lization and delayed surgical intervention.185187 Using thetreatment strategies of delayed surgical repair and ECMO,when necessary, infants did not require ECMO when theirinitial preoperative compliance measurement was greater than0.25 mL/cm H2O/kg and initial tidal volume was greaterthan 3.5 mL/kg. An improvement in the tidal volume of4 mL/kg after repair correlated with survival.188

Studies have indicated that preoperative measurement offunctional residual capacity may predict fatal pulmonaryhypoplasia.184 In addition, serial measurements of totalpulmonary compliance have been found useful in predictingoutcome in high-risk infants.189

Although no single parameter has proven sufficient as aprognostic factor in managing CDH infants, recent multicen-ter studies have shown that significant independent predictorsof total mortality include prenatal diagnosis, birth weight,low 1- and 5-minute Apgar scores, score for neonatal acutephysiology (SNAP-II), and right-sided defect.139,190192

Treatment

Success in the management of CDH has improved dramati-cally from 1929 when Greenwald and Steiner27 wrote, Forthe patient in whom the hernia makes its appearance at birth,little or nothing can be done from a surgical standpoint.A number of innovative treatment strategies have been used,although consistent impact on overall survival is still difficultto obtain.

PRENATAL CARE

The diagnosis of a CDH is being made with increasingfrequency by prenatal US examination. This study may beinitiated when a discrepancy between size and dates is noted.The prenatal diagnosis of CDH should be complemented by acareful search for other congenital anomalies, particularlythose affecting the cardiovascular and nervous systems.Evaluation of fetal karyotype should be accomplished byamniocentesis or chorionic villus or fetal blood sampling.Currently, the standard of care is to support the fetus andmother while bringing them to delivery as close as possibleto term. The advantage of prenatal diagnosis is in beingable to properly prepare and inform the parents about pos-sible treatments and outcomes. The fetus and mothershould be referred to an appropriate tertiary perinatal centerwhere the full array of respiratory care strategies, includingNO, oscillating ventilators, and ECMO are immediatelyavailable. Anything less may potentially compromise thebest possible outcome.143 Spontaneous vaginal delivery ispreferred, unless obstetric issues supervene. The mere diag-nosis of a CDH is not an indication for elective cesareansection.

At this time, fetal intervention with attempted in uterocorrection of the defect is investigational and highly experi-mental.105,193195 In North America, trials of fetal trachealocclusion for CDH in an effort to promote antenatal lunggrowth have been abandoned, because they did not showimproved survival rates versus contemporary conventional

treatments.193,196 Tracheal occlusion resulted in lung enlarge-ment but did not reverse the pathologic process associatedwith pulmonary hypoplasia. The selection criteria for the se-verity of pulmonary hypoplasia to enter the fetal treatment tri-als has also been questioned.93,94,193,197199 The NorthAmerican trial used an LHR less than 1.4 as entry criterion;the Eurofetus trials have advocated LHR less than 1.0 as entrycriterion. Fetoscopic tracheal occlusion trials are ongoing inEurope, with over 200 cases reported,198 and there are plansfor an international prospective randomized trial involvingNorth American centers that participate in NAFTNet (theNorth American Fetal Treatment Network).

Although prenatal corticosteroids are used to enhance lungdevelopment in premature infants, the role of antenatal corti-costeroid therapy in CDH patients remains undetermined.The rationale for such therapy to induce pulmonary matura-tion in a hypoplastic lung is based on animal studies andisolated case reports.200203 Balanced against these observa-tions is the growing evidence from premature infant studiesthat such drugs may also have adverse perinatal and long-term effects.204,205 The true potential of this therapy in im-proving CDH outcomes awaits the results of a randomizedprospective study.

PREOPERATIVE CARE

Resuscitation

After the birth of the infant and confirmation of the diagnosisof CDH, all efforts should be made to stabilize the cardiorespi-ratory system while inducing minimal iatrogenic injury fromtherapeutic interventions. It is essential to consider that theCDH is a physiologic emergency and not a surgical emergency.The respiratory distress associated with a CDH in the new-born results from a combination of two factors previouslydiscussed: uncorrectable pulmonary hypoplasia and poten-tially reversible pulmonary hypertension. The balance be-tween these two factors determines the response to therapyand ultimately the outcome. Clinically, both are manifestedby an increase in pulmonary vascular resistance and elevatedpulmonary artery pressures, right-to-left shunting at the duc-tal and foramen levels, and progressive hypoxemia. Becausethere are no proven therapies to promote pulmonary growthat this time, therapeutic interventions are aimed at governingpulmonary vascular tone.

Resuscitation begins with endotracheal intubation andnasogastric tube insertion. Ventilation by mask and Ambubag is contraindicated to avoid distention of the stomachand intestines that may be in the thoracic cavity. Arterialand venous access should be acquired through the umbilicus.If the umbilical venous catheter can be passed across the liverinto the right atrium, it can be useful for monitoring centralvenous pressures as well as obtaining mixed venous bloodgas samples. Although the umbilical artery is excellent formonitoring systemic blood pressure and obtaining postductalarterial blood gas specimens, additional information can beobtained by monitoring arterial oxygen saturation in a pre-ductal position either with a right radial arterial catheter ora transcutaneous saturation probe. An important part of thetreatment algorithm is an attempted estimation as to whetherthe infant has enough lung capacity formeaningful gas exchange.

817CHAPTER 63 CONGENITAL DIAPHRAGMATIC HERNIA AND EVENTRATION

It is important to consider this fact before exposing an infantand family to heroic treatment strategies.

As in any neonatal resuscitation, meticulous attention mustbe paid to maintaining proper temperature regulation, glucosehomeostasis, and volume status in the neonate in an effort tomaintain adequate oxygen delivery. Any stressful stimulus canfurther exacerbate already elevated pulmonary pressures andlead to increased shunt flow and further systemic desatura-tion. Infants should be properly sedated, and any combinationof agents, including midazolam, fentanyl, or morphine, can beused. Muscle paralysis is strongly discouraged because of itsuntoward consequences on ventilatory mechanics and poten-tial morbidity. Infants not cooperating with ventilator strat-egies generally need attention to their discomfort, not muscleparalysis. Systemic hypotension and inadequate tissue perfu-sion may be observed and reversed with intravenous fluidadministration, including crystalloid, blood products, andcolloid. Cardiotonic drugs, such as dopamine or dobutamine,may be required. Because of the unstable pulmonary vasculartone and the compromised alveoli, excessive intravenoushydration should be avoided, because it may lead to pul-monary edema, loss of compliance, and further impairmentof gas exchange.

Metabolic acid-base disturbances are usually related tohypoperfusion and should be corrected by fluid manage-ment or bicarbonate administration. Metabolic acidosis canbe reversed with bicarbonate administration if ventilationcan be appropriately managed. Severe hypercapnia (PCO2 >70 mmHg) should bemanaged by changing ventilator strategy.

There is no need for a chest tube in the absence of an activeair leak, pneumothorax, or hemothorax.206,207

Ventilation

The type of mechanical ventilator needed for the infant with aCDH is a matter of personal and institutional preference. Mostinfants can be successfully managed with a simple pressure-cycle ventilator, using a combination of high rates (100breaths per minute) and modest peak airway pressures (18to 22 cm H2O and no PEEP) or lower rates (20 to 40 breathsper minute) and higher pressures (22 to 35 cmH2O, 3 to 5 cmPEEP). The goal of such ventilatory support is to maintainminute ventilation while obtaining a preductal PO2 greaterthan 60 mm Hg (SaO2 90% to 100%) with a correspondingPCO2 of less than 60 mm Hg. pH and PCO2 levels have beenshown to be important in modifying pulmonary vasculartone.307b The successful clinical manipulation of these param-eters in therapeutic interventions in neonates with persistentpulmonary hypertension represents an initial treatmentstrategy. It is now clear, however, that the extremes of hyper-ventilation with induced alkalosis should be avoided becausesuch therapy compounds the pulmonary problems withserious iatrogenic injury.208 A respiratory strategy based onpermissive hypercapnia and spontaneous respiration hasproven to be quite successful.206 If conventional mechanicalventilatory techniques cannot reverse the hypoxemia orhypercarbia, high-frequency techniques using an oscillatingventilator may be required. This technique may be effectivein removing carbon dioxide and temporarily stabilizing aninfant in severe respiratory distress. When such techniqueshave been used as initial therapy, survival results have beenquite good.137,209,210

Pharmacology

A broad spectrum of drugs and antihypertensive agents hasbeen used in attempts to modify the pulmonary vascularresistance in infants with CDH and respiratory failure. Expe-rience has been extrapolated from clinical trials of infantswith persistent pulmonary hypertension of the newborn(PPHN) and other forms of neonatal respiratory failure.

In the past, agents such as tolazoline,211,212which exerts itseffects through a-receptor blockade, had been used to lowerpulmonary vascular resistance in the face of hypoxemia andrespiratory failure.212,213 Its efficacy in CDH infants wasmarginal. Other drugs, such as nitroprusside, isoproterenol,nitroglycerin, and captopril, have not been effective.214 Theadministration of various prostaglandin derivatives, includingprostaglandin D2 (PGD2), prostaglandin E1 (PGE1), and pros-tacyclin, and of the cyclooxygenase inhibitor indomethacinhas also been disappointing.115,215

New management strategies for treating persistent pulmo-nary hypertension now undergoing clinical evaluation includevarious calcium channel blockers, prostacyclin derivatives,endothelin receptor antagonists, and phosphodiesterase-5inhibitors such as sildenafil.216,217

Surfactant

Animal models have demonstrated that experimentallyinduced CDH lungs are surfactant deficient,218 but such re-sults have not been replicated in human studies. Early reportsin infants with CDH demonstrated alterations in surfactantlevels and composition.219,220 However, recent studies haveindicated that the surfactant pool in infants with CDH is nodifferent than control patients, even in infants requiringECMO support.221224 There may be alterations in syntheticandmetabolic kinetics for individual components.221 In termsof improving respiratory function and outcomes, clinical andexperimental investigations with surfactant administrationhave been mixed.224228 A multicenter review of surfactantadministration in CDH patients showed no overall benefitto its use and demonstrated a lower survival rate in preterminfants compared with full-term infants.229 At this time, thereare no clinical data to support the administration of surfactantin the management of CDH infants.

Nitric Oxide

NO is a potent mediator of vasodilatation and was originallyidentified as endothelial-derived relaxing factor.230 Becauseit is a highly diffusible gas that is rapidly inactivated by bind-ing to hemoglobin, it is particularly suited for administrationto the pulmonary vasculature with mechanical ventilatorytechniques. In clinical studies, NO was effective in improvingoxygen saturation levels in neonates with respiratory failuredue to PPHN.231,232 In an animal model of PPHN, NOdecreased pulmonary artery pressures and increased arterialoxygen saturation without discernable side effects.233 Unfor-tunately, its effects in CDH infants with respiratory failure havebeen mixed.86,231,234238 There are no data to show that NOadministration improves survival or decreases the require-ment for ECMO.239 The variable physiologic response toNO in these infants may be related to the method of its admin-istration.228,240 NO administered through a nasal cannula hasbeen used for the treatment of late pulmonary hypertensionfollowing extubation.231 The exact role of NO in the treatment

818 PART VI THORAX

of pulmonary hypertension and respiratory failure in CDHinfants has not been defined despite its widespread use.

SURGICAL MANAGEMENT

Timing of Surgical Repair

Historically, CDH was considered a surgical emergency.Infants were rushed to the operating room as soon as possibleafter birth in the belief that reduction of the abdominal con-tents from the chest would relieve the compression of thelungs. Frequently, after a brief postoperative honeymoonperiod marked by adequate gas exchange, progressive deteri-oration in the infants respiratory status ensued with elevatedpulmonary vascular resistance, right-to-left shunting, hypox-emia, and ultimately death resulting from respiratory failure.

As management techniques for neonatal respiratory failureevolved, a period of medical stabilization and delayed surgicalrepair, in an attempt to improve the overall condition of theinfant with CDH, was proposed.117,180,241249 At the sametime, there was increasing evidence of the potential detrimen-tal effects of early surgical repair on respiratory function.250

Since then, multiple single-institution studies have reportedimproved survival rates with delayed surgery as part of theirtreatment protocols, whereas others have found no changesin overall outcome. Importantly, no study has shown a de-crease in survival rates with this technique. Although delayedsurgical repair is now widely practiced, there is no statisticalevidence that supports this approach over immediate repairat this time.251

The optimal timing of operative repair when using astrategy of delayed repair also remains undetermined. Theperiod of preoperative stabilization has varied from severaldays to several weeks.186,253255 Some authors have reportedwaiting until the infant is successfully weaning off mechanicalventilation and requiring low ventilator settings. Others followthe severity of pulmonary hypertension with serial echocar-diographic examinations and wait until the hypertensionhas abated or at least stabilized.256258

Operative Repair

Most surgeons approach the defect through a subcostal inci-sion, although the repair can be done through a thoracotomyincision as well. For rare cases in which reduction of theherniated contents is difficult because of an abnormallyshaped liver or spleen, a combined approach can be used.259

Both thoracoscopic and laparoscopic techniques have beenused to repair these defects.260265a Although thoracoscopicrepairs have application in stable CDH patients266 and canbe accomplished with primary or prosthetic material closure,a recent report by Gander and colleagues261 suggeststhoracoscopic repair is associated with an unacceptably highrecurrence rate within 1 year after repair.

After division of the abdominal wall muscles and entranceinto the abdominal cavity, the viscera are gently reduced fromthe defect and completely eviscerated for adequate visualiza-tion. The spleen on the left side and the liver on the right areusually the last organs to be mobilized from the chest cavity(Fig. 63-5, A and B). Mobilization can be difficult and mustbe done without injury to either organ. On the right side,the kidney and adrenal gland may be found in the chest as

well. Abnormal drainage of the hepatic veins on either sidemay complicate mobilization of the liver.

Once the abdominal contents are reduced, the defect in thediaphragm in the posterolateral position can be examined. In20% of patients, a hernia sac formed by parietal pleura andperitoneum is present and must be excised to minimizechances of recurrence.16 Usually, there is an anterior rim ofdiaphragm of varying size. The posterior rim of diaphragmmust be searched for in the retroperitoneal tissue, because itmay be rolled up like a window shade by the peritoneum.The peritoneum must be opened over this fold and the dia-phragmatic tissue mobilized. When tissue is adequate, a pri-mary repair with interrupted nonabsorbable suture materialcan be performed (Fig. 63-5, C). In some cases, the posteriorrim of tissue may disappear along the lateral chest wall. Ifenough diaphragmatic tissue exists anteriorly, it can be sutureddirectly to the body wall with sutures placed around the ribs.

If the defect is too large to be closed in a primary fashion, anumber of reconstructive techniques have been describedusing various nearby structures, such as prerenal fascia, ribstructures, and various abdominal wall muscle flaps.267272

If there is any chance that ECMO support might be requiredin the management of the infant, however, the use of complexreconstructive techniques requiring extensive tissue dissec-tion is contraindicated because of the risk of bleeding. Theuse of prosthetic material to complete the diaphragmatic clo-sure has gained widespread acceptance (Fig. 63-5, D). Afloppy, tension-free diaphragmatic repair can be accom-plished, which may lessen the degree of intra-abdominal pres-sure when closing the abdominal wall.273 In addition to therisk of infection, the major drawback to using a prostheticpatch closure is the risk of dislodgment and subsequent reher-niation.274 This complication may be lessened by using acone-shaped patch.275 Complications of prosthetic patchrepair occur in approximately 10% to almost 50% of cases.Patients who develop a recurrent hernia present with bowelobstruction or respiratory distress or may be asymptom-atic.276,277 Recently, the split abdominal wall muscle flaprepair was shown to be safe to use on ECMO and was associ-ated with only one recurrence in 23 patients, with a meanfollow-up of 4.8 years.278

With the loss of intra-abdominal domain, abdominal wallclosure may not be possible at all or may result in unaccept-able intra-abdominal pressure (i.e., abdominal compartmentsyndrome), even after extensively stretching the abdominalwall. In these situations, simple closure of the skin can beaccomplished with repair of the resultant ventral wall defectsome months later. If the skin cannot be closed successfully,temporary closure using prosthetic material, such as a silo,can be used. Biologic closure should then be obtained as soonas safely possible in the postoperative period. Drainage of thechest cavity on the repaired side with a tube thoracostomy isnot indicated except for active bleeding or uncontrolled airleak. It has been proposed that such a tube with even a smalldegree of negative suction may add to the barotrauma andpulmonary hypertension imposed by mechanical ventilationon a hypoplastic lung.254,279 Additional surgical proceduresat the time of the repair, such as correction of the nonrotationas well as appendectomy, are not indicated and should beavoided if ECMO is to be considered.

The repair of recurrent defects can present a formidablesurgical challenge. Since the most common organ involved in

819CHAPTER 63 CONGENITAL DIAPHRAGMATIC HERNIA AND EVENTRATION

recurrent herniation is either the small or large bowel, intestinaladhesions to the disrupted diaphragm or intrathoracic organsmay compromise attempted closure. Repair is most commonlyapproached through the abdomen but can be accomplishedthrough a thoracotomy aswell. If adequate diaphragmatic tissueis present, then primary reapproximation should be attempted.Otherwise, different techniques for prostheticmaterial insertionhave been tried 269,276,280 Because most recurrent CDH occurafter initial patch repair and often well away from the neonatalperiod, once the baby is more stable, repair using a latissimusdorsi muscle flap through a thoracic approach may providethe best means to prevent further recurrence.281

Anesthesia

To avoid the stresses of transport and sudden changes inventilation parameters imposed by a trip to the operating room,a number of centers have adopted the policy of performing

surgical repair of CDH infants in the neonatal intensive careunit. This change in location allows for the lowest degree ofdisruption in the neonates environment. Anesthesia is achie-ved by intravenous narcotic and muscle relaxant techniques.With intravenous anesthetics, the infant ventilator can be usedcontinuously rather than a conventional anesthesia machine.

Postoperative Management

Postoperative management should continue the trends andgoals established before the operative procedure. Ventilatorsupport should be tailored to keep preductal SaO2 greater than90% and PCO2 less than 60 mm Hg.282 Echocardiogramsshould be obtained routinely to assess pulmonary hyperten-sion, shunt flow, and ventricular performance. Therapeuticinterventions discussed previously may be used if respiratorydecompensation develops. Weaning from ventilator supportshould be slow and deliberate as tolerated by the infant.

BA

C DFIGURE 63-5 A, Schematic drawing of an unreduced left congenital diaphragmatic hernia as seen from the abdomen. B, The same hernia but nowreduced, demonstrating that the spleen is usually the last organ to be reduced from the chest cavity. Sutures have been placed for a primary repair.C, Completed primary repair of a left congenital diaphragmatic hernia. D, Repaired left congenital diaphragmatic hernia using prosthetic material.(From Spitz L, Coran AG [eds]: Rob & Smiths Pediatric Surgery. London, Chapman & Hall, 1996.)

820 PART VI THORAX

Meticulous attention to fluid status must be maintained,particularly in the immediate postoperative period. As a resultof surgical intervention, these infants are often hypovolemicand frequently require extra volume administration over time.

EXTRACORPOREAL MEMBRANE

OXYGENATION

Even with recent advances in treatment strategies, overwhelm-ing respiratory failure requiring ECMO support occurs in 10%to 20% of CDH infants.206,283285 Initially, infants were placedon ECMO after developing respiratory failure following theimmediate repair of the diaphragmatic defect. With the evolu-tion of delayed surgical repair, ECMO is now considered a partof the preoperative stabilization process.

Clinical criteria for determining ECMO use in infants withCDH have been based on factors predictive of at least an 80%mortality rate with mechanical ventilation.214 A number ofparameters have been proposed, including the calculationof the oxygenation index (OI) and the alveolararterial oxygendifference AaDO2. For CDH patients, the most common rea-son for the initiation of ECMO was an OI of 40 or greater,and it is often considered for an OI as low as 25.283 Generallyaccepted criteria for initiating ECMO support for neonatalrespiratory failure based on AaDO2 criteria include a valueof 610 or greater despite 8 hours of maximal medical manage-ment. It must be realized that such criteria continue to be in-stitution specific and that no calculations can replace clinicaljudgment and frequent bedside assessment. Failure to im-prove in the setting of severe pulmonary hypertension andprogressive hypoxemia despite maximum medical interven-tion remains a valid qualifying criterion for ECMO support.

Controversy still exists as to whether ECMO supportshould be offered to all infants with CDH and respiratory fail-ure.32,140,286,287 The issue of severe pulmonary hypoplasiaincompatible with life must be kept in mind when ECMO isbeing considered. This intervention is successful when used tosupport an infant with a reversible process of pulmonary hyper-tension. However, it is not a treatment for those infants withirreversible hypoplasia. Differentiating these infants on clinicalparameters can be quite difficult. A newborn with a CDH whois unable to reach a preductal oxygen saturation level of at least90% or a markedly elevated PCO2 level unresponsive to any typeof ventilatory intervention during the pre-ECMO course has ahigh likelihood of having irreversible hypoplasia.179,289 On theother hand, others have proposed that all infants should beECMO candidates. Ultimately the decision to use ECMO is aclinical decision. If the infants tissue oxygen requirements arenot being met, as manifest by end-organ failure, despite bestconventional care, ECMO is a reasonable consideration.

Although widely accepted as a treatment for the respiratoryfailure associated with CDH, the impact of ECMO on improv-ing overall survival continues to be debated. Over the pastdecade, a number of studies have demonstrated improvedsurvival rates in CDH infants with ECMO as part of the treat-ment strategy.283,290,291 However, other institutions haveeither not noted any improvements resulting from ECMO orhave been able to manage their infants without it with equiv-alent success.137,248,292,293,301 Overall survival rates of infantstreated with ECMO vary from 34% to 87% and are clearlydependent on a number of variables, including gestationalage and birth weight, respiratory function, and the degree

of pulmonary development and associated pulmonary hyper-tension.219,256,292,294 The impact of barotrauma and oxygentoxicity from overly aggressive respiratory care strategieson outcome cannot be overemphasized. As conventionaltreatment strategies continue to improve, ECMO use andconcomitant survival rates following ECMO may decrease.

A number of surgical issues are relevant in the managementof CDH infants while on ECMO. Both venovenous andvenoarterial techniques have been reported to be equallyeffective in supporting patients while on bypass.284,295 Withvenovenous bypass, severe right-sided heart failure can bemanaged temporarily with a PGE1 infusion to keep the ductusopen until the pulmonary hypertension resolves or by con-verting to venoarterial support. The timing of the surgicalrepair of the defect in relation to ECMO support remains var-iable. As a result of the acceptance of delayed surgical repair asa treatment strategy, more than 90% of CDH infants requiringECMO support are placed on bypass before undergoingsurgical repair.242 Surgical repair of the defect while on ECMOcan then be accomplished but has been associated with hem-orrhagic complications in 60% of the patients.244,296 Survivalrates after surgery on ECMO have varied from 43% to80%.287,297,298 To minimize the risk of hemorrhagic compli-cations, a number of techniques have been proposed, includ-ing the use of heparin-bonded ECMO circuits, performance ofthe surgical repair just before expected decannulation, and ag-gressive management of the anticoagulant status of the infant,including the use of antifibrinolytic therapy. Because of the co-agulation problems, less than 20% of infants are reportedlyrepaired while on ECMO.299 The majority undergo repairafter the completion of ECMO. This delayed operativeapproach, sometimes not occurring until several days afterdecannulation, has been extremely successful, with survivalrates of almost 80% and higher.258,284,300 However, thereare currently no available studies comparing either pathway.

OUTCOME

Survival rates for infants born with a CDH vary from approx-imately 60% to 90% because of the use of more physiologictreatment strategies, including gentle ventilation techniques,high-frequency ventilation, cardiovascular pharmacologic sup-port, and ECMO.* With the gradual improvement in survivalrates over the past 2 decades, there is a greater appreciationfor issues related to the long-term development of CDH survi-vors and the frequency of associated morbidities, as a greaternumber of physiologically compromised infants are survivingbeyond the neonatal period. It is now recognized that CDHsurvivors are at significant risk for chronic neurologic, develop-mental, gastrointestinal, nutritional, pulmonary, musculoskele-tal, and other disorders. Late deaths have been reported inapproximately 10% of initial survivors, mainly because of theconsequences of persistent pulmonary hypertension or iatro-genic complications.19,39,306,307The requirement for coordinatedlong-term follow-up and care of these patients has becomeevident from studies carried out over the past decade.303,307a,308

Pulmonary issues are the most common long-term prob-lems in the postnatal period and include chronic lung diseaseor bronchopulmonary dysplasia, reactive airway disease,

*References 191, 206, 211, 241, 287, 301305.

821CHAPTER 63 CONGENITAL DIAPHRAGMATIC HERNIA AND EVENTRATION

pulmonary hypertension, and pneumonia. Pulmonary devel-opmental studies have shown that alveolar multiplicationcontinues for several years after birth. However, a normalnumber is never achieved in CDH hypoplastic lungs. Overtime, the alveoli in both lung fields may become emphysema-tous, as the contralateral lung may herniate across the medi-astinum on chest radiographs. Gradual remodeling of thepulmonary vascular bed occurs. However, vascular growthmay not match alveolar growth.309,310 Pulmonary functiontesting remains the most useful test, because ventilation-perfusion studies have been associated with conflictingreports on pulmonary growth.311

Immediately following surgical repair of the hernia and forthe first 6 months of life, abnormalities in pulmonary functionvalues have been reported in suchmeasurements as functionalresidual capacity (FRC), compliance (C), airway resistance(R), and maximum expiratory flow rate at FRC.151,312,313

Significant improvements in lung function become evidentduring the first year of life, with only mild abnormalities insubsequent tests noted after 2 years of age, indicating that lungfunction does improve over time. These improvements in lungfunction parameters, such as compliance and airway resis-tance, correlate with the growth of the infant, and any com-promise of the nutritional status of a CDH infant shouldraise concern about lung growth and development.19 Chroniclung disease has been reported in CDH survivors, particularlyin those requiring ECMO support.314,315Whether this findingis related to the pathology of the disease or has been inducediatrogenically resulting from techniques of ventilation isunclear.250 Treatment strategies for these patients haveincluded the use of supplemental oxygen, bronchodilatortherapy, corticosteroids, diuretics, and appropriate immuniza-tions. Prolonged ventilator support and tracheostomy may berequired in a small percentage of patients.316

In long-term studies of pulmonary function in survivors,many adolescents and adults have been found to have nearlynormal exercise capacity and cardiorespiratory response toexertion.151,315,317321 Abnormalities in such parameters asforced expiratory volume in 1 second (FEV1), forced vitalcapacity (FVC), and maximum midexpiratory flow and peakexpiratory flow rates indicate that obstructive and restrictiveventilatory impairments are present in up to 50% of sur-vivors.311,318,320,322 The functional consequences of theseflow abnormalities are reportedly minimal.

The risk of pneumonia in CDH survivors, particularly ininfancy and early childhood, is significant and has beenreported in up to 35% of patients by the age of 12. Viralbronchiolitis, particularly with respiratory syncytial virus(RSV), is a concern in the first 3 years of life.151,323

Although it is known that patients with congenital heartdisease and CDH have a poor prognosis, the long-term con-sequences of structural cardiac abnormalities in survivorsare unknown. Although the frequency of cardiovascularmalformations ranges from 11% to 17% and includes majorstructural defects, such as atrial and ventricular defects, con-otruncal defects, and left ventricular outflow tract obstructivedefects, the risk of death in these patients can be as high as3 times that for patients with CDH alone.48,324 Prolongedelevation in pulmonary artery pressure, whether it resultsfrom pulmonary hypoplasia, bronchopulmonary dysplasia,or structural cardiac disease, impacts survival, and late deathshave been associated with persistent pulmonary hypertension.

Pulmonary artery pressures determined by echocardiographynormalize in approximately 50% of all patients with CDH by3 weeks of age but can remain elevated for months in up toone third of surviving infants.256,307,325

A high incidence of neurodevelopmental abnormalitieshave been detected in CDH survivors. Developmental delayhas been reported in a number of surviving infants as wellas abnormalities in motor and cognitive skills.314,326 Bothmotor and language problems are evident within the first3 years of life, and infants with motor problems detected atage 1 year were more likely to have abnormal postnatal neu-roimaging studies.327329 Progressive sensorineural hearingloss has been demonstrated in up to 50% or more of CDHsurvivors with no discernable etiology. Its onset appears tobe within the first 2 years of life, but late onset deficits inpatients with previously normal audiology tests have beenreported.62,330 It is a progressive abnormality and requires fre-quent audiology follow-up. Aggressive use of aminoglycosideantibiotics and furosemide diuretics may be part of the etiol-ogy. Other neurologic findings reported in CDH survivorsinclude visual disturbances, seizures, and abnormal com-puted tomography (CT) and MRI studies.314,331 Most studieshave implicated ECMO as a factor in these neurologic prob-lems, but infants treated without ECMO are also at risk.332334

CDH survivors have a high incidence of gastrointestinalconditions, of which gastroesophageal reflux is the mostsignificant (Fig. 63-6).52,314,335,336 The condition may occurin as many as 80% of patients after CDH repair and in60% of long-term survivors.337 Infants requiring patch clo-sure of the defect, having an intrathoracic position of thestomach at the time of repair, or requiring ECMO supportare at higher risk for developing symptomatic reflux.52,336a338

Antireflux surgery for severe disease is required in 15% to35% of cases. Nutritional and growth-related problems havebeen found in a significant number of survivors.92,339,340

Aggressive nutritional management using gastrostomy feedingsmay be required.303

A number of skeletal disorders have been reported, inclu-ding chest wall deformities and scoliosis.341,342 Chest wall

FIGURE 63-6 Barium sulfate esophagogram in an infant with a left con-genital diaphragmatic hernia demonstrating a dilated, ectatic esophagus.The stomach was oriented vertically and emptied slowly.

822 PART VI THORAX

deformities have been associated with patch repair of the de-fect. Most defects are minor, and treatment of these problemshas included initial attempts at bracing followed by surgicalcorrection if progressive.

Recurrent diaphragmatic hernia and small bowel obstruc-tion are the dominant surgical challenges following initialrepair. Recurrent hernias may occur in up to 50% of infantsundergoing patch repair of the defect and in 10% of primaryrepairs, and they tend to occur in the first 4 years of life.342344

A small bowel obstruction may occur in a small percentage ofpatients and may be related to adhesions, reherniation, or,rarely, a volvulus. Chylothorax can also occur after bothprimary and patch closure and may require surgical interven-tion if conservative management is unsuccessful.65

There is a growing realization that infants with a right-sideddiaphragmatic defect may present with management chal-lenges and outcomes different from those with left-sideddefects. Herniation of the liver into the right chest can be asurgical challenge in diaphragmatic repair, and cases of hepa-topulmonary fusion have been reported.345347 Infants withright-sided defects may have a higher requirement for patchrepair of the diaphragm as well as for ECMO support.348,349

Over the last decade, it has become clear that CDH survivorspresent many complex management challenges and requirelifelong medical surveillance and follow-up. Comprehensivemultispecialty clinics that provide specialty physician andsupport services, along with evidence-based guidelines, areimportant in advancing the care of these patients.307a,342

FUTURE THERAPIES

Despite the advancements that have been made in treating in-fants with CDH, it still represents a frustrating and complexclinical problem. As the striking variance in survival ratesattests, no currently used therapeutic intervention or manage-ment strategy has emerged for widespread successful applica-tion. Even with the increasing success of current treatmentstrategies, such as permissive hypercapnia, delayed operativerepair, antihypertensive pharmacology, and advanced venti-latory techniques, a cohort of infants refractory to these inter-ventions continue to be candidates for novel treatments.

Fetal intervention in the management of CDH remainshighly controversial. The concept of fetal surgical interventionevolved from the experimental observations in lambs that thereduction of compressive forces on the lung resulted in con-tinued pulmonary growth and development.91,98,101,194,350

With the development of fetal surgical techniques, initialstudies attempted direct surgical repair of the defect withreduction of the herniated contents.351,352 When no clinicaladvantage in survival was demonstrated, this approach wasterminated. Experimental evidence for the important role oflung fluid dynamics in fetal lung dev