Chapter2C Pathology: Embryologic Abnormalities

Content and Objectives

Pulmonary Sequestration 2C-3

Chest X-ray Findings in Arteriovenous Malformation of the Great of Galen 2C-7

Situs Inversus Totalis 2C-10

Congenital Cystic Adenomatoid Malformation of the Lung 2C-14

VATER Association 2C-20

Extralobar Sequestration with Congenital : A Complicated Case Study 2C-24

Congenital Chylothorax: A Case Study 2C-37

Continuing Nursing Education Test CNE-1 Objectives: 1. Explain how the diagnosis of is made. 2. Discuss the types of imaging studies used to diagnose AVM of the great vein of Galen. 3. Describe how imaging studies are used to treat AVM. 4. Explain how situs inversus totalis is diagnosed. 5. Discuss the differential diagnosis of congenital cystic adenomatoid malformation. (continued)

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-1 6. Describe the diagnosis work-up for VATER association. 7. Explain the three classifications of pulmonary sequestration. 8. Discuss the diagnostic procedures for congenital chylothorax.

2C-2 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics Chapter2C Lung Pathology: Embryologic Abnormalities

Editor Carol Trotter, PhD, RN, NNP-BC

Pulmonary Sequestration pulmonary sequestrations is cited as the 1902 theory of Eppinger and Schauenstein.4 The two postulated an accessory he clinician frequently cares for infants who present foregut tracheobronchia budding distal to the normal buds, Twith respiratory distress and/or abnormal chest x-ray with caudal migration giving rise to the sequestered tissue. The findings of undetermined etiology. One of the essential com- type of sequestration, intralobar or extralobar, would depend ponents in the process of patient evaluation is consideration on the timing of the accessory foregut budding (Figure 2C-1). of differential diagnosis with correlation to radiologic find- Early gestational development of an accessory bud would ings and clinical presentation. Sequestrations are estimated result in development of the anomalous tissue in the intralobar to account for 0.15–1.7 percent of all congenital pulmonary area, with resultant intralobar sequestration. Later embryonic malformations.1 Although rare, often asymptomatic, and fre- development would allow the separation of normal lung tissue quently not presenting in the neonatal period, pulmonary and pleura, resulting in extralobar sequestration.6 sequestrations or bronchovascular foregut malformation Foregut connections are not present in the majority of anomalies (with or without respiratory distress) can result in cases. Because nonpatent stalks and esophageal diverticulae abnormal radiographic findings and should be considered in have been observed between the foregut and the sequestra- the differential diagnosis. tion, the absence of these connections could be postulated to be a result of an involution of the original foregut connection.6 DEFINITION Vascular supply is thought to occur from the persistence of A pulmonary sequestration is a mass of abnormal pulmo- portions of intercommunicating capillary networks that supply nary tissue that does not have normal bronchial communica- the early tracheal bud from the sixth aortic arch (pulmonary tion with the tracheobronchial tree and that receives its blood artery) and the fourth arch (). The anomalous lung tissue supply from anomalous systemic arteries rather than from the and its persistent vessels descend with the celiac axis to supply pulmonary artery. Venous drainage can be into systemic or the lung from the thoracic aorta or from the aorta below the dia- pulmonary .2,3 Traditionally, a sequestration that has phragm.6 Pathologically, the sequestered lung tissue is embry- its own separate pleural investment is called extralobar. It is onic and profusely cystic. It contains disorganized, airless alveoli, called intralobar if it is located within the normal lung without bronchi, cartilage, and respiratory epithelium. On x-ray, seques- a separate pleural covering. Because the lesion is so variable trations usually appear as medially located, triangular or oval- and gastroenteric connections may exist, it has been sug- shaped lung masses. The mass may appear cystic and similar to gested that the term bronchovascular foregut malformation be other forms of congenital cystic lung , such as congenital used.4,5 However, the intra-extralobar terminology remains in adenomatoid malformation. The diagnosis is confirmed by doc- common use and will be used in this article. umenting the anomalous blood supply through aortography, ultrasonography, or contrast CT scanning. Other radiographic EMBRYOLOGY findings may include , atelectasis of normal lung The theory of embryogenesis that best explains the pul- tissue, or displacement of mediastinal structures due to the mass monary, vascular, and foregut anomalies associated with effect of the sequestration.5

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-3 FIGURE 2C-1 n Drawings illustrating successive stages in the development of the bronchi and .

From: Moore KL, and Persaud TVN. 2008. Before We Are Born: Essentials of Embryology and Birth Defects, 8th ed. Philadelphia: Saunders, 203. Reprinted by permission.

CLASSIFICATION OF SEQUESTRATIONS anomalies—such as tracheoesophageal fistula, congenital Sequestrations have been classified as intralobar, extralobar heart disease, and diaphragmatic hernia—are more common. (accessory lobe), or Scimitar syndrome. Differentiating char- Communications with the , bronchi, stomach, and acteristics of these three types of sequestrations are presented small bowel have been reported but are rare. Most extralobar in Table 2C-1. sequestrations are diagnosed at an earlier age than are intralo- Intralobar sequestration (Figure 2C-2) is anomalous lung bar sequestrations.8,9 tissue located within normal lung tissue and visceral pleura Scimitar syndrome (Figure 2C-3) is an anomaly of the and is most commonly located in the posterior basal segments entire right lung in which the lung may have only two lobes of the lower lobe, slightly more often on the left.7 Rarely, it and is hypoplastic. The anomalous pulmonary vein drains can be located in upper lobes or bilaterally. It is the most into the inferior vena cava. There may be an associated dex- common type of sequestration occurring 75 percent of the trocardia or congenital cardiac anomalies.8,10 time.7 The clinical presentation may be recurrent or other chronic respiratory problems, such as abscesses of the CASE STUDY affected lobe. Therefore, intralobar sequestrations are more A full-term 3.31 kg male was delivered by cesarean section frequently diagnosed after the neonatal period.5 Associated to a 34-year-old gravida 5, para 3, ab 1 mother. The delivery anomalies are less frequent with intralobar than with extralo- was uncomplicated, and the infant received Apgar scores of bar sequestrations.1 8 and 9 at one minute and five minutes. The was Extralobar sequestration (see Figure 2C-2) is less common complicated by iron-deficiency , a urinary tract infec- than intralobar, with a male predominance. The sequestration tion during the first trimester, and during can be located above or below the diaphragm, and, unlike the third trimester. During the pregnancy, an ultrasound of with an intralobar sequestration, the anomalous lung tissue the revealed a possible abdominal mass. Subsequent pre- is outside the visceral pleura and receives its blood supply natal magnetic resonance imaging of the fetus confirmed the from the aorta, usually below the diaphragm. Associated

2C-4 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics TABLE 2C-1 n Classification of Pulmonary Sequestrations Extralobar (Accessory Lobe) Intralobar Scimitar Sequestration Sequestration Syndrome Frequency Rare; four times more common in males Six times more common than extralobar; slight male predominance Age at diagnosis Approximately 60% <1 year 50% >20 years Infancy Parenchyma Separated from remainder of lung by Two types: (1) absence of major Hypoplasia of right lung often pleural investment ; (2) bronchial tree and associated with bronchial lung complete; sequestration of anomalies (aplasia, hypoplasia, superfluous portion of lung stenosis) Vascular: Arterial From aorta—usually from below From descending aorta, above or May have hypoplastic right diaphragm below diaphragm, as one or pulmonary artery, anomalous several arteries, occasionally from subdiaphragmatic arterial supply intercostal or innominate artery to right lower lobe Venous Systemic (drainage into hemizygous, Drainage toward pulmonary veins, Anomalous pulmonary venous azygous veins) or portal system rarely into systemic veins drainage of right lung to vena cava (left-toright shunt) causing curved vascular shadow in right lower lung field Location In left costodiaphragmatic sinus or below Two-thirds left; rare bilateral; dorsal Right lung diaphragm segment of lower lobes; rarely upper lobes or lingula Diaphragmatic defect 60% Rare Associated anomalies Frequent, including tracheoesophageal Occasional cystic change or Dextroposition of heart with or and gastric fistulas, tracheal anomalies, sequestered portion of lung; other without congenital cardiac ectopic gut, diaphragmatic hernia and anomalies and malformations anomalies, hemivertebrae other diaphragmatic malformations, similar but much less frequent is associated with cases of pericardial cysts, vertebral anomalies, than in extralobar hypoplasia or aplasia of right lung anomalous pulmonary venous return, congenital heart disease Adapted from: Platzker AGG. 1979. Congenital anomalies causing respiratory failure. In Neonatal Pulmonary Care, Thiebeault D, and Gregory C, eds. Menlo Park, California: Addison-Wesley, 398. Permission conveyed through Copyright Clearance Center, Inc.

mass, which was felt to be consistent with possible neuroblas- Rotation is not present. The spine and clavicles are straight, toma. A nonstress test was reactive. with the ribs of equal length on either side of the spine. The infant required free-flow oxygen and continuous posi- The soft tissues of the neck and chest are of normal thickness. tive airway pressure by face mask for grunting and retracting The bony framework is intact, with 12 ribs bilaterally and in the delivery room. He was admitted to the NICU under normal vertebrae. hood oxygen but weaned to room air at approximately six The tracheal air column is straight, with bifurcation at the hours of age. His clinical respiratory course was consistent fourth thoracic vertebra. with transient tachypnea of the newborn (TTN). The hilum appears normal, the thymus is not visible, and the The infant’s admission physical examination revealed heart is of normal configuration, although a mass overlies the minimal retractions, with a respiratory rate of 60 per minute. lower cardiac silhouette. The chest was symmetrical, no masses could be palpated in The diaphragm is between T8 and T9 on the right and at the abdomen, and the examination was otherwise unremark- T9 on the left. able. The admission CBC and other laboratory values were The pleurae reach the edges of the bony , and the cos- within normal limits. Figure 2C-4 shows the first x-ray for tophrenic angles are sharp and clear. this patient. The intercostal spaces are normal in size. The lung fieldsare clear. X-Ray Evaluation Gastric air is present on the left and throughout portions of Indication for the x-ray was respiratory distress. the intestinal tract. Penetration: the x-ray appears to be slightly overpene- A large mass, measuring approximately 4.5 cm by 6.5 cm, trated because the soft tissues of the extremities are not well overlies the lower cardiac silhouette at the level of the 7th visualized. thoracic vertebra and extends to the 11th thoracic vertebra.

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-5 R ADIOLOGY BASICS R ADIOLOGY BASICS FIGURE 4 I Admission chest x-ray. Note the large mass overlying the FIGURE 5 I Angiogram demonstrating arterial blood supply to the FIGURE 2C-2 n Intralobar and extralobar sequestrations. FIGURE 2C-4lower n Admission cardiac shadow chest x-ray. and extending Note the largeinto the mass abdominal pulmonary sequestration at the level of T9 (feeding I I FIGURE 2 Intralobar and extralobar sequestrations. A sequestered FIGURE 3 Scimitarcavity. overlyingsyndrome. theThe lowerhypoplastic cardiac right shadow lung may and have artery). The celiac artery and the superior mesenteric A sequesteredsegment segment of of lobe lobe has has no no bronchial bronchial communication communication with only two lobes. The pulmonary veins of the lower lobes, extending into the abdominal cavity. artery are also identified. with the trachea.the trachea. Arterial Arterial blood bloodsupply supply is from is fromthe aorta the aorta or other or and occasionally the upper lobe, unite to drain into the systemic vessel.other systemic vessel. inferior vena cava (IVC). The large vessel can join the IVC at its junction with the right or descend to join the infradiaphragmatic vena cava.

CLINICALminimal retractions, COURSE with a ANDrespiratory DIAGNOSTIC rate of 60 per minute. From:From: Luck Luck SR,SR, Reynolds M, M, and and Raffensperger Raffensperger J. 1986. J. 1986. Congenital Congenital bron- WORKUP bronchopulmonary malformations. Current Problems in Surgery The chest was symmetrical, no masses could be palpated in the chopulmonary malformations. Current Problems in Surgery 23(4): 260. The infant underwent a bone marrow aspirate analysis, 23(4):Reprinted 260. by Reprinted permission. with permission from Elsevier. abdomen, and the examination was otherwise unremarkable. ADIOLOGY BASIC From:which Luck SR,was Reynolds negative M, and for Raffensperger tumor cells, J. 1986. making Congenital the bron-diagnosis of R S chopulmonaryThe admission malformations. CBC and Current other Problems laboratory in Surgery values23(4): 300.were within FIGURE 2C-3 n Scimitar syndrome. Reprintedneuroblastoma by permission. unlikely. Further evaluation on day 2 of life Intralobar sequestration (Figure 2) is anomalous lung tis- normal limits. Figure 4 shows the first x-ray for this patient. FIGURE 2 I Intralobar and extralobar sequestrations. A sequestered FIGURE 3 I Scimitar syndrome. The hypoplastic right lung may have included a computerized axial tomography (CAT) scan of the The hypoplastic right lung may have only two lobes. The pulmonary segment of lobe has no bronchial communication with sue located withinonly two normal lobes. The lung pulmonary tissue andveins visceral of the lower pleura lobes, and hypoplastic.chest, abdomen, The anomalous and pelvis, pulmonary which revealed vein drains a large into thoracoab the - the trachea. Arterial blood supply is from the aorta or isveins most of commonly the lowerand occasionally lobes, located and inthe occasionally the upper left lobe, lower the unite upperlobe. to drain Rarely,lobe, into unite the it can inferiorX-Ray vena Evaluation cava. There may be an associated or to drain into the inferior vena cava (IVC). The large vessel can join dominal tumor. other systemic vessel. be located ininferior upper vena lobes cava or (IVC). bilaterally. The large Itvessel is thecan joinmost the com- congenitalIndication cardiac for anomalies. the x-ray 6,8was respiratory distress. the IVC at its junctionIVC at its junctionwith the with right the atrium right atrium or descend or descend to join to the 6 The infant was intubated and underwent a left thoracot- moninfradiaphragmatic type of joinsequestration. the vena infradiaphragmatic cava.The clinical vena cava.presentation may be Penetration: the x-ray appears to be slightly overpenetrated recurrent pneumonias or other chronic respiratory problems, CASEomybecause PRESENTATIONand transdiaphragmatic the soft tissues of biopsy the extremities of the mass. are Pathology not well such as abscesses of the affected lobe. Therefore, intralobar ofA full-termthevisualized. tissue 3.31 revealed kg male a hamartoma,was delivered which by cesarean is a tumor section or mass of tissue resulting from failure of embryologic development. sequestrations are more frequently diagnosed after the neona- to Rotationa 34-year-old is notgravida present. 5, para The 3, abspine 1 mother. and clavicles The delivery are straight, A large mass, measuring approximately 4.5 cm by 6.5 cm, 5 tal period. Associated anomalies are less frequent with wasThis uncomplicated,with is consistentthe ribs ofand equalwith the ainfantlength diagnosis received on either of Apgarpulmonary side scores of the ofsequestra spine. 8 - overlies the lower cardiac silhouette at the level of the 7th 1 tion. Following the , further radiographic evalu- intralobar than with extralobar sequestrations. andThe 9 at soft one tissues minute of andthe neckfive minutes. and chest The are pregnancyof normal thickness.was thoracic vertebra and extends to the 11th thoracic vertebra. Extralobar sequestration (Figure 2) is less common than complicatedation included by iron-deficiency digitalized angiographyanemia, a urinary (Figure tract 2C-5), infec- which The bony framework is intact, with 12 ribs bilaterally and intralobar, with a male predominance. The sequestration can tion during the first trimester, and oligohydramnios during showednormal a feedingvertebrae. artery to the hamartoma/sequestration at Clinical Course and Diagnostic Workup be located above or below the diaphragm, and, unlike with an thethe third level trimester. of T9. During the pregnancy, an ultrasound of intralobar sequestration, the anomalous lung tissue is outside theThe fetus tracheal revealed aair possible column abdominal is straight, mass. with Subsequent bifurcation pre- at the The infant underwent a bone marrow aspirate analysis, Ultrasoundfourth thoracic of the vertebra. mass showed the aorta to be posterior to which was negative for tumor cells, making the diagnosis of the visceral pleura and receives its blood supply from the natalthe magnetic mass and resonance the inferior imaging vena of cava the to fetus be displacedconfirmed anteriorly.the aorta, usually below the diaphragm. Associated anomalies— mass,The which hilum was appears felt to benormal, consistent the withthymus possible is not neuroblas- visible, and the neuroblastoma unlikely. Further evaluation on day 2 of life Venousheart drainage is of normal of the configuration, mass was not although identified. a mass Fluoroscopy overlies included a computerized axial tomography (CAT) scan of the such as tracheoesophageal fistula, congenital heart disease, toma.of the A nonstress diaphragm test showedwas reactive. normal movement of the right dia- and diaphragmatic hernia—are more common. Commun- Thethe infant lower required cardiac free-flow silhouette. oxygen and continuous posi- chest, abdomen, and pelvis, which revealed a large thoraco- phragm but poor movement of the left diaphragm. ications with the trachea, bronchi, stomach, and small bowel tiveThe airway diaphragm pressure byis betweenface mask T8 for and grunting T9 on and the retracting right and at T9 abdominal tumor. have been reported but are rare. Most extralobar sequestra- in theAnon delivery theesophagram left. room. He and was upper admitted gastrointestinal to the NICU study under showed The infant was intubated and underwent a left thoracoto- displacement of the esophagus anteriorly by the mass, without tions are diagnosed at an earlier age than are intralobar hoodThe oxygen pleurae but reach weaned the to edges room ofair theat approximately bony thorax, six and the my and transdiaphragmatic biopsy of the mass. Pathology of sequestrations.6,7 hoursanomalies, costophrenicof age. fistulas,His clinical angles or respiratoryareconnections sharp and course betweenclear. was theconsistent esophagus or the tissue revealed a hamartoma, which is a tumor or mass of other gastrointestinal structures and the mass. Scimitar syndrome (Figure 3) is an anomaly of the entire withThe transient intercostal tachypnea spaces of theare newbornnormal in(TTN). size. tissue resulting from failure of embryologic development. right lung in which the lung may have only two lobes and is The lunginfant’s fields admission are clear. physical examination revealed This is consistent with a diagnosis of pulmonary sequestra- From: Luck SR, Reynolds M, and Raffensperger J. 1986. Congenital bron- IMPRESSION/DIAGNOSIS chopulmonary malformations. Current Problems in Surgery 23(4): 260. Gastric air is present on the left and throughout portions of tion. Following the thoracotomy, further radiographic evalua- Reprinted by permission. The infant’s initial respiratory course was consistent From:From: Luck Luck SR, SR, Reynolds Reynolds M, andand Raffensperger Raffensperger J. 1986. J. 1986. Congenital Congenital bron- the intestinal tract. tion included digitalized angiography (Figure 5), which bronchopulmonarychopulmonary malformations. malformations. Current ProblemsCurrent inProblems Surgery 23(4): in Surgery 300. with transient tachypnea of the newborn and not thought Reprinted by permission. EONATAL ETWORK Intralobar sequestration (Figure 2) is anomalous lung tis- 23(4): 300. Reprinted with permission from Elsevier.N N to be secondary to his congenital pulmonary malformation. 70 sue located within normal lung tissue and visceral pleura and hypoplastic. The anomalous pulmonary vein drains into the is most commonly located in the left lower lobe. Rarely, it can inferior vena cava. There may be an associated dextrocardia or EONATAL ETWORK be located in upper lobes or bilaterally. It is the most com- congenital cardiac anomalies.6,8 N N 71 mon type of sequestration.6 The clinical presentation may be2C-6 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics recurrent pneumonias or other chronic respiratory problems, CASE PRESENTATION such as abscesses of the affected lobe. Therefore, intralobar A full-term 3.31 kg male was delivered by cesarean section sequestrations are more frequently diagnosed after the neona- to a 34-year-old gravida 5, para 3, ab 1 mother. The delivery tal period.5 Associated anomalies are less frequent with was uncomplicated, and the infant received Apgar scores of 8 intralobar than with extralobar sequestrations.1 and 9 at one minute and five minutes. The pregnancy was Extralobar sequestration (Figure 2) is less common than complicated by iron-deficiency anemia, a urinary tract infec- intralobar, with a male predominance. The sequestration can tion during the first trimester, and oligohydramnios during be located above or below the diaphragm, and, unlike with an the third trimester. During the pregnancy, an ultrasound of intralobar sequestration, the anomalous lung tissue is outside the fetus revealed a possible abdominal mass. Subsequent pre- the visceral pleura and receives its blood supply from the natal magnetic resonance imaging of the fetus confirmed the aorta, usually below the diaphragm. Associated anomalies— mass, which was felt to be consistent with possible neuroblas- such as tracheoesophageal fistula, congenital heart disease, toma. A nonstress test was reactive. and diaphragmatic hernia—are more common. Commun- The infant required free-flow oxygen and continuous posi- ications with the trachea, bronchi, stomach, and small bowel tive airway pressure by face mask for grunting and retracting have been reported but are rare. Most extralobar sequestra- in the delivery room. He was admitted to the NICU under tions are diagnosed at an earlier age than are intralobar hood oxygen but weaned to room air at approximately six sequestrations.6,7 hours of age. His clinical respiratory course was consistent Scimitar syndrome (Figure 3) is an anomaly of the entire with transient tachypnea of the newborn (TTN). right lung in which the lung may have only two lobes and is The infant’s admission physical examination revealed

N EONATAL N ETWORK 70 R ADIOLOGY BASICS

FIGURE 4 I Admission chest x-ray. Note the large mass overlying the FIGURE 5 I Angiogram demonstrating arterial blood supply to the lower cardiac shadow and extending into the abdominal FIGURE 2C-5pulmonary n Angiogram sequestration demonstrating at the levelarterial of T9blood (feeding supply cavity. artery).to the The pulmonary celiac artery sequestration and the superior at the mesenteric level of Chest X-Ray Findings in arteryT9 are(feeding also identified. artery). The celiac artery and the superior mesenteric artery are also identified. Arteriovenous Malformation of the Great Vein of Galen

he most common neonatal intracranial arteriovenous Tmalformation (AVM) is an aneurysm of the vein of Galen.11 This aneurysm presents in the immediate neona- tal period in 90 percent of cases and predominantly affects males.12 The primary abnormality consists of multiple arterial feeding vessels joined via a nidus (central nucleus) to drain- ing veins. The arterial vessels vary in structure from normally differentiated arteries to primitive vessels. Histology reveals arterial vessels that are dysplastic, dilated, and tortuous, with hyperplastic and disorganized smooth muscle fibers. The internal elastic lamina of these vessels is fragmented or absent. The veins are dysplastic with anomalous veinlike channels; reactive muscular hyperplasia; and degenerative changes of fibrosis, atrophy, thrombi, and calcification.13 Hemodynamically, there is short-circuiting of the blood from artery to vein, leading to a cerebrovascular steal and minimal retractions, with a respiratory rate of 60 per minute. a volume-overloaded systemic circulation. The typically The chest was symmetrical, no masses could be palpated in the high flow of these malformations results in marked dilation abdomen, and the examination was otherwise unremarkable. of the feeding arteries and draining veins.13 In some cases, The admission CBC and other laboratory values were within venous outflow obstruction occurs, and the proximal drain- normal limits. Figure 4 shows the first x-ray for this patient. ing veins dilate massively. Extremely large aneurysms act like an intracranial-mass lesion and can obstruct the aqueduct X-Ray Evaluation of Sylvius, causing hydrocephalus. Brain parenchyma can Indication for the x-ray was respiratory distress. become necrotic from ischemia, and hemorrhagic infarction Penetration: the x-ray appears to be slightly overpenetrated can occur as a result of thrombosis within the malformation. because the soft tissues of the extremities are not well During fetal life, the systemic AVM is in a parallel circula- visualized. tion with the low-resistance placenta, and flow through the Rotation is not present. The spine and clavicles are straight, A large mass, measuring approximately 4.5 cm by 6.5 cm, fistula is small. However, the fetal cardiovascular circulation with the ribs of equal length on either side of the spine. Followingoverlies thethe lowerdiagnostic cardiac evaluation silhouette ofat theradiographs, level of the bone 7th may still be affected in utero, as evidenced by cardiomegaly; The soft tissues of the neck and chest are of normal thickness. marrowthoracic aspiration, vertebra andaortogram, extends toand the biopsy, 11th thoracic the diagnosis vertebra. of cardiac hypertrophy; and cerebral pathology such as hemor- The bony framework is intact, with 12 ribs bilaterally and extralobar pulmonary sequestration was confirmed. rhage, leukomalacia, and cortical necrosis in neonates who normal vertebrae. Clinical Course and Diagnostic Workup die soon after birth.14 The tracheal air column is straight, with bifurcation at the TREATMENTThe infant underwent AND OUTCOME a bone marrow aspirate analysis, Following birth, hemodynamic abnormalities resulting fourth thoracic vertebra. whichResection was negative of the tumorfor tumor was delayedcells, making secondary the diagnosisto a wound of from the arteriovenous shunting include lowered systemic The hilum appears normal, the thymus is not visible, and the infectionneuroblastoma at the unlikely.thoracotomy Further incision evaluation site. During on day antibiotic 2 of life vascular resistance. Compensatory increases in stroke volume, heart is of normal configuration, although a mass overlies therapyincluded for a computerizedthe wound , axial tomography the infant required(CAT) scan reintuba of the- heart rate, and blood volume lead to an increase in cardiac the lower cardiac silhouette. tionchest, for abdomen, persistent and left lungpelvis, atelectasis which revealed and deteriorating a large thoraco- respi- output and eventual high-output . The increased The diaphragm is between T8 and T9 on the right and at T9 ratoryabdominal status. tumor. stroke volume and decreased peripheral vascular resistance on the left. OnThe dayinfant 16 was of life,intubated the infant and underwentreturned to a leftthe thoracoto-operating produce a widened pulse pressure.13 Pulmonary artery pres- The pleurae reach the edges of the bony thorax, and the roommy and for transdiaphragmatic the successful removal biopsy ofof thethe sequesteredmass. Pathology tissue, of sure increases to systemic or near-systemic levels as a result of costophrenic angles are sharp and clear. withthe tissue chest revealed tube placement. a hamartoma, He whichwas successfully is a tumor orextubated mass of increased pulmonary blood flow from the malformation and The intercostal spaces are normal in size. fourtissue days resulting postoperatively from failure and ofwas embryologic discharged todevelopment. his parents the normally high pulmonary vascular resistance at birth. The The lung fields are clear. atThis 29 isdays consistent of age. with a diagnosis of pulmonary sequestra- right ventricle ejects an increased volume of blood against Gastric air is present on the left and throughout portions of tion. Following the thoracotomy, further radiographic evalua- high pulmonary artery pressure. A right-to-left shunt occurs Revised and updated from: Salmons S. 1995. Pulmonary sequestration. across the ductus arteriosus and foramen ovale as a result of the intestinal tract. Neonataltion included Network 14(6):digitalized 69–73. Usedangiography with permission (Figure of Springer 5), which Publishing Company, LLC, www.springerpub.com/nn. high pulmonary artery pressure and lower systemic vascular resistance.11,15

N EONATAL N ETWORK 71 Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-7 TABLE 2C-2 n Chest X-Ray Findings in Arteriovenous FIGURE 2C-6 n Chest x-ray of a term neonate presenting with Malformation of the Great Vein of Galen cardiomegaly. See “Chext X-Ray Evaluation” for discussion of findings. • Cardiomegaly, with more prominent right atrial and right ventricular enlargement • Widening of the superior mediastinum • Anterior displacement of the upper airway and pharynx • Posterior displacement of the intrathoracic portion of the trachea Adapted from: Swischuck LE. 2004. Imaging of the Newborn Infant and Young Child, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 1058–1061.

The initial response of high output heart failure is fol- lowed by volume overload, decompensation, and low-output failure. A large volume of blood shunting through the aneu- rysm commonly leads to congestive heart failure secondary to high-output failure in the early neonatal period. Frequently, cardiac findings are so acute that a cardiac disorder is the usual primary presumed diagnosis. Clinical features can include cyanosis from right-to-left shunting through the ductus and/or foramen ovale and decreased peripheral perfusion. A wide pulse pressure is present. The heart is hyperdynamic. Upon auscultation, a split second heart sound; a louder-than-normal second heart normal; the thoracic portion of the trachea appears more pos- sound from pulmonary valve closure; and in some cases, if terior, whereas the upper airway and pharynx have a more marked failure is present, a third and a fourth heart sound anterior displacement. These changes occur secondary to the may be heard. Systolic murmurs resulting from tricuspid large dilated brachiocephalic vessels pushing the intratho- regurgitation or increased flow through the valves may be racic portion of the trachea back and the upper airway and present. Arteries proximal to the malformation experience pharynx forward. Less commonly, the chest x-ray presenta- increased pulsations and those distal, decreased pulsations, tion is that of cardiomegaly with slightly decreased pulmo- leading to increased carotid pulsations and decreased femoral nary vasculature. It has been theorized that this presentation pulses. Murmurs may be auscultated over the area of the mal- occurs as a result of normal hemodynamic changes in the formation as a result of flow turbulence in the area, and bruits immediate postnatal period: increased pulmonary vascular may be auscultated. Hepatomegaly occurs as congestive heart resistance and a right-to-left shunt through the patent ductus failure evolves.15,16 arteriosus and foramen ovale causing excess pulmonary blood A more rapid diagnosis can be made if the presence of flow and pulmonary vascular changes leading to pulmonary a continuous cranial bruit, usually found over the poste- hypertension.18 rior cranium, is detected early. Once fulminant congestive Echocardiography shows normal cardiac structure, heart failure occurs, a decrease in cervical venous pulsations enlargement of the right atrium and ventricle, or four-cham- and a less audible bruit result.17 Typically, the first diagnos- ber cardiomegaly.15 A right-to-left shunt may be seen at the tic impression is ductal dependent congenital heart disease ductal or atrial levels. Detection of dilation of the descending with high-output cardiac failure. Coarctation of the aorta is aorta and superior vena cava in subxiphoid and suprasternal often considered because of the difference between the pulses views can strongly suggest the diagnosis of cerebral AVM.13 and the rapid onset of cardiac failure. A positive response to A diastolic reversal of blood flow on the transverse aortic prostaglandin E1 had been reported in two cases of neonates arch may be seen in some cases, aiding diagnosis. Diagnostic with AVM, a response that may further delay accurate diag- considerations should include causes of cardiomegaly with a nosis. Right-to-left shunting at the ductal and atrial levels, structurally normal heart. evidenced by a PaO2 gradient of 10 torr, may also prompt the Early detection provides the neonate with the best chance diagnosis of pulmonary hypertension.15 for effective treatment and intact survival. Ultrasound, mag- The usual chest x-ray findings include cardiomegaly with netic resonance imaging, and computerized tomography pulmonary congestion and increased right atrial and right (CT) can demonstrate and delineate the characteristics of the ventricular size (Table 2C-2). These changes occur second- malformation. Ultrasound is a useful and convenient tool for ary to increased venous return to the right atrium from the bedside assessment of the critically ill neonate. Angiography malformation. The superior mediastinum appears wider than

2C-8 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-7 n CT showing an arteriovenous malformation of physical exam was positive for a 39-week, AGA male with a the great vein of Galen, ventriculomegaly, and soft anterior fontanel, an active precordium, a Grade II–III calcifications. systolic ejection murmur at the left sternal border with wide radiation over the precordium, a liver 2.5 cm below the right costal margin, decreased perfusion and slight mottling of the lower extremities with decreased femoral pulses, and a blood pressure of 50 systolic and 28 diastolic with a hematocrit of 50 percent. The neonate’s responsiveness to stimulation, tone, and activity was decreased. The admission diagnoses were term AGA male, , respiratory depres- sion, hypotension, cardiac murmur—rule out congenital heart disease, patent ductus arteriosus shunting, pulmonary hypertension, and sepsis. The patient was maintained on low ventilatory settings, given 10 mL/kg of volume expansion, and started on 10 mcg/kg/minute of dopamine for persistent hypoten- sion. A chest x-ray (Figure 2C-6) was taken (see following evaluation). An echocardiogram was obtained; it revealed pulmonary hypertension with a right-to-left atrial and ductal shunt. A sepsis workup was obtained and antibiotics begun. Cardiology was consulted; their impression was probably pul- monary hypertension with no structural heart disease. On day 2, the patient’s neurologic status remained abnormal and congestive heart failure unresponsive to management. These findings prompted evaluation for a cranial bruit, which was present over the posterior cranium. A computerized tomog- raphy scan was obtained (Figure 2C-7). The CT scan demon- strated a large AVM involving the cortex and right temporal, parietal, and occipital lobes; calcifications; intraventricular can further establish the nature of the AVM’s blood supply hemorrhage; and hydrocephalus. Following the results of the and drainage. CT scan and after neurology and neurosurgical consultation, The treatment of choice for AVM in recent years is inter- the parents requested that life support be withdrawn. ventional radiology. Transcatheter occlusion of the feeding arterial branches of the AVM can be carried out with acrylic Chest X-Ray Evaluation polymers, wire-fiber microcoils, or both.14 The success of this Indication for the x-ray was initial evaluation following deliv- embolization procedure is quite variable. Permanent brain ery room resuscitation, intubation, and umbilical artery line damage is a risk, and the AVM may recur as new feeding placement and admission to the NICU. channels open up.11 Penetration appears to be normally exposed. Rotation is slightly toward the right. CASE STUDY The soft tissues of the neck, chest, and abdomen appear to A 3,300 g, AGA, term male neonate was delivered by be of normal thickness. spontaneous vaginal delivery to a 24-year-old, gravida 3, para The bony framework is intact, with 12 ribs bilaterally. The 0, ab 2 mother. This mother had prenatal care beginning in clavicles are intact, and the humeri and vertebral bodies are the second trimester. Her serology and hepatitis B surface without abnormality. antigen were negative, her was A positive, and her The trachea shows a straight air column. An endotracheal rubella status was immune. The pregnancy and labor were tube is positioned at the second thoracic vertebra (T2). The unremarkable, and rupture of the membranes occurred 12 right and left mainstem bronchi are visible over the heart. hours before delivery. The infant required resuscitation fol- The hilum shows a wide opacified mediastinum. The heart lowing birth for lack of respiratory effort and a heart rate is markedly enlarged, with a cardiothoracic ratio of 0.75. No of 70. Following bag and mask ventilation and cardiac com- distinctive pattern of heart shape is appreciated. pressions, the newborn was intubated and transferred to The diaphragm on the right is slightly domed, with expan- the NICU. Apgar scores were 1, 6, and 8 at one, five, and sion to the ninth thoracic vertebra, and the diaphragm on the seven minutes. After admission to the NICU, the patient was left at the tenth vertebra is consistent with an inspiratory film. placed on intermittent mandatory ventilation. The admission

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-9 R ADIOLOGY BASICS

FIGURE 1 I The gastrointestinal tract: S–Stomach, D—Duodenum, FIGURE 2 I Abdominal x-ray showing a single gastric bubble. J–Jejunum, SI–Small intestine, I–Ileum, A–Appendix, C–Caecum, AC–Ascending colon, TC–Transverse colon, The pleura reach the edge of the bony thorax. Normal cos- FIGURE 2C-8DC–Descending n The gastrointestinal colon, SC–Sigmoid tract. colon, R–Rectum tophrenic angles are seen. Gastric air is present on the left, and a feeding tube is posi- tioned in the stomach. Air is present throughout the intestine. Lung fieldsare somewhat difficult to evaluate because of car- diomegaly. They appear lucent and have increased pulmonary vascular markings. The endotracheal tube is located at T2, and an umbilical artery line lies to the left of the vertebral column at T7. The impression is cardiomegaly with a wide mediastinum and increased pulmonary blood flow. The endotracheal tube and umbilical artery line are in acceptable positions. Based on this initial chest x-ray, congenital heart disease is suspected. With the additional data of an echocardiogram showing a S structurally normal heart, the diagnostic possibilities listed in Table 2C-2 should be considered. TC D Revised and updated from: Carey BE. 2000. Chest x-ray findings in arteriovenous malformation of the great vein of Galen. Neonatal Network J 19(3): 71–74. Used with permission of Springer Publishing Company, LLC, www.springerpub.com/nn. DC AC SI Situs Inversus Totalis I xternally, the human body appears symmetric; if a line is C intestinal wall (i.e., “double wall sign”): The intestine is Edrawn down the middle of the body, each side appears A SC outlined by air in the peritoneum and air in the intestinal identical. However, this is not true of the internal . lumen. This is best appreciated on the lateral film. For example, there is one heart, which lies in the left chest, R 4. Evaluate for the presence of radiodensities such as calcifica- one liver, in the right abdomen, and one stomach, in the left tions and air fluid levels. If these exist, calcifications within abdomen. The term situs refers to the position or location of Key: S–stomach, D–duodenum, J–jejunum, SI–small intestine, or around the bowel will be seen as white masses and a an organ, specifically, the position of the atria and abdominal structures,I–ileum, A–appendix, which include C–caecum, the AC–ascendingvertebral column, colon, lowerTC– ribs, bowel filled with fluid will cast vague and confluent gray 19 transverse colon, DC–descending colon, SC–sigmoid colon, R– 5 viscera in relation to the midline of the body. There are three andrectum. pelvis. Note any asymmetry. The placement of shadows. Calcifications may be caused by sterile meconi- types of situs: solitus, inversus, and ambiguous. Situs solitus From:catheters, Quinn D,if andany, Shannon in abdominal LF. 1995. vessels Congenital should anomalies be noted. of the um peritonitis, which appears as small, rounded opacities; refers to the normal arrangement of organs, with the right 2. Nextgastrointestinal examine tract. the Partsoft I: tissues The stomach. of the Neonatal left upper Network quadrant, 14(8): renal calculi; that are retroperitoneal; or atrium, liver, gallbladder, trilobed lung, and inferior vena cava right64. upper quadrant, both flanks (the outer lateral neuroblastoma. on the right side and the left atrium, stomach, , bilobed areas of the abdomen), mid-abdomen, and pelvis. In lung, and descending aorta on the left side (Figures 2C-8– each quadrant, check for normal organ masses (i.e., DEVELOPMENT OF THE STOMACH 2C-10). Situs inversus totalis refers to a mirror image reversal is relevant.liver, spleen, Early and in stomach).development, Any theshift embryo of organs is orsymmet intes-- Development of the gastrointestinal tract, an early event, of the normal position of the internal organs (Figures 2C-11 ric,tine both from sides the being normal identical. location20 The should heart be begins noted. formation begins during the fourth week of gestation and is completed and 2C-12).19 The incidence of situs inversus totalis is 1 in 3.at Assessapproximately the contents 18 daysof the gestation GI tract. with Look the at theappearance abdominal of by the tenth week.6 The stomach arises during the fourth every 8,000 to 25,000 births, and the condition is most often pairedcontour cardiac for tubes.bulging22 Atflanks approximately or mild to marked22 days distention.gestation, week of gestation as a spindle-shaped dilation of the diagnosed by radiographic examination.20 Situs ambiguous, theDistention cardiac tubes may lengthen be due to and physiologic rotate to orthe structural right. This obstruc- is the foregut.6,7 In the subsequent weeks, the stomach dilates and often referred to as heterotaxia, is the random arrangement of firsttion sign or accompanyof asymmetry respiratory in the embryo. distress23 orThe mechanical rotation ofventi- the rotates, resulting in a change in appearance and position. the internal organs and is associated with splenic abnormali- heart,lation. which Follow is often the calledcourse looping, of air throughoutis one of the themost GI impor tract,- The rotation is around a longitudinal and anterioposterior ties and congenital heart disease.21 The purpose of this article tantkeeping steps in in formation mind the agebecause of the it patientdetermines and the normalstructure pro- of axis. The effects of this longitudinal rotation are (1) the lesser is to discuss the embryology, pathophysiology, and diagnosis twogression separate of systemsair through for pumpingthe GI tract blood. postnatally.20 The apexA complete of the curvature moves to the right, (2) the greater curvature moves of situs inversus totalis and to review a case study with radio- heartobstruction moves from will the cause right opacity side of distalthe thorax to the to obstruction. the left side to the left, (3) the original left side becomes the ventral sur- graphic findings. in theLook next for 10–12 free air. days, A large by which collection time ofmost free of air the will heart lead lies to face, and (4) the original right side becomes the dorsal in theabdominal left chest. distention22 Dextrocardia and an resultselevated when diaphragm, the heart and fails out- to surface.7,8 During the anterioposterior rotation, the caudal EMBRYOLOGY AND DEVELOPMENT migratelines tostructures the left thorax.such as Situs the inversusfalciform totalis ligament. results Smallwhen (pyloric) portion moves to the right and upward, whereas the The majority of literature published to date on embryo- theamounts cardiac tubesof free rotate air may to thebe leftevident and onthe eitherplacement side of the cephalic (cardiac) portion moves left and downward.6 logic factors predisposing to situs inversus totalis focuses on heart and other internal organs presents a mirror image of the abnormal development of the heart. Therefore, a discussion normal arrangement. In other words, the liver is in the left of the mechanisms controlling heart rotation and migration abdomen, the stomach is in the right abdomen, the trilobed N EONATAL N ETWORK 57

2C-10 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-9 n Situs solitus: Normal anatomic arrangement of FIGURE 2C-10 n Normal (situs solitus) chest and abdominal x-ray chest and abdominal organs. of full-term infant.

Courtesy of Wesley Medical Center, Wichita, Kansas.

From: Moller JH. 1990. Malposition of the heart. In Fetal, Neonatal, and Infant Cardiac Disease, Moller JH, and Neal WA, eds. Stamford, in situs inversus. However, it remains uncertain what causes Connecticut: Appleton & Lange, 756. Reprinted by permission. 20 Permission conveyed through Copyright Clearance Center, Inc. the production of the Shh protein. Situs inversus tends to be familial.25 This led researchers to believe that a gene is responsible for this abnormality. lung is in the left chest, and the bilobed lung is in the right Recently, a gene called Pitx2 has been identified as control- chest (see Figures 2C-11 and 2C-12). ling the secretion of Shh and Nodal. Pitx2, Shh, and Nodal The exact mechanism that controls rotation and migration all appear on the left side of the heart in the chick embryo of the internal organs, or left-right asymmetry, is unknown. and are produced throughout development. Researchers have Research has concentrated on the looping of the heart manipulated and inserted the gene and successfully produced because it is believed that this organ is the “most sensitive chicks with situs inversus and situs ambiguous.20,24 Exactly how to abnormalities.”20 Molecular signaling and left right asym- the signals are given and where they begin is uncertain, but it metry research has been conducted on chick embryos, which is believed that they begin in the midline of the notochord.24 are similar to the embryos of other vertebrates. The current view among researchers is that organ rotation and migra- PATHOPHYSIOLOGY tion are the result of a chain of signals. Secretion of a protein Situs inversus totalis can present either as an isolated finding named “sonic hedgehog” (Shh) influences the expression of with no apparent adverse effects or as part of a complex syn- two transforming growth factors referred to as Nodal and drome. Uncomplicated situs inversus totalis is frequently not Lefty. When these proteins are secreted on the left side of the diagnosed in the neonatal period.26 A MEDLINE search for embryo, the heart loops to the right, resulting in situs solitus. situs inversus totalis in the neonate conducted for 1980–1999 If the Shh protein is secreted on the right side, the heart loops revealed very few cases identified in the neonatal period. to the left, resulting in situs inversus.20,24 If the Shh protein However, numerous articles present case studies of the dis- is secreted on both sides, the signal is unclear; 50 percent of covery of situs inversus totalis in children and adults by radio- such cases will result in situs solitus and 50 percent will result graphic findings when the patient presented for examination

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-11 FIGURE 2C-11 n Situs inversus: Mirror reversal of the normal FIGURE 2C-12 n Chest and abdominal x-ray of full-term infant anatomic arrangement of chest and abdominal with situs inversus. organs.

Courtesy of Wesley Medical Center, Wichita, Kansas.

From: Moller JH. 1990. Malposition of the heart. In Fetal, Neonatal, and Infant Cardiac Disease, Moller JH, and Neal WA, eds. Stamford, Connecticut: Appleton & Lange, 756. Reprinted by permission. Situs inversus totalis occurs in association with many dif- Permission conveyed through Copyright Clearance Center, Inc. ferent types of syndromes and is associated with cardiac anomalies in approximately 3–9 percent of cases.23 Raines and Armstrong report a term male infant who presented with cyanosis at seven hours of age. The infant had situs inversus for various other medical reasons. For example, Harrington totalis and aortic atresia with a hypoplastic left ventricle. After and colleagues discuss a six-week-old infant who presented life support was removed, the neonate died because of the with a two-week history of vomiting and weight loss. cardiac anomaly.31 Radiographic examination revealed situs inversus, and an ultra- Several authors report situs inversus totalis occurring in sound showed a thickened pylorus on the left side.27 Kulick association with other anomalies and syndromes present- and colleagues present a case study of a 25-year-old man who ing in the neonatal period.25,32–34 One particular syndrome, presented in the emergency room following a motor vehicle Kartagener’s syndrome, is a rare, autosomal recessive dis- accident; situs inversus was discovered by radiographic exami- order consisting of situs inversus totalis, abnormal parana- nation.28 Kodama and colleagues present a case study of a sal sinuses, and that affects approximately 20 68-year-old man who presented with chest pain; situs inversus percent of those diagnosed with situs inversus.19 However, was discovered by radiographic examination.29 Watson and 50 percent of those diagnosed with Kartagener’s syndrome colleagues describe the case of a 35-year old man with situs have situs inversus and 50 percent have situs solitus.19 The inversus totalis who required liver transplantation due to major component of the syndrome, also known as immotile cryptogenic cirrhosis. The cirrhosis was unrelated to the situs cilia syndrome (ICS), is immotile or abnormal movement of inversus totalis and the transplantation was successful.30 cilia located in the , ventricles of the brain, oviducts, and vasa efferentia of the testes.19,35 The incidence

2C-12 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics of ICS is 1:20,000–68,000, and it is rarely diagnosed in the patent foramen ovale, small patent ductus arteriosus with left neonatal period.36,37 There are no complications associated to right flow, minimal tricuspid insufficiency, and no chamber with situs inversus totalis in individuals with ICS. However, enlargement. In addition, the echocardiogram showed that the because of the defective cilia, bacteria clearance in the sinuses aorta and inferior vena cava were switched in their positioning and bronchial tree is impaired, which may result in recurrent in the chest, confirming the diagnosis of situs inversus totalis. An respiratory tract . abdominal sonogram revealed the liver in the left upper quad- rant, the spleen in the right upper quadrant, and the stomach ASSESSMENT AND DIAGNOSIS in the right abdomen. A CT scan of the paranasal sinuses was Diagnosis of situs inversus totalis typically does not occur in done to screen for Kartagener’s syndrome and was found to be the neonatal period. Most often, situs inversus totalis is diag- normal. A peripheral blood smear was examined to assess for nosed in neonates only after radiographic evaluation for respi- Howell-Jolly bodies, which were not present. A blood culture, ratory distress or another reason. A radiographic examination drawn at admission because of the possibility of sepsis associated of the chest and abdomen reveals a stomach bubble in the with the presenting symptom of respiratory distress, was nega- right abdomen and the apex of the heart in the right chest tive at final reading. The infant began feedings on day 1 of life (see Figure 2C-12). Dextrocardia is identified on the chest and was advanced as tolerated. Baby M was discharged on day x-ray, which leads to further cardiac evaluation, including an 9 after an uneventful hospital stay. A family pedigree obtained echocardiogram. by the geneticist revealed no other family members with situs After the heart is examined and the major arteries and veins abnormalities; therefore, chromosomal studies were deferred. are located, an abdominal ultrasound is obtained to deter- An echocardiogram obtained at the two month follow-up visit mine abdominal organ placement. Physical assessment of an with the cardiologist showed normal heart function. The infant infant with situs inversus totalis reveals that the cardiac point is currently thriving, with no evidence of adverse effects related of maximal impulse (PMI) is on the right chest, as opposed to to the diagnosis of situs inversus totalis. the left sternal border or substernally, and the liver is palpable in the left abdomen. X-Ray Interpretation (Figure 2C-12) The following case study summarizes the diagnostic Indication: Respiratory distress following delivery. workup and uncomplicated course of a newborn presenting Penetration: Appears to be normally exposed. with situs inversus totalis. Situs inversus totalis was diagnosed Rotation: None. after an x-ray was obtained to evaluate the newborn for respi- Lung expansion: Good inspiration, with diaphragm at T9. ratory distress. Soft tissues: Normal thickness of soft tissues of chest and arms. CASE STUDY Bony framework: Appears intact, with no anomalies of the Baby Girl M was born at 39 weeks gestation to a 17-year- ribs, extremities, clavicles, or vertebrae. Twelve ribs present old gravida 1, para 0 mother. The mother received adequate bilaterally. prenatal care and reported smoking one pack of cigarettes per Abdominal structures: Liver on the left and stomach bubble day. Medications during pregnancy included prenatal vitamins on the right. Normal appearance of bowel gas pattern, origi- and metronidazole for Trichomonas. The infant was born by nating in the right abdomen. spontaneous vaginal delivery with vertex presentation and clear Lung fields:Clear lung fields with mild left perihilar streaking. amniotic fluid. At delivery, Baby Girl M weighed 2,727 g with Cardiac size and contour: Normal heart size. Heart a length of 47 cm and a head circumference of 34 cm. Weight, borders visible, with apex of heart in the right chest. Cardiac- length, and head circumference were appropriate for gestational tothoracic ratio of approximately 0.50:1. age. Apgar scores were 7, 8, and 9 for one, five, and ten minutes, Impression: Situs inversus totalis. respectively. At delivery, the infant exhibited a weak cry and central cyanosis and was given oxygen via mask. Following an SUMMARY initial blood glucose of 33 mg/dL (1.8 mmol/liter) and oxygen The etiology of situs inversus totalis remains uncertain. saturation reading of 80 percent, peripheral venous access was However, the literature establishes that isolated situs inversus obtained, dextrose fluids were initiated, and oxygen was pro- totalis is usually asymptomatic in the neonate. This case vided by nasal cannula. A chest x-ray revealed situs inversus (see study illustrates the importance of physical assessment skills Figure 2C-12). The infant was transferred to a regional medical in identifying situs inversus totalis in the neonate. Current center for consultation with pediatric cardiology and genet- research may reveal the etiology of this rare but fascinating ics staff. Upon admission to the regional medical center, the abnormality. infant’s vital signs were within normal limits, and oxygen satura- tions were 93–99 percent on room air. The PMI was noted on Revised and updated from: Spoon JM. 2001. Situs inversus totalis. Neonatal Network 20(1): 59–63. Used with permission of Springer Publishing the right chest, and the liver edge was palpable at the left costal Company, LLC, www.springerpub.com/nn. margin. An echocardiogram revealed a structurally normal heart,

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-13 FIGURE 2C-13 n Schematic drawings demonstrating the various Congenital Cystic differential diagnoses of neonatal chest lesions. (A) Normal lungs, with symmetric appearance; (B) hydrothorax, Adenomatoid Malformation with fluid compressing and restricting growth of the normal lung; (C) CCAM, with cystic appearance and connection to the tracheobronchial tree; (D) BPS, depicting an anomalous blood of the Lung supply to an aberrant lung tissue mass; (E) CDH, with bowel and stomach above the diaphragm; (F) bronchogenic cyst, centrally located and well defined. Liz Pittman, MSN, RN, NNP-BC

ongenital cystic adenomatoid malformation (CCAM) Cof the lung also known as congenital pulmonary airway malformation (CPAM), is a rare, multicystic lesion with embryonic origins. Approximately 421 cases have been docu- mented since the lesion was first described in 1949.38 Usually, only one lobe is affected, most often the lower lobe.39 CCAM represents 25 percent of all congenital lung lesions.40 There is no race predominance, nor is there a left- or right-side trend.41 Males may be at greater risk than females for CCAM development.42 Ch’in and Tang first described CCAM in 1949. These doctors depicted a neonate with general anasarca caused by mechanical compression of the mediastinal structures with obstruction of venous return.43 Interestingly, their descrip- tion of CCAM and its implications are similar to what we know today, over 50 years later. Precise etiology, then and now, eludes detection.44–46 This article reviews the pathogenesis, radiographic diag- nosis, and treatment of a neonate with CCAM. The condi- From: Hilpert PL, and Pretorius DH. 1990. The thorax. In Diagnostic tion should be considered in the differential diagnosis of any Ultrasound of Fetal Anomalies: Text and Atlas, Nyberg DA, Mahony neonate presenting with an abnormal mass or lesion on chest BS, and Pretorius DH, eds. Chicago: Year Book Medical, 273. radiograph. Reprinted by permission.

EMBRYOLOGY AND PATHOPHYSIOLOGY The specific embryonic origin and pathogenesis of CCAM OTHER LUNG LESIONS are unknown.44,45,47 As the lower respiratory tract develops, Five other congenital lung lesions, four of which are dia- proper communication between the epithelium of the devel- grammed in Figure 2C-13, may be difficult to differenti- oping laryngotracheal tube and the surrounding mesenchyme ate from CCAM on x-ray: congenital diaphragmatic hernia is essential. This is to ensure normal growth of the conduct- (CDH), bronchopulmonary sequestration (BPS), broncho- ing airways, connective tissue, cartilage, muscle, and blood genic cyst, hydrothorax, and congenital lobar emphysema and lymphatic vessels throughout the .48 A (CLE). CDH occurs after the components of the embryonic faulty interaction between the endoderm-derived epithelium diaphragm do not fuse completely around the sixth week of and the mesenchyme is thought to account for a subsequent fetal life. When the intestines return to the abdomen around overgrowth of the terminal bronchioles.44,49 These excess ter- the 24th day of fetal life, a posterolateral defect in the dia- minal bronchioles form the various-sized cysts exhibited in phragm allows the intestines to enter the chest region. This CCAM.46,50 differs substantially from the structure of the CCAM, which The fact that a CCAM lesion is without any significant car- is connected to the tracheobronchial tree and does not inter- tilage is critical. Without cartilaginous support, the lesion col- fere with the diaphragm. lapses during expiration, trapping inhaled air.41 The degree of BPS is a foregut anomaly that occurs when a lung bud air trapping is clinically exhibited as respiratory distress with develops distal to the tracheobronchial tree and is not in varying degrees of severity. Postnatally, respiratory distress communication with the tracheobronchial tree.50,51 The BPS may develop as the lesion expands further, with air trapping therefore cannot fill with air. The CCAM originates from and shifting of the mediastinal structures compromising con- the tracheobronchial tree and is in communication with the tralateral lung function. airway, so it can fill with air.52 In addition, the vascular supply

2C-14 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-14 n Pathophysiology of a large CCAM. FIGURE 2C-15 n Stocker’s classification of Types I, II, and III CCAM. Note the , mediastinal shift, and .

From: Bianchi DW, Crombleholme TM, and D’Alton ME. 2000. Fetology: Diagnosis and Management of the Fetal Patient. New York: McGraw-Hill, 289. Permission conveyed through Copyright Clearance Center, Inc.

distress; or they can have severe cardiorespiratory compro- mise as a result of nonimmune and pulmonary hypoplasia (Figure 2C-14). The hydrops fetalis is thought to occur as a result of two events: (1) The mass created by the CCAM is thought to shift the mediastinum, impeding venous return and resulting in hydrops fetalis.43 (2) The mass can also directly compress the heart and mediastinal struc- tures, which interferes with effective cardiac contractions and cardiac output.56 Heart failure and subsequent hydrops fetalis may result, as postulated initially by Ch’in and Tang.43 The degree of mediastinal shift and cardiac compression From: Bianchi DW, Crombleholme TM, and D’Alton ME. 2000. depends on the growth and size of the CCAM. To examine Fetology: Diagnosis and Management of the Fetal Patient. New York: McGraw-Hill, 293. Permission conveyed through Copyright the mass effect of the CCAM, a study utilized fetal sheep Clearance Center, Inc. models and surgically implanted intrathoracic tissue expand- ers. That experiment demonstrated the expander caused central venous obstruction and an increase in central venous to the BPS originates from the aorta.51 The vascular supply pressure, resulting in hydrops fetalis.50 for the CCAM originates from the pulmonary artery.53,54 Pulmonary hypoplasia can occur when the CCAM com- Bronchogenic cysts are also foregut anomalies. The loca- presses normal lung tissue.38 This worsens as the growth of tion of the cyst (peripheral or mediastinal) depends on the terminal bronchioles progresses. Pulmonary hypoplasia in timing of the separation from the developing bronchiole. this case is similar to the pulmonary hypoplasia seen with These cysts have fibrous walls, whereas CCAM cyst walls a CDH in which the bowel is the space-occupying lesion. lack a significant cartilage structure. Intrapulmonary bron- Pulmonary hypoplasia may also occur in lesions in which chogenic cysts have a blood supply similar to that of CCAM pleural effusions have developed secondary to hydrops fetalis. (pulmonary), whereas mediastinal bronchogenic cysts are Pulmonary hypoplasia is not limited to the ipsilateral side. supplied by systemic vessels.52 Shifted intrathoracic structures may occupy space needed for A hydrothorax is simply fluid in the pleural space. It can normal growth, thus compromising lung development on occur secondary to a chyloric leak or fluid retention with the contralateral side as well. hydrops fetalis.40 Hydrothorax differs from CCAM in its fluid composition and lack of cysts. CLASSIFICATIONS Congenital lobar emphysema is the hyperinflation of a Two classification systems are used to describe the various lobe. CLE represents a developmental deficiency of the carti- characteristics of CCAM. Stocker and colleagues devised the lage within the bronchus of the involved lobe.55 This permits first in 1977.42 Adzick and colleagues articulated the second the bronchus to collapse, obstructing expiration. The alveolar in 1985.53 The first, most recognized throughout the litera- septa are not destroyed.52 ture and widely used clinically, describes CCAM as Types I, II, and III (Figure 2C-15). A definitive typing follows exami- SYMPTOMS OF CCAM AT BIRTH nation of the histologic makeup of the CCAM postresec- Neonates born with CCAM can be asymptomatic at birth; tion. Various histologic appearances of the CCAM reflect the they can demonstrate mild to moderate degrees of respiratory origin of terminal bronchiole overgrowth. The addition of a

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-15 Type IV CCAM to the Stocker and colleagues classification often occur concurrently. Because of its mass effect, Type III system has been suggested.47,57 However, limited information CCAM often presents with hydrops fetalis. Death in these is available about this in the literature, and Type IV has not cases occurs within one to five hours because of an inability been widely used in the clinical setting. to ventilate the infant.59 Eighty percent of patients with Type Type I CCAMs, consisting of multiple large cysts (>2 cm III CCAM present with severe cardiorespiratory compromise in diameter), make up 50 percent of the cases.58 These cysts because of pulmonary hypoplasia.38 often cause a mediastinal shift. Lesions have no bronchial car- tilage and are lined by ciliated pseudostratified epithelium. Prenatal Ultrasound Presentation Type I CCAMs carry a good prognosis.39 New techniques make possible the diagnosis of many Type II CCAMs account for 40 percent of the cases.58 They lung lesions prenatally, either through routine ultrasound or consist of multiple small cysts (<1 cm in diameter), no mucous after follow-up for suspected polyhydramnios. If ultrasound or cartilage cells are present, and the cysts are lined by ciliated remains inconclusive, prenatal magnetic resonance imaging cuboidal and columnar epithelium. Specific to Type II CCAM (MRI) is advocated for further evaluation.60 Poor prognostic is the periodic presence of striated muscle fibers between features of CCAM detected prenatally include polyhydram- cysts.59 Type II CCAM has a histologic appearance similar nios, hydrops fetalis, and ascites. Polyhydramnios may result to that of the developing lung during the canalicular period, from decreased amniotic fluid absorption caused by hypo- between 16 and 25 weeks of fetal growth. It is most com- plastic lungs.61 Polyhydramnios may also occur as a result of monly associated with other anomalies, such as bilateral renal esophageal compression, either by the CCAM itself or by the agenesis, renal dysplasia, truncus arteriosus, tetralogy of Fallot, shifted mediastinal structures as the lesion grows.50 This shift hydrocephalus, jejunal atresia, CDH, deformity of the clavicles is noted as a potentially ominous sign, warranting close sur- and spine, and (fused lower limbs with no feet).42 veillance for subsequent hydrops fetalis development. Prognosis depends on associated anomalies and their severity.38 Type III CCAMs are bulky, firm, large, microcystic masses Diagnostic Workup and Differential Diagnosis that produce a mediastinal shift. They make up 10 percent In cases where the CCAM of the lung is not identified of the CCAM cases.58 The microcystic, or Type III, CCAM prenatally, determining the etiology of the presenting respira- is thought to occur during the pseudoglandular period, tory distress may be confusing and challenging. The initial between the 5th and 17th weeks of fetal growth. The lesions diagnostic tool is the chest x-ray. This alone may not provide consist of irregular shaped, alveolus-sized structures (<5 mm enough information to confirm a diagnosis of a specific lung in diameter) with cuboidal epithelium without cilia. These lesion, however, necessitating further evaluation via com- lesions have a poor prognosis.42,46 puted tomography (CT) scan or MRI. The other classification system, derived by Adzick and Appearance of the chest x-ray varies, depending on the colleagues, describes the CCAM as either macrocystic or type of CCAM present and the amount of fluid vs air within microcystic, using gross anatomy, ultrasound findings, and the cysts. This variable appearance is attributed to the initial prognosis. Microcystic lesions have a poor prognosis and presence of fluid within the cysts soon after birth. As the cysts are more often associated with hydrops fetalis. Hydrops fetalis expand with air and the fluid dissipates, changes on x-rays are is rarely associated with the less solid macrocystic lesions apparent, with the cysts either displaying air-fluid levels or (>5 mm), which thus have a more favorable prognosis.53 appearing lucent.40 Chest x rays may be homogeneous to non- homogeneous and from lucent to echogeneic in appearance. CLINICAL PRESENTATION AND SYMPTOMS Type I CCAM appears as a multicystic pattern with cystic CCAM presents as respiratory distress in the neonatal spaces containing air.42 The cysts may differ in size and air- period 50 to 85 percent of the time.52 Neonates with CCAM fluid level. One dominant cyst may appear as a lucent mass commonly are premature, which further complicates their on the film. Comparing the unusual mass to the normal lung respiratory status.49 Other cases remain asymptomatic and, if tissue may help to distinguish the presence of CCAM. A not detected prenatally, could go undiagnosed for months mediastinal shift may also be present, especially as the cysts to years. Asymptomatic cases are most often associated with expand and as air is trapped in the cystic structures. Type II Type I CCAM. If the CCAM remains undetected in the neo- CCAM is rarely described radiographically because the focus natal period, it later presents as recurrent pulmonary infec- is on other anomalies and on the poor postnatal prognosis. tions, or it may be discovered incidentally on a chest x-ray. This type is documented more as a nonhomogeneous mass With Type I CCAM, the most common symptom is pro- on a chest x-ray. In Type III, the large homogeneous mass is gressive respiratory distress as demonstrated by cyanosis, obvious because it fills the hemithorax and shifts the medias- retractions, and grunting by two minutes of life and for up tinal structures. to four weeks of age. Vomiting has been documented as a When any nonspecific assortment of features appears on common, subtle initial sign as well.59 Clinical presentation of the initial chest x-ray, other chest occupying lesions must Type II CCAM is variable because other congenital anomalies be included in the differential diagnosis. These include the

2C-16 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-16 n Algorithm for management of a fetus with CCAM.

Ultrasound, amnio/pubs, cardiac echo

Other anomalies Isolated lesion or pre-eclampsia Prognostic evaluation Gestational age, Hydrops mediastinal shift, placentomegaly, No hydrops hydrops

Counsel <24 weeks 24–32 weeks >32 weeks Ultrasound and counsel PRN

No hydrops RESECT No Terminate IN UTERO Deliver early, intervention pregnancy resect ex utero Deliver at term, resect ex utero Deliver (c-section) near term

From: Bianchi DW, Crombleholme TM, and D’Alton ME. 2000. Fetology: Diagnosis and Management of the Fetal Patient. New York: McGraw-Hill, 289. Permission conveyed through Copyright Clearance Center, Inc.

previously discussed CCAM, CDH, BPS, bronchogenic cyst, Congenital lobar emphysema presents on chest x-ray as hydrothorax, and CLE. Congenital diaphragmatic hernia on a unilateral, overinflated lobe evidenced by spreading of the chest x-ray may have a mediastinal shift away from the herni- ribs and compression of the diaphragm on the affected side.63 ated side. Initial chest x-rays with fluid-filled bowel demon- A mediastinal shift may also occur. CLE differs from CCAM strate radiologically as a cystic appearance. The appearance of radiologically in that it involves a single cyst vs multiple cysts.64 CDH differs from CCAM in that the presence of air within the structure occurs sooner because air has entered the esoph- MANAGEMENT agus during resuscitative measures.52 Insertion of a nasogas- Exactly when to intervene for an infant with CCAM is tric tube could help distinguish CDH from other lung lesions controversial. Debate exists as to whether the size or the by determining the location of the stomach bubble within type of CCAM should be the determining prognostic factor the thorax.40,46 On the initial chest x-ray, bronchopulmonary to indicate certain interventions.65 The presence of hydrops sequestration appears as a water-density mass.40,52 BPS may fetalis is known to have a poor prognosis, most likely to end have a cystic appearance similar to CCAM. Doppler tech- in fetal demise or neonatal death.40 When CCAM is dis- nology may be required to differentiate BPS from CCAM covered on the prenatal ultrasound, serial ultrasounds are through the detection of a systemic feeding vessel.52,54 done to monitor the progression of growth, shifting of the Bronchogenic cysts often are not evident in the neonatal mediastinum, development of hydrops fetalis, or involution period.52 If visible on chest x-ray, however, their appearance of the mass.66 Although the pregnancy is sometimes termi- varies. Cysts appear round or oval, can be filled with fluid nated when hydrops fetalis develops, new techniques of fetal or air, or can appear as a homogeneous mass. In hydrotho- surgery have provided options to minimize or alleviate the rax, the fluid around the affected lung has a homogeneous, consequences of a developing CCAM. Interventions for these radiodense, opacified appearance.62 No cystic structures are high-risk include prenatal resection of the CCAM present, and the mediastinum may or may not be shifted to and thoracoamniotic shunts to decompress a large dominant the contralateral side. cyst.40 These interventions are reserved for CCAMs with a

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-17 FIGURE 2C-17 n Sample of the serial cross-sectional plane of dismal prognosis, such as concurrent hydrops fetalis. An algo- the thorax ultrasound pictures in chronological rithm is presented to review common clinical steps in making 4 order at (A) 23 weeks gestation, (B) 30 /7 weeks 4 decisions regarding prenatal care for the fetus with CCAM gestation, and (C) 33 /7 weeks gestation. (Figure 2C-16). Note the slight regression of the CCAM size and, in B, the obvious Postnatal management of a patient with CCAM includes shift of the heart. The heart gradually moves toward midline, with cyst regression. stabilizing the respiratory status by supplying oxygen or intu- bating as the situation necessitates. Obtaining serial chest x-rays is essential because overinflation of the CCAM is pos- sible when delivering positive pressure ventilation.46,59 The use of high-frequency oscillatory ventilation (HFOV) may benefit these patients because of their high risk for air leaks into the thorax, mediastinum, and/or pericardial region.46 Neonates with CCAM as well as severe respiratory distress are also at risk for persistent pulmonary hypertension of the newborn (PPHN).67 They may require aggressive support with nitric oxide or extracorporeal membrane oxygenation (ECMO). For these reasons, neonates with suspected CCAM should, if at all possible, be delivered at a tertiary care center that can meet their medical needs.49 A Treatment for CCAM of the lung is lobectomy, even in asymptomatic cases, to decrease the risk of growth and super- imposed infections with respiratory compromise.38,50 Also, there is a documented risk of the lesion developing into a malignancy, thus, surgical removal is recommended.40,50 Timing of the lobectomy depends on clinical symptomatol- ogy. Surgery is emergent only in cases of respiratory distress. Asymptomatic CCAM of the lung requires prompt but not emergent removal to avoid adverse sequelae, including infec- tion and malignant changes within the mass. In asymptomatic cases, Bunduki recommends resection after two months, thus providing better clinical conditions.66 The following case study illustrates the course of one neonate with Type I CCAM.

B CASE STUDY Baby R is a 3,440 gm male born at term to an 18-year-old mother who had received routine prenatal care. The preg- nancy was complicated by preterm labor and a fetal thorax abnormality detected through routine ultrasound at 20 weeks gestation. The mother was referred to a perinatologist at 23 1/7 weeks gestation for the remainder of her prenatal care. The perinatologist did serial ultrasounds to evaluate the progression of the suspected CCAM (Figure 2C-17). The ultrasound at 23 weeks demonstrated a 2.9 × 3.3 × 4 cm cystic mass in the left chest that was displacing the heart to the right and was thought to be a probable CCAM. On ultrasound examination at 30 4/7 weeks gestation, the mass was noted to be smaller and the heart more midline. At 33 4/7 weeks gestation, the size of the CCAM had not changed, and the C heart was seen at midline. Courtesy of Dr. Howard Thompson and Freeman Hospital, Joplin, The mother was referred to a tertiary care center for con- Missouri. sultation regarding possible delivery at an institution with readily available access to ECMO and pediatric surgeons. Later, the perinatologist and a local neonatologist agreed

2C-18 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-18 n Initial chest x-ray taken on day of birth. FIGURE 2C-19 n Cross-sectional CT scan of the thorax demonstrating the space occupying cystic lesion Note the mediastinal shift. CCAM is over the left chest. A large air- within the left side of the chest. filled dominant cyst appears lucent over the lung field.

Courtesy of Freeman Hospital, Joplin, Missouri. Courtesy of Freeman Hospital, Joplin, Missouri. to allow the mother to deliver locally because they believed based on the size of the cysts evaluated on the prenatal ultra- Diaphragm: Approximately T8. sound—that the probable CCAM would be a small Type I. Intercostal spaces: Normal in size. All understood that the baby may need to be transported Left lung field: Reticular opacities with cystic air-filled elsewhere if his condition was not stable. pockets over the left lower lobe. The mother experienced preterm labor at 36 1/7 weeks Right lung field:Appears clear. gestation, received terbutaline and magnesium sulfate, and Gastric air: Present on the left upper quadrant of the was sent home on nifedipine. She delivered Baby R vaginally, abdomen; air is present in a large portion of the bowel, with without complications, at term at the local hospital. Apgar the exception of the rectum. scores were 9 and 10 at one and five minutes, respectively. Impression: Based on prenatal assessment, space occupying Baby R’s exam was essentially within normal limits, with no the cystic lesion on the left side of the chest is most likely a signs of respiratory distress. Because of his prenatal history, CCAM. however, a chest x-ray and CT scan were ordered for further The CT scan (see Figure 2C-19) illustrates clearly the pres- evaluation (Figures 2C-18 and 2C-19). ence of a large, lucent, reticular structure on the left. This air- filled mass was measured. The report indicates the presence X-Ray Evaluation (Figure 2C-18) of tiny cystic foci along the periphery of the lesion in the left Indication: Evaluation of congenital lung lesion detected on lower base. No signs of a pleural effusion are present, and the prenatal ultrasound. remaining lung fields appear clear. Penetration: Appears to be slightly overpenetrated; the soft Baby R’s clinical course was unremarkable. He breastfed tissues of the extremities are not well visualized. without difficulty and was discharged at 34 hours of life. The Rotation: Present. The neonate is slightly rotated to the parents were instructed to visit their pediatrician at two weeks right, making the ribs on the left appear longer. of age. The pediatrician had referred Baby R to a pulmo- Soft tissues: The lower extremities, the groin, and under the nologist for follow-up of the CCAM. Because Baby R was arms appear to be of normal thickness. without present pulmonary compromise, he was referred to Tracheal air column: Deviated to the right. a pediatric surgeon for further evaluation and treatment fol- Hilum: Appears shifted to the right, with visible thymus. lowing discharge. Heart: Normal size but shifted to the right.

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-19 Follow-Up Care Baby R was seen at one month of age for a consultation VATER Association with a pediatric surgeon to determine further intervention. The exam at this time was remarkable for decreased breath sounds and dullness with percussion over the left chest. The Janie M. Spoon, MSN, RN, NNP-BC point of maximal impulse was displaced to the right. The chest x-ray at this time revealed a large (6 cm) dominant cyst over ATER association was first described in 1973 as a non- the left chest; it had expanded from 3 cm at birth. This large Vrandom group of related defects, as follows: V = verte- cyst was shifting structures to the right, including the apex of bral defects, A = anal atresia, TE = tracheoesophageal fistula, the heart, causing atelectasis of the right lung. The x-ray at R = radial limb dysplasia.68 Since that time, various expansions this time demonstrated the air trapping and the expansion of of the acronym have been suggested in an effort to further cysts that can occur within this lesion. define the scope of the VATER association. Temtamy and A left lower pulmonary lobectomy was performed at two Miller expanded the V in VATER to include vascular anoma- months of age. Baby R tolerated the procedure without com- lies, specifically, ventricular septal defect and single umbilical plications. A follow-up chest x-ray showed repositioning of artery.69 An expansion of the acronym to VACTERL has been the mediastinal structures, with the heart in midline. The suggested, with the C denoting cardiovascular anomalies and left chest was filled with expansion of the left upper and lin- the L denoting limb anomalies.70 R can now represent both gular lobes. The lower lobe specimen sent to pathology was radial limb dysplasia and renal anomalies. The designation of described as a collapsed 3 × 2 cm cystic area. A 1 cm cyst was VATER or VACTERL association can be made for infants also dissected from the lobe. The final diagnosis was benign with at least three of the defects designated in the acronym.71 Type I CCAM. LITERATURE REVIEW Long-Term Care Weaver and colleagues reported an evaluation of 46 The expectant long-term care for Baby R and other neo- patients (24 males and 22 females) with two or more of the nates with CCAM without pulmonary hypoplasia that has defects of VATER association. The most common compli- been resected is uneventful. Baby R will be followed by his cation of pregnancy was polyhydramnios, and 47.8 percent regular pediatrician and has no special needs or follow-up of the mothers were primiparas. Chromosome studies done visits with the surgeon. The physical performance of patients in 19 of the infants were reported normal. According to the who have had CCAM is reported to be equal to that of their evaluation, 27 infants (57.8 percent) had vertebral anoma- peers.38 Baby R has no increased risk of pulmonary infections lies, 26 infants (56.6 percent) had imperforate anus, 31 or physical limitations. No genetic defect needs to be consid- infants (67.4 percent) had tracheoesophageal malformations, ered with other siblings or offspring. The long-term outcome 7 infants (15.2 percent) had radial dysplasia, 29 infants (60.9 is favorable, with little to no decrease in pulmonary function- percent) had renal anomalies, and 36 infants (78.3 percent) ing, possibly because of the healthy lung’s chronic compensa- had cardiac defects. Other anomalies, reported at an inci- tion and because of normal continued development of the dence of 12 to 18 percent, were ear anomalies, lower extrem- alveoli.38 ity defects, genital and gonadal anomalies, thumb defects, and abnormal curvature of the vertebral column (scoliosis, SUMMARY lordosis, or kyphosis).72 The etiology of CCAM of the lung remains unclear. Khoury and colleagues reported an evaluation of Presentations vary, with clinical outcomes that may be unpre- 11,366 infants with birth defects. There were 50 infants dictable. The neonatal nurse should be equipped to detect with VACTERL association, representing an incidence of the sometimes subtle radiologic images these lesions produce 1.6/10,000 live births. The only statistically significant and should be able to distinguish CCAM from similar chest demographic datum was an increased occurrence of the asso- masses. Expediting this diagnosis postnatally benefits the ciation in Caucasian male infants.70 neonate by preventing further expansion of the cysts, which According to the evaluation, 18 infants (36 percent) had can cause a cascade of complications, including air leaks, car- vertebral anomalies, 20 infants (40 percent) had anal atresia, diorespiratory compromise, and PPHN. 40 infants (80 percent) had cardiac anomalies, 12 infants (24 percent) had tracheoesophageal fistula (TEF), 41 infants Originally published: Pittman L. 2002. Congenital cystic adenomatoid mal- (82 percent) had renal anomalies, and 34 infants (68 percent) formation of the lung. Neonatal Network 21(3): 59–65. Used with permis- sion of Springer Publishing Company, LLC, www.springerpub.com/nn. had limb anomalies. Other associated defects included cleft The author discloses no relevant financial interests or affiliations with any lip/palate, omphalocele, neural tube defects, and diaphrag- commercial interests. matic hernia.70 Botto and colleagues reported on the largest popula- tion reviewed to date to evaluate the incidence of major

2C-20 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics congenital defects. The authors evaluated approximately 10 births.79 Khoury and colleagues reported an occurrence of million infants born between 1983 and 1991 listed in the 50 cases in the approximately 24,000 live births that were International Clearinghouse for Birth Defects Monitoring examined, representing an incidence of 1.6 in 10,000 births.70 Systems. There were 2,295 infants with three or more major Botto and colleagues reported an occurrence of 286 cases congenital anomalies with unknown etiology. Of those in the approximately 10,000,000 live births that were exa- infants, 286 (12 percent) had VATER association, with mined, representing an incidence of 0.03 in 10,000 births.71 8 infants portraying all five anomalies of the association. The authors reported that 75 percent of infants with VATER asso- DIAGNOSIS AND TREATMENT ciation had additional defects, suggesting a possible “overlap” The clinical appearance of VATER association depends on with other associations.71 the anomalies present. Any infant with one of the anomalies Numerous case studies in the literature describe infants of the association should be examined thoroughly for addi- with some aspect of VATER association in addition to other tional anomalies, and a detailed prenatal and family history anomalies. Corsello and colleagues described a 36-week should be obtained. The vertebral defects may not be appar- gestational age infant with a birth weight of 1,890 grams ent but can be confirmed by skeletal surveys. Infants with with severe perinatal asphyxia who died shortly after birth. imperforate anus may present with no external opening or a The autopsy revealed esophageal atresia with tracheoesopha- perineal fistula. Surgical repair is determined by the level of geal fistula, laryngeal stenosis, anal atresia, multiple cardiac the anorectal pouch. defects, and a .73 Murr and colleagues Infants with esophageal atresia will present with excessive described a 37-week gestational age infant with a birth weight salivation and respiratory distress. Esophageal atresia with of 1,410 grams who died shortly after birth. The autopsy distal TEF is the most common type of tracheoesophageal revealed multiple vertebral anomalies, anal agenesis, bilateral fistula, occurring in 85 percent of all TEF cases.81 Diagnosis renal dysplasia, single umbilical artery, and pulmonary hypo- can be confirmed by placing a nasogastric replogle catheter plasia.74 Hattori and colleagues described an infant born with and obtaining an x-ray. In the case of esophageal atresia, the anal atresia, vertebral defects, and . The infant catheter cannot be advanced to the stomach and will remain had episodes of respiratory distress at 10 and 11 months of age in the upper esophageal pouch. Infants with esophageal and was subsequently diagnosed with a displaced bronchus.75 atresia and no TEF will have a gasless abdomen. Surgical repair is usually done immediately and delayed only in prema- ETIOLOGY AND INCIDENCE ture infants and those with a long gap between the pouch and The VATER association is referred to as an association, the distal portion of the esophagus. Success of the operation as opposed to a syndrome or a sequence. A sequence and a depends on the age and weight of the infant and the nature syndrome are patterns of anomalies with a “single known or and severity of associated anomalies. Complications include presumed cause” (p. 488).76 An association is a “nonrandom respiratory compromise, dysphagia and feeding intolerance occurrence of multiple malformations for which no specific or related to strictures, and gastroesophageal reflux.81 common etiology has been identified” (p. 489).76 The etiology Infants with VATER association do not generally exhibit of VATER association is unknown and is most often a “spo- any form of mental retardation. However, there are often radic occurrence in an otherwise normal family” (p. 664).77 developmental delays due to the nature of the defects.77,78 Quan and Smith, and Temtamy and Miller hypothesized Postnatal growth restriction is common, but catch-up growth that defects in the developing mesoderm prior to the 35th can be achieved over the long term.82 day of embryogenesis are a possible etiology.68,69 Beals and The following case study illustrates the course of one Rolfe suggested that because of the variability in presenta- neonate with VATER association. tion of anomalies, there may be “multiple insults” rather than a single etiology.78 Kim and colleagues studied “Gli genes, CASE STUDY which encode transcription factors mediating sonic hedge- Baby S was a 39-week gestation, 2,680 g, AGA male infant hog (Shh) signaling in mice” and hypothesized that expo- born to a 31-year-old gravida 3, para 2 mother. Her prenatal sure to teratogens during pregnancy may result in alternate screening tests were as follows: blood type A positive, VDRL pathways that may in turn produce many of the anomalies in nonreactive, HIV negative, hepatitis negative, and rubella this association (p. 311–312).79 A population-based study by immune. The mother had received adequate prenatal care, Loffredo and colleagues found a strong association between and her only medication during pregnancy had been prenatal maternal diabetes and multisystem anomalies. In addition, vitamins. She reported smoking one pack of cigarettes per day the incidence of VACTERL association in infants of diabetic during the pregnancy. Her medical history included migraine mothers was five times greater than that of infants of nondia- headaches, cholecystectomy, and gestational diabetes in a betic mothers.80 previous pregnancy. Her family history was remarkable for The incidence of VATER (or VACTERL) association hypertension and diabetes. A routine prenatal ultrasound varies. One study reported it as approximately 1 in 5,000 live showed limb anomalies.

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-21 FIGURE 2C-20 n Right arm. X-ray demonstrates shortened FIGURE 2C-21 n Left arm. X-ray demonstrates absent radius and forearm. club hand.

Courtesy of Wesley Medical Center, Wichita, Kansas. Courtesy of Wesley Medical Center, Wichita, Kansas.

The mother received no medications during labor, and her (Figure 2C-22). The following evaluation was made of the membranes were artificially ruptured approximately one hour x-ray shown in Figure 2C-22: prior to delivery. The infant was born by spontaneous vaginal Indication: Evaluation for congenital anomalies associated delivery under epidural anesthesia with vertex presentation with VATER association and clear amniotic fluid. Apgar scores were 9 and 9 at one and Penetration: Apparently normal, with soft tissues of the five minutes, respectively. The infant received stimulation and body visible oral suction following delivery. Copious oral secretions were Rotation: Slightly rotated, as indicated by elevated left clavi- noted following delivery, and attempts to pass an orogastric cle and shortened rib distance on right tube to the stomach were unsuccessful. In addition, the infant Soft tissues: Normal thickness had upper limb anomalies. The infant was admitted to the Bony structures: 13 sets of ribs and mild sacral dysplasia with NICU for further evaluation. asymmetry of L4-5 and coccyx Physical examination on admission revealed a two-vessel Tracheal air column/esophagus: Normally placed trachea , imperforate anus, shortened forearms bilate- with carina between T4 and T5, tip of the orogastric tube rally, and a left radial club hand consisting of two digits overlying the left side of the vertebral column and stopping (Figures 2C-20 and 2C-21). A peripheral IV was placed and at the level of T3–T4 dextrose solution was initiated. A blood culture and complete Hilum: Normal with visible thymus, normal postdelivery blood count were obtained and antibiotic therapy begun. A perihilar streaking noted on right chest xray showed the tip of the orogastric tube at T3–T4, Heart: Normal heart size, although large thymus obscures 13 sets of ribs, a sacral fusion anomaly, and normal heart size left upper heart border

2C-22 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-22 n Chest and abdomen. (1) orogastric tube stops at FIGURE 2C-23 n Esophageal atresia with distal T3–T4, (2) 13 sets of ribs, and (3) sacral fusion tracheoesophageal fistula. anomaly.

From: Spitz L. 2005. Esophageal atresia and tracheoesophageal malformation. In Pediatric Surgery, 4th ed., Ashcraft KW, Holcomb GW, and Murphy JP, eds. Philadelphia: Saunders, 355. Reprinted with permission from Elsevier Science.

TEF with reanastomosis of the esophagus was done. Because Courtesy of Wesley Medical Center, Wichita, Kansas. of anal atresia, a divided sigmoid colostomy was also per- formed, and a broviac catheter was placed in anticipation of extended need for intravenous access. A chest tube for drain- Diaphragm: Approximately T9, indicating good lung age was inserted during surgery and removed on day 8. The expansion infant was extubated to room air on day 5. On day 7, the Intercostal spaces: Normal in size, slightly more compressed thoracotomy site was erythematous with yellow drainage. A on right because of rotation blood culture and surface culture from the site were obtained, Lung fields: Clear left lung field, accentuated perihilar streak- and vancomycin and gentamicin therapy was begun. Both ing on right cultures remained negative, and the infant received 48 hours Gastric air: Present in stomach and throughout intestinal of antibiotics. A Gastrografin swallow study done on day 8 tract, no air in rectum showed a mild narrowing at the anastomosis without extrava- A renal ultrasound showed both the kidneys and adrenal sation of contrast and mild gastroesophageal reflux into the glands normal in size, shape, and echogenic texture. An echo- lower esophagus. The infant was started on metoclopramide cardiogram showed normal cardiac function and a tiny mus- to facilitate gastric emptying, and ranitidine was initiated to cular ventricular septal defect. decrease possible irritation to the reanastomosis. On day 1, the infant was taken to the operating room for bronchoscopy and subsequent repair. The bronchoscopy SUMMARY demonstrated esophageal atresia with a distal tracheoesopha- Baby S began oral feedings on day 8 at 20 mL/kg/day. geal fistula entering the membranous portion of the trachea The infant reached full enteral feedings on day 11 and was located immediately above the carina (Figure 2C-23). The subsequently advanced to an ad lib demand schedule. The infant was subsequently intubated. Ligation and repair of the broviac catheter was removed on day 13.

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-23 An orthopedic surgeon was consulted to evaluate abnor- FIGURE 2C-24 n Three types of lung sequestration. malities of the upper extremities and hip laxity noted on admission examination. The orthopedic specialist found decreased abduction of the hips bilaterally with no instability and normal range of motion on exam. An ultrasound showed bilateral posterior subluxation with no frank dislocation. The infant was evaluated by a physical therapist and received daily splinting and stretching of the upper extremities, with contin- ued evaluation planned following discharge. When the infant was discharged on day 15, she was breast- feeding on a demand schedule with bottle supplementation and continued to receive ranitidine and metoclopramide. Follow-up was scheduled with the cardiologist, the orthope- dic surgeon, and the family physician.

Originally published: Spoon JM. 2003. VATER association. Neonatal Network 22(3): 71–74. Used with permission of Springer Publishing Company, LLC, www.springerpub.com/nn. The author discloses no relevant financial interests or affiliations with any commercial interests.

Extralobar Sequestration with Congenital

Diaphragmatic Hernia: A From: Wheeler TC, and Jeanty P. 1993. Lung sequestration, extralobar subdiaphragmatic. Retrieved September 25, 2003, from www. sonoworld.com/TheFetus/page.aspx?id=403. Reproduced with Complicated Case Study permission from TheFetus.net.

Kathryn Harris, MSN, RN, NNP-BC common site of herniation is in the posterolateral region of the diaphragm; the result is known as Bochdalek’s hernia. ulmonary anomalies such as congenital diaphragmatic The other sites of herniation, which are less common, are Phernia (CDH) and extralobar sequestration present with an anterior hernia between the sternal and costal portions of varying degrees of respiratory distress in term newborns.83 the diaphragm (known as Morgagni’s hernia) and an esopha- The degree of respiratory distress ranges from mild tachy- geal hernia. There is a tendency for the right pleuroperitoneal pnea to rapid, severe respiratory deterioration immediately canal to close before the left, leading to a larger number of after birth. left-sided diaphragmatic hernias.84 CDH is a failure in the development of the diaphragm, Because the size of the hernia can range from a small slit which normally occurs at the end of the sixth week of fetal to the complete absence of the entire diaphragm on one side, development. The diaphragm develops when the pleuroperi- the amount of abdominal contents migrating into the thorax toneal membrane joins with the mesentery of the esophagus varies from the stomach alone to a significant portion of the and the septum transversum, the tissue that separates the intestines and liver. When abdominal contents move into heart from the liver. During this development, two openings, the thorax, they compress the developing lungs, heart, and the pleuroperitoneal canals, form on each side of the esopha- trachea. Normal lung development is arrested at this stage, gus. Fusion of the upper and lower portions of these canals resulting in marked hypoplasia of the lung on the side of the separates the pericardial cavity from the pleural cavities and defect and, to a lesser degree, hypoplasia of the opposite lung. the pleural cavities from the peritoneal cavity.84 Diaphragmatic Herniation of the abdominal contents can occur as early as development is complete when these structures and canals ten weeks gestation or as late as the third trimester. The sever- close, creating a barrier between the thoracic and the abdomi- ity of the lung hypoplasia is directly related to the phase of nal cavities. If these canals stay open or if there is a defect lung and vascular development that is occurring at the time in the formation of the diaphragm, the abdominal organs of compression. Once the abdominal contents have herniated can migrate up into the thorax as early as 10 weeks gesta- into the chest, the lungs cannot develop normally.85 Thus, tion. There are three potential areas of herniation. The most

2C-24 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics the earlier the migration of the abdominal contents into the NICU physician, the extracorporeal life support (ECLS [or chest, the more compromised the affected lung will be. ECMO]) team, and the general surgeon not to offer ECLS Pulmonary sequestration is a rare congenital abnormality to this family until after 35 weeks gestation. Aggressive toco- consisting of a perfused but unaerated mass of lung tissue that lytics were employed in an attempt to prolong the pregnancy, often has an arterial blood supply. There are three forms of and bed rest was ordered. JG’s mother went into spontane- pulmonary sequestration: extralobar (ELS), intralobar (ILS), ous labor at 37 weeks gestation. and extralobar/extrathoracic (Figure 2C-24). Pulmonary sequestrations account for approximately 6 percent of all con- Delivery Room Management genital pulmonary malformations. ILS, the more common Our delivery room strategy includes immediate ventilation, type, occurs when the sequestration is contained within the administration of bovine lung extract surfactant (bLES), the visceral pleura of the lung itself.86 ELS accounts for approxi- placement of an umbilical venous catheter, and the adminis- mately 25 percent of sequestration cases and occurs when the tration of fentanyl and pancuronium (Pavulon). The infant sequestration is enclosed within its own pleura.86,87 An ELS is stabilized on a transport overhead warmer and a transport has no connection to the normal pulmonary structures and ventilator and is transferred to the NICU/PICU for further cannot function as regular lung tissue.88 ELS is also known management. as bronchopulmonary foregut malformation, accessory JG was born by spontaneous vaginal delivery and was lung, aortic pulmonary lobe, and Rokitansky lobe.89 Bagwell estimated to be about 3.5 kg (7 lb, 11 oz). At birth, JG notes that intralobar lesions rarely have associated anoma- had a heart rate of less than 100, had no respiratory effort, lies, whereas anomalies are associated with extralobar lesions and was blue and limp. His Apgar scores were 2 and 7. He in from 15 to 50 percent of instances. Intracardiac anoma- was immediately intubated, and bLES was administered. lies, lung agenesis, and diaphragmatic hernia are associated Following intubation, a temporary umbilical venous catheter with ELS.90 was inserted, and JG was sedated and paralyzed prior to trans- Although CDH is often an isolated congenital abnor- port. He was stabilized on the transport ventilator. Because mality, other associated heart, kidney, lung, skeletal, and/or of the high likelihood of the need for ECLS, JG was admitted neurologic abnormalities may occur.91 The Bochdalek type to the PICU. of diaphragmatic hernia is more commonly associated with other anomalies; of these, 20 percent are heart defects and PICU Management Pre-ECLS 5–16 percent are chromosomal anomalies.92 On admission, JG was placed on conventional mechanical ventilation. An umbilical arterial catheter was inserted, and CASE STUDY the umbilical venous catheter was replaced with a triple-lumen Antenatal History/Management catheter. The initial arterial blood gas (ABG) was pH = 7.07,

JG, a term male infant, was born at 37 weeks gestation to a PaCO2 = 77, PaO2 = 48, HCO3 = 25, and base deficit = –7.6.

39-year-old, gravida 3, para 2 woman. The mother’s medical The oxygen index (OI = mean airway pressure × FiO2/PaO2), history included bronchitis, asthma, and postpartum depres- which is used as an indicator of oxygenation, was 18.8. Infants in sion. Her asthma was treated with inhalers and fluticasone respiratory failure qualify for ECLS with an OI of 40 or higher. and salmeterol inhalation (Advair). She has two healthy chil- JG became more acidotic, with high PaCO2 despite numerous dren who were born at term. ventilation adjustments. High-frequency oscillating ventilation On a routine antenatal ultrasound at 17 weeks gestation, a and inhaled nitric oxide (iNO) were instituted. There was no left CDH was diagnosed, a severe mediastinal shift was noted, clinical improvement with iNO, but JG deteriorated when the and the left lobe of the liver was seen in the left hemithorax. iNO was discontinued, so it was restarted. Increasing respi- Serial ultrasounds showed polyhydramnios. An amniocentesis ratory and metabolic acidosis and persistent shunting at the revealed normal XY chromosomes. JG’s mother was followed atrial and ductal levels were noted despite increased ventila- through the Fetal Diagnostic Service at our hospital; she tion, sodium bicarbonate administration, and volume support. received serial ultrasounds and echocardiograms. JG’s parents There was a significant difference in pre- and postductal satu- met with the NICU physician and the general surgeon as part rations, shunting from right to left via the patent ductus arteri- of our CDH counseling/management protocol. Mother, osus (PDA), and left-to-right shunting via the patent foramen father, and the two siblings attended anticipatory grief and ovale (PFO) on the echocardiogram. A dopamine infusion of reproductive psychiatric counseling in view of this high-risk 10 mcg/kg/minute was initiated to support the blood pregnancy. pressure. JG’s mother went into preterm labor at 33 5/7 weeks Despite escalating treatment, JG continued to deteriorate. gestation. She was transferred from an outlying hospital to The pre-ECLS workup was initiated. Head and abdominal our center for assessment. The antenatal echocardiograms ultrasounds and an echocardiogram were done. The head revealed small pulmonary vessels. In view of these vessels ultrasound revealed a small subependymal cyst, which did and the severe left hernia, the decision was made by the not prevent ECLS qualification. The abdominal ultrasound

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-25 FIGURE 2C-25 n JG’s initial chest x-ray before being placed on FIGURE 2C-26 n JG’s initial abdominal ultrasound before being ECLS. placed on ECLS. Trachea deviated to the right. Tracheal air column deviated to the Extralobar sequestration located on right side of abdomen. Note right. Mediastinal shift to the right. Compressed right lung fields. blood vessel supplying the sequestration. Sequestration borders Right heart border shifted to the right. Stomach bubble and bowel marked with crosses. gas visible in left chest. NG tube in situ and deviated to the right. Unable to identify the ELS on this film.

Courtesy of Children’s and Women’s Health Centre of British Columbia, Vancouver, British Columbia. Courtesy of Children’s and Women’s Health Centre of British Columbia, Vancouver, British Columbia. revealed bowel loops and the liver in the left hemithorax. No spleen was visualized. A mass was noted between the inferior vena cava (IVC) and the aorta: it was suspected to of ECLS offered in our center are venovenous (VV) ECLS, be an extralobar sequestration. The echocardiogram showed which provides lung support but limited cardiac support, normal cardiac anatomy, a dilated right ventricle with ade- and venoarterial (VA) ECLS, which provides complete heart quate function, a left-sided aortic arch, and a deviation of and lung support. ECLS provides well-oxygenated blood the heart and major vessels to the right. The left pulmonary to the sick infant, eliminating the need for aggressive, and artery was of reasonable size, with normal venous return. The often damaging, ventilation to achieve the same oxygenation. left ventricle was of normal size, but the right ventricle was Blood flow through the ECLS circuit is ensured through use dilated, with suprasystemic pressures indicating high pulmo- of the largest cannula that can fit into the vessel and by full nary vascular resistance. Mild tricuspid regurgitation was also heparinization of the infant’s blood for the entire ECLS run. noted, indicating persistent pulmonary hypertension of the newborn (PPHN). The systemic blood pressure was low, and ECLS Course the peripheral pulses were weak. JG remained acidotic, with In our center, neonates requiring ECLS because of pulmo- increasing lactic acid levels despite alkalinization to pH 7.4 nary pathology are normally supported with VV ECLS using and an attempt to increase the systemic blood pressure above a 10.0–12.0 French (Fr) double-lumen cannula and an 8.0 Fr the pulmonary vascular resistance. JG did not improve, and cephalad catheter. At 10½ hours of age, using a right-neck his OI reached 64. The ECLS team was mobilized. approach, JG was cannulated with great difficulty because of ECLS is a form of cardiopulmonary bypass that allows the small diameter of his vessels. JG was cannulated using for oxygenation and support of an infant in critical condi- 8.0 Fr single-lumen catheters via the right internal jugular tion who has a recoverable disease process. ECLS involves vein and the right carotid artery and was placed on VA ECLS. artificial oxygenation and cardiac support using a pump The vessel anatomy prevented insertion of a cephalad catheter that circulates, oxygenates, warms, and returns the blood in the jugular bulb. The small cannulas were extremely restric- to the infant via large cannulas using technology similar to tive to ECLS flow, and any movement JG made decreased the that employed for cardiopulmonary bypass. The two forms ECLS flows, reducing the level of support to suboptimal. The

2C-26 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-27 n Color Doppler of JG’s initial abdominal reinitiated on day 2 because of high pulmonary pressures on ultrasound. the echocardiogram. JG required iNO at 20 parts per million Same view as Figure 2C-26 with color Doppler outlining blood flow throughout his entire ECLS run. Minimal improvements in into sequestration. his chest x-ray or chest movement were noted for the first few days on ECLS, despite additional bLES, which was expected. Rest ventilation settings were maintained for JG except when trials off ECLS were attempted. Lung contribution was assessed daily using an oxygen challenge. For this, his ventila-

tor oxygen was increased to FiO2 1.0 for ten minutes, and the ABG was repeated. Improvements were noted two days into the ECLS run. JG had four trials off ECLS, on days 5, 7, 10, and 13. He had significant episodes of PPHN during these trials off ECLS and required the use of vasodilators, iNO, paralysis, sedation, and dopamine. He was decannulated on day 13. Following decannulation, he remained sedated and paralyzed on con- ventional ventilation and iNO. He was paralyzed for 24 hours after decannulation, and then the paralysis was lifted. On day 19 of life, JG was taken to the operating room for a flap closure of his diaphragmatic hernia. The ELS was not resected at that time. His initial postoperative course was complicated by ongoing , venous congestion in his lower limbs, and increased intra-abdominal pressures. Postoperative chest x-ray is seen in Figure 2C-28. Figure 2C-29 depicts the chest x-ray of another infant showing significant left-sided asymme- try whose CDH was repaired on circuit, with a postoperative Courtesy of Children’s and Women’s Health Centre of British chest tube in situ. JG was paralyzed for four days following Columbia, Vancouver, British Columbia. his diaphragmatic hernia repair. He continued on iNO until day 27. JG was extubated four days later, on day 31, but failed extubation because of increased work of breathing, desatura- cannula that was situated in the jugular vein occluded the tions, and poor lung volumes. He was reintubated. lumen completely; as a result, JG developed significant upper JG had two other trials of extubation between days 48 and body and head swelling consistent with superior vena cava 60 of life, but both were unsuccessful. He also had ongoing (SVC) syndrome. SVC syndrome occurs when blood flow problems with left pneumothoraces (Figure 2C-30), pre- from the head through the SVC is restricted, causing conges- venting a transfer to his local hospital. On day 60, JG was tion. The congestion was directly related to the right internal transferred to the PICU in his local hospital and remains ven- jugular cannula, which prevents cerebral blood drainage from tilated, with resolving left pneumothoraces. The ELS was not the right side of the head. JG’s ECLS run was 13 days long resected at the time of the CDH repair; it will be monitored and was complicated by severe PPHN and marked edema. as he grows. Cardiovascular. JG’s clinical course throughout the Clinical Course (Systems Approach) ECLS run was complicated by extreme PPHN with sig- Chest. The initial chest x-ray (Figure 2C-25) showed small nificant shunting, tricuspid regurgitation, and poor cardiac lungs bilaterally with a tidal volume of about 1.5–2 mL/kg. function. Echocardiograms confirmed the presence of a mass The chest and abdominal ultrasounds precannulation showed density between the IVC and the aorta on the right side a left thorax filled with bowel, a right pleural effusion, and above the right diaphragm with an arterial supply, identified a small, hypoplastic left lung. The spleen was localized in as an extralobar sequestration. The sequestration did not con- the left lower chest, and a mass sequestration with an arte- tribute to PPHN or to cardiac failure, so no other investiga- rial blood supply was noted above the right diaphragm. tions were undertaken following the ECLS run or after CDH Figures 2C-26 and 2C-27 depict the precannulation abdomi- repair. Indications of continued PPHN were found on echo- nal ultrasounds identifying the ELS. cardiogram in the first hours of ECLS and throughout his Once ECLS support was established, JG’s ventilation was run. JG remained on dopamine throughout his ECLS run at reduced to “rest” settings with a rate of 10 breaths per minute, 5–10 mcg/kg/minute and required significant volume infu- peak airway pressures of 33 cmH2O, PEEP of 10 cmH2O, sions to support his blood pressure, perfusion, and cardiac and and FiO2 of 0.25. The iNO was discontinued. The iNO was urine output. He required diuresis with a furosemide (Lasix)

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-27 FIGURE 2C-28 n JG’s initial chest x-ray following CDH repair FIGURE 2C-29 n Chest x-ray of KP (a 38-week-gestation neonate (day 19). with CDH) following CDH repair on ECLS. Note pleural effusion in left basal lung fields. NG tube in situ. Staples KP was unable to be removed from bypass for surgery. Note ECLS in situ. Right perihilar congestion. Right middle lobe congestion. cannulae and postoperative chest tube. Asymmetry of left chest No postoperative chest tubes placed. wall. Small pleural effusion in left basal lung field. Right upper lobe collapse. Endotracheal tube located at T3. NG located in stomach. Staples in situ. Marked body wall edema.

Courtesy of Children’s and Women’s Health Centre of British Columbia, Vancouver, British Columbia.

were taken from limited laboratory studies. IV sildenafil was Courtesy of Children’s and Women’s Health Centre of British added to JG’s vasodilator regimen on day 6 of life, and a trial Columbia, Vancouver, British Columbia. off ECLS was initiated on day 7. He decompensated during the trial off ECLS with an unsustainable blood pressure and had a significant episode of desaturation. During this trial infusion and the use of the artificial kidney in the ECLS circuit off ECLS, the echocardiogram showed tricuspid regurgita- to augment his innate renal function and to help treat the sig- tion and suprasystemic right atrial pressures, which confirmed nificant edema that resulted from his volume overload. JG’s ongoing PPHN. ECLS was restarted. On day 10, JG’s right PPHN was unresponsive to iNO and ECLS, so the medical atrial pressures had improved, and another trial off ECLS was team sought alternative treatments for his PPHN. made. This attempt failed after 3½ hours because of profound Phenoxybenzamine is an alpha blocker, an afterload hypotension that was unresponsive to volume infusions, and reducing agent, and a potent vasodilator traditionally used administration of dopamine and norepinephrine. He was to decrease pulmonary artery pressures and early signs of resupported with ECLS. The ECLS team expressed concern pulmonary hypertension in infants following heart surgery.93 about the degree of PPHN and whether it was reversible. Because of JG’s severe PPHN, phenoxybenzamine was initi- Sildenafil and phenoxybenzamine have significant systemic ated on day 5 of life to see if the pulmonary artery pressures hypotensive side effects, which likely caused the profound could be reduced. Although they decreased, the pressure hypotension. The sildenafil, phenoxybenzamine, and norepi- reduction was not enough to reverse the ductal and atrial nephrine were discontinued once ECLS was reestablished. shunts. After the phenoxybenzamine failed, intravenous (IV) Following the day 10 trial off ECLS, JG’s blood gases were sildenafil was initiated. poor, and the circuit and patient ventilation were increased. Sildenafil, more commonly known as Viagra, is a pulmo- Because of the significant hypotension and the instability of nary vasodilator that has been used orally in the treatment his blood pressure, he was treated with hydrocortisone. of PPHN with success. It could not be given orally to JG Discussion was undertaken about the possibility of repair because of his unrepaired diaphragmatic hernia and the sub- of JG’s CDH and ELS on circuit and the ongoing risks of sequent risk of bowel ischemia. IV sildenafil is released with continuing prolonged ECLS therapy. Continued efforts were special permission in Canada as an experimental drug and has made to wean JG off ECLS support, and the decision was had limited use in human trials. There were no clinical trials made to repair the CDH when JG was stable off of ECLS. of IV sildenafil in neonates, and the dosage recommendations Then the team set day 13 of ECLS as the ECLS run end

2C-28 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-30 n JG’s chest x-ray with recurrent left basal The CDH repair was delayed by 48 hours to ensure nega- (day 48). tive blood cultures. His surgery was on day 19. On day 22, Note NG and NJ tubes. Endotracheal tube looks low. Right heart JG had abdominal swelling, redness, marked abdominal border is very shaggy, with streaky infiltrates on the right. Left wall edema, occult blood in his stool, and dilated loops of upper lobe looks hazy. Area of lucency on lower left is consistent bowel on abdominal x-ray. Treatment with metronidazole with a pneumothorax. (Flagyl) for suspected necrotizing enterocolitis, which was later disproved, was begun. By day 25, abdominal symptoms regressed, and the antibiotics were discontinued. A culture from the central line and the blood, on day 26, was positive for coagulase-negative Staphylococcus, and vancomycin was started. A Candida diaper rash was also treated with topical nystatin. On day 33, JG had a mild separation of his incision, which was treated with topical polysporin ointment. Neurologic. JG was sedated and paralyzed from birth and was anesthetized for the cannulation. By day 1 of ECLS, he was deparalyzed but remained heavily sedated. As JG’s ECLS run continued, he required increased sedation for increased tolerance and membrane absorption of his seda- tion. Midazolam was later added to augment his fentanyl infusion. JG also required intermittent boluses of medication to sedate and paralyze him prior to handling and suctioning. When he was being trialed off ECLS or when components of his circuit were changed, JG was sedated and reparalyzed to prevent agitation and to reduce his oxygen requirements. JG’s pupils were reactive to light, and his anterior fontanel and his cranial ultrasounds were unchanged throughout his ECLS run. He moved all limbs well and responded to voices and touch during his ECLS run. JG was decannulated on day 13, and his sedation was significantly weaned by day 14. Courtesy of Children’s and Women’s Health Centre of British Columbia, Vancouver, British Columbia. JG was paralyzed for 24 hours after decannulation. He was reparalyzed briefly on two occasions for a pulmonary hem- orrhage on day 16 of life and for his diaphragmatic hernia repair on day 19. He was deparalyzed on day 22. JG was point, without possibility of resupport with ECLS if PPHN slowly weaned from his IV fentanyl and midazolam, and his recurred following decannulation (removal from ECLS medications were converted to oral morphine and lorazepam support). JG was successfully decannulated on day 13. He (Ativan) once he reached full feedings. required dopamine for 24 hours after decannulation but JG is now an alert and responsive baby who shows no defi- did not require vasodilator therapy for PPHN. JG remained cits in motor function, neurologic status, or hearing. He is on edematous and required diuretic therapy for several weeks low doses of morphine and lorazepam and is on a weaning after his CDH repair on day 19, despite good renal function regime. JG tolerates being up in his bouncer chair and enjoys and urine output. He remained on hydrocortisone until 24 his pacifier, but he has not yet been fed orally because of his hours following repair of the diaphragmatic hernia. endotracheal tube. At 30 days of age, a small coarctation of the aorta was seen Gastrointestinal. JG received nothing by mouth until on echocardiogram. No surgical intervention was required at after his CDH repair because of the amount of the bowel that time; the coarctation is being monitored. in his chest and the risk of ischemia. Feedings were initiated Infection. JG was initially placed on prophylactic treat- on day 27, but he did not tolerate nasogastric (NG) feedings ment with ampicillin and gentamicin on admission as per even in small volumes of 2 mL every two hours. He had a the NICU CDH protocol and because of exposure to the nasojejunal (NJ) tube placed on day 29. He attained full NJ ECLS circuit. On days 5 and 6, his blood cultures grew feedings of breast milk on day 38. Mycoplasma, and the antibiotics were changed to erythro- Family. JG’s family is doing well. His siblings visit reg- mycin and clindamycin. At 14 days of age, JG was febrile; ularly and are adapting to the PICU environment with the his umbilical lines were removed, and a new radial arterial assistance of play therapy and counseling. JG’s mother and line and central venous catheter were placed. Blood cultures father are attending regular counseling. Other challenges were drawn, and vancomycin and cefotaxime were started. faced by this family were the distance between their home

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-29 FIGURE 2C-31 n Differential diagnoses of neonatal chest lesions. FIGURE 2C-32 n A pulmonary sequestration. (A) Normal lungs, with symmetric appearance. (B) Hydrothorax, (A) The sequestration is seen as an unaerated mass of lung. If separate with fluid compressing and restricting growth of the normal from the remaining lobes, it is an extralobar sequestration; if lungs. (C) CCAM, with cystic appearance and connection to the within, an intralobar sequestration. (B) Systemic arteries that tracheobronchial tree. (D) BPS, depicting an anomalous blood supply the sequestration lie within the inferior pulmonary supply to an aberrant lung tissue mass. (E) CDH, with bowel and ligament. (C [inset]): During removal of the sequestration, the stomach above the diaphragm. (F) Bronchogenic cyst, centrally thoracic aorta must be carefully inspected throughout its length to located and well defined. identify what are often multiple arterial branches to the lobe.

From: Nakayama DK. 1997. Lung bud anomalies. In Critical Care of the Surgical Newborn, Nakayama DK, et al., eds. Oxford, England: Wiley-Blackwell, 217. Reprinted by permission.

From: Hilpert PL, and Pretorius DH. 1990. The thorax. In Diagnostic ELS AND CDH: Ultrasound of Fetal Anomalies: Text and Atlas, Nyberg DA, Mahony BS, and Pretorius DH, eds. Chicago: Year Book Medical, 273. A REVIEW OF THE LITERATURE Reprinted by permission. Diaphragmatic hernia and extralobar sequestration occur secondary to abnormalities in the development of the lung, the blood vessels, and the diaphragm in the earliest weeks of and our hospital and the separation of one parent from the fetal development.94 Many theories have been proposed to older siblings. This family’s course was further complicated explain these abnormalities, but there is no consensus within by the sudden death of JG’s maternal grandfather on JG’s the literature. day of life 51. Summary. On day 60, JG remains ventilated on moder- EXTRALOBAR SEQUESTRATION ate settings and has yet to be successfully extubated. He has Etiology and Pathophysiology recurrent left pneumothoraces. He becomes easily fatigued, Pulmonary sequestration is part of a spectrum of related tachypneic, and tachycardic with any exertion or crying. He congenital lesions that includes congenital cystic adeno- remains on weaning doses of oral morphine and lorazepam matoid malformation (CCAM), bronchogenic cyst, and and remains on oral diuretics. He is on full NG feedings and congenital lobar emphysema (Figure 2C-31).90 Gustafson is gaining weight slowly. He has been returned to his refer- and colleagues describe a spectrum of lung anomalies that ring hospital for further management, and his family is very range from an abnormal blood supply that is attached to a pleased with his return to their hometown and his progress normal lung to abnormal lungs that have no abnormal blood to date. JG is still a medically fragile infant. He will be moni- supply.95 CCAMs are congenital masses that communicate tored closely for his coarctation, sequestration, and pulmo- with the tracheobronchial tree and rarely have an anomalous nary hypoplasia and will be followed in our facility for his blood supply. Bronchogenic cysts are congenital areas of non- developmental needs and post-ECLS follow-up, including functioning lung tissue that are usually filled with mucus and ongoing hearing screening. Hearing screening is particularly can be found in the lung or mediastinum.96 Congenital lobar important because of the prevalence of hearing deficits in emphysema occurs when there is overdistention of one or ECLS and CDH survivors. more normal lung lobes after birth. The causes of CLE range

2C-30 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-33 n Blood flow of the pulmonary sequestration. FIGURE 2C-34 n Normal development of the lung bud and, later, the esophagus and trachea. Large venous tributaries that flow from the lobe must be identified and controlled during surgery to remove the sequestration. A plane is developed bluntly between the sequestration and normal lung tissue, with vessels and aberrant bronchi divided when they are encountered.

From: Heithoff KB, et al. 1976. Bronchopulmonary foregut malformations: A unifying etiological concept. American Journal of Roentgenology 126(1): 52. Reprinted by permission from the American Journal of Roentgenology.

1 From: Nakayama DK. 1997. Lung bud anomalies. In Critical Care of 80 percent incidence of ELS on the left side. Schnapf notes the Surgical Newborn, Nakayama DK, et al., eds. Oxford, England: a 95 percent left-sided occurrence. Schnapf also notes a more Wiley-Blackwell, 217. Reprinted by permission. common association with other foregut anomalies, such as diaphragmatic hernia, with ELS than with ILS.86 Shreve cites a 59 percent occurrence of associated anomalies with ELS from abnormal lung tissue preventing deflation of the lobe of compared to a 14 percent association with ILS.83 Table 2C-3 the lung, to defects in the airway, to an obstruction.90 A pul- compares the characteristics of ELS and ILS. monary sequestration is a cystic mass of nonfunctioning lung Congenital malformations associated with ELS are more tissue that does not connect to the tracheobronchial tree but serious and occur in combination.1 They include diaphrag- has an arterial blood supply. The blood supply originates from matic hernia (30 percent of patients), pectus excavatum, anomalous vessels (Figures 2C-32 and 2C-33).95 congenital heart disease, CCAM, and vertebral anomalies.89 The literature contains many hypotheses about the for- Other malformations of the foregut also occur.96 The inci- mation of pulmonary sequestrations. The most plausible is dence of CDH associated with ELS is variable. Aideyan the accessory bud theory. Heithoff and colleagues note that states there is a 30 percent association of CDH with ELS.99 a lung bud normally arises from the foregut at five weeks Shreve notes a 40 percent association.83 In one review of ELS, embryonic age. It develops into the laryngotracheal tube and then splits into two primitive lungs by seven weeks embry- FIGURE 2C-35 n Development of a pulmonary sequestration— onic age (Figure 2C-34). In the case of sequestration, an in this case, a bronchopulmonary foregut additional abnormal lung bud arises below the normal loca- malformation. tion and moves caudally as the normal esophagus develops (Figure 2C-35).97 Whether the subsequent abnormality takes the form of an extralobar or an intralobar sequestration seems to depend on the time at which this accessory budding occurs. If it occurs early in embryonic development, before the pleura is com- pletely formed, then the accessory bud is found within the lung tissue and becomes an intralobar sequestration. If it occurs later in development, after the lung pleura is formed, then the lung bud is separate from the normal lung, becomes encased within its own pleura, and develops into an extralobar sequestration.96,97 When an ELS develops and moves outside of the thoracic space, it is known as an extralobar/extratho- racic sequestration. Pryce notes that there is a marked left- From: Heithoff KB, et al. 1976. Bronchopulmonary foregut malformations: A unifying etiological concept. American Journal sided tendency in ELS, but that the incidence of ILS is evenly of Roentgenology 126(1): 52. Reprinted by permission from the distributed between sides.98 Savic and colleagues cite an American Journal of Roentgenology.

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-31 TABLE 2C-3 n Comparison of Intralobar and Extralobar Pulmonary Sequestrations Sequestration Characteristic Intralobar Extralobar Incidence Uncommon Rare Sex Equal Male (80%) Laterality 60% left 90% left Location Posterior basal segment Above or below diaphragm Pleural investment Not separate, sequestration part of normal lobe Has its own separate pleural investment—visceral pleura Age at presentation and 50% >20 years, adolescent to young adult; recurring 60% <1 year, neonate, respiratory distress symptoms pulmonary infection Arterial supply Systemic: from aorta; often a single large vessel Systemic: from pulmonary artery or aorta; usually small vessels Venous drainage Pulmonary: inferior pulmonary vein Systemic: azygos or hemiazygos vein; less often portal vein Associated anomalies Uncommon Common (>50%), such as congenital diaphragmatic hernia (30%) Foregut connection Very rare More common Bronchial communication Present, small None From: Shamji FM, Sachs HJ, and Perkins DG. 1988. Cystic disease of the lungs. Surgical Clinics of North America 68(3): 590. Reprinted by permission. diaphragmatic hernias were present 58 percent of the time rare. This baby would present with difficulty swallowing and and were always located on the same side as the ELS.100 Other bloody emesis.96 Other infants with ELS may present with authors state that eventration of the diaphragm is the most hydrops fetalis, bilateral hydrothoraces, and severe pulmonary common anomaly associated with ELS (60 percent), followed hypoplasia. Babies with a large left-to-right shunt through by diaphragmatic hernia (30 percent).101 the sequestration may present with congestive heart failure in the newborn period. Cardiac failure resulting from over- Diagnosis and Clinical Presentation circulation through an aberrant systemic artery is especially Isolated extralobar sequestrations are usually asymptom- prevalent in the newborn population.106 Symptoms of cardiac atic and have been found incidentally on prenatal ultrasound, failure in a neonate with ELS include pulmonary edema, on postnatal chest x-ray, or during the repair of a diaphrag- hyperactive precordium, tachypnea, grunting, cyanosis, and matic hernia.86,102-104 Some have been diagnosed antenatally poor feeding.91,106 and have regressed by the time of birth; this is more typical of On chest x-ray, neonates with ELS present with an ELS than of other cystic lesions.105 ELS can be diagnosed on abnormality resembling a cystic area, a mass, or abnormal prenatal and postnatal ultrasound scans. Sequestrations and air-fluid levels.96 The sequestration must be identified and other cystic lung lesions have similar presentations on pre- distinguished from other pulmonary lesions. Postnatal inves- natal ultrasounds.106 Nadler and Barksdale describe ELS as a tigations for an ELS include chest x-ray, ultrasound, echocar- solid mass lesion on ultrasound that is similar in nature to a diogram, computed tomography (CT), magnetic resonance neuroblastoma.107 imaging, and angiography.108 Simple chest x-rays are often The ultrasound diagnoses of ELS and neuroblastoma are useful in the diagnosis of pulmonary sequestrations because distinguished by the gestational age at initial presentation, the films frequently show some abnormality.96,109 The iden- the location of the lesion, and the degree of echogenicity. tification of the ELS and its blood supply is necessary, espe- The ELS is more echogenic than a neuroblastoma on prena- cially if a surgical intervention is planned.106 The mapping of tal ultrasound, and the neuroblastoma does not present until the blood supply to the ELS can be done via CT scan using the third trimester, whereas the ELS presents in the first or a contrast medium or with a cardiac catheterization. The second trimester.107 Table 2C-4 presents information on dif- purpose of the investigation is to identify the lesion, its blood ferential diagnoses of various fetal thoracic masses. supply, and any abnormal connection to other structures and More than half the cases of ELS are diagnosed when the whether the lesion needs to be removed.110 patients are younger than one year, but this is because other, Complications of ELS can include nonimmune hydrops more serious congenital anomalies are present.96 The infant fetalis secondary to vena cava compression by the mass,103 with ELS may present with an infected sequestration, but high-output cardiac failure caused by massive shunt- only if there is a communication with the foregut, which is ing of blood from the aorta or the supplying vessel to the

2C-32 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics TABLE 2C-4 n Differential Diagnoses of Fetal Thoracic Masses FIGURE 2C-36 n Schematic of a diaphragmatic hernia. Condition Appearance “Window” view looking into the thorax and abdomen shows the herniation of the intestine into the thorax through a posterolateral Cystic adenomatoid malformation defect in the left side of the diaphragm. Note that the left lung is Types I and II Macrocysts compressed and hypoplastic. Type III Increased echogenicity Pulmonary sequestration Solid mass Diaphragmatic hernia Cystic mass; look for peristalsis Bronchogenic or enteric cyst Cystic Congenital bronchiectasis Cystic Mediastinal Complex masses Anterior thoracic meningocele Cystic mass Mediastinal Cystic From: Nakayama DK et al. 1997. Lung bud anomalies. In Critical Care of the Surgical Newborn. Oxford, England: Wiley-Blackwell, 204. Reprinted by permission.

sequestration and edema,3 caused by an abnormal connection between the esophagus and the sequestration,95 and secondary infection resulting from the 111 From: Sadler TW. 2010. Langman’s Medical Embryology, 11th ed. inability of the abnormal tissue to drain. Philadelphia: Lippincott Williams & Wilkins, 163. Reprinted by permission. Management and Treatment Antenatal treatment of ELS is expectant unless the fetus presents with hydrops. In hydropic fetuses, surgical treat- intestine. Malrotation is present in all cases of CDH because ment or thoracic draining of the lesion is needed to prevent the intestines have not been fixed to the posterior abdomi- fetal demise. If hydrops is not present, the fetus is monitored nal wall. This malrotation is often corrected by the surgeons throughout the pregnancy with postnatal diagnosis and treat- when the hernia is repaired.108 ment.105 The postnatal management of an infant with isolated, Diaphragmatic hernias vary in size and in the degree asymptomatic ELS is also expectant. Those with ELS who are to which they interfere with normal lung development. symptomatic suffer from respiratory distress and should be Displacement of the viscera into the thoracic cavity prenatally managed as such. prevents normal growth and development of the ipsilateral Surgical resection of the ELS is the treatment of choice lung.90 The mediastinal shift and compression by the abdomi- for infants who present with chronic infection or symptoms nal viscera that occur during gestation affect the development resulting from compression of normal lung tissue. Because of the contralateral lung as well. There is an overall reduction of its separation from the normal lung tissue, an ELS can be in the number of bronchi and alveoli, as well as changes in excised without loss of normal lung tissue.86 If an ELS is dis- the arterial vessels supplying the lung.108 The branching of covered during another operation (e.g., a CDH repair), then the bronchi and pulmonary vessels during the pseudoglandu- it should be excised.112 Delayed intervention in the infant with lar phase (5–17 weeks gestation) is altered and can be inter- a symptomatic ELS can result in erosion of the bronchus, rupted by the migration of the abdominal contents into the secondary infection, or distention of the sequestration.91 thoracic cavity.85 The compression of the developing bronchi- oles during this early period stops the normal development CONGENITAL DIAPHRAGMATIC HERNIA of bronchi, reducing the number of alveoli in both lungs. Etiology and Pathophysiology The pulmonary hypoplasia, then, is found in both lungs, but Diaphragmatic hernias usually occur in the early stages to a lesser degree in the contralateral lung.108 Because the of fetal development as a result of the failure of the fusion development of the pulmonary vessels mirrors the develop- of pleuroperitoneal membranes. Because the left side of the ment of the bronchi, the impact of the viscera in the chest diaphragm closes after the right side, most diaphragmatic also alters the branching of the pulmonary vessels and the hernias (85–90 percent) occur on the left. Most left-sided area of the vascular bed. Pulmonary vascular development is hernias contain small bowel, spleen, stomach, and colon and hypoplastic, with abnormal muscularization of the pulmo- occasionally the left lobe of the liver (Figure 2C-36). Right- nary arterioles. The increased muscularization of the arteri- sided hernias usually contain the right lobe of the liver and oles, the small vascular bed size, and the decreased number of

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-33 FIGURE 162C-37I Pathophysiology n Pathophysiology of acute of acute respiratory respiratory failure failure in in 5 percent,Cardiac theanomalies symptoms and appear cardiac later, dysfunction with vomiting, are also abdomi- com- neonates with congenital diaphragmatic hernia. neonates with congenital diaphragmatic hernia. ponentsnal pain, of and illness respiratory in infants distress. with CDH.44 In theIn one mildest retrospective cases of analysisCDH, the of 166symptom patients is feedingwith CDH, intolerance. 63 percent9 These had anotherwise associ- Congenital Diaphragmatic Hernia 118 atedasymptomatic cardiac lesion, infants the often most become common symptomatic associated following anomaly. the Associated cardiac defects noted in infants with CDH can Pulmonary Hypoplasia initial feeding. Left Ventricular Hypoplasia rangeThe from ultrasound ventricular presentation septal defects of most to Pentalogy lung anomalies of Cantrell. is a Surfactant Deficiency Pentalogycompressed of orCantrell deviated is an heart association or an ofarea a diaphragmaticof abnormal hernia,echogenicity omphalocele, in the thorax. sternal12 On and fetal pericardial ultrasound, defects, the differ- and 119 Hypoxemia congenitalential diagnosis heart includesdisease. CDH, Fauza cystic and masses, Wilson anddescribe cardio- a Hypercarbia collection of anomalies that45,46 they label “CDH syndrome”; Acidosis vascular abnormalities. The antenatal ultrasound thediagnosis anomalies of CDH include is challengingpulmonary hypoplasia,because the PDA, features PFO, of Persistent Fetal Circulation intestinal malrotation and volvulus, abnormally small47 chest Pulmonary Arterial bowel, lung, and liver appear similar on ultrasound. In fact, Right-to-Left Shunting 118 Vasoconstriction cavity, and various other liver and spleen deformities. Heart Intrapulmonary Shunting not all CDHs are evident on antenatal ultrasound which also anomalieshinders diagnoses. in infants48 withWhen CDH a CDH that are is notlarge, part it ofpresents the CDH on syndrome include hypoplastic left heart syndrome, atrial Pulmonary ultrasound as abdominal contents in the chest, mediastinal Hypertension septalshift, abnormaldefect, ventricular abdominal septalanatomy, defect, and tetralogyan abnormal of Fallot,stom- 91,108,118,120 Ebstein’sach position. anomaly,5,49 Polyhydramnios and coarctation is oftenof the present aorta. on ultra- From: Arensmen RM, and Bambini DA. 2000. Congenital There is evidence that the hernia can cause malformations of From: Arensmen RM, and Bambini DA. 2000. Congenital diaphragmatic sound in infants with CDH and may be a predictive factor of diaphragmatic hernia and eventration. In Pediatric Surgery, 3rd ed., the heart and can48 cause it to be small. Researchers hypoth- herniaAshcroft and KW, eventration. et al., eds. In Philadelphia:Pediatric Surgery, Saunders, 3rd ed., 302. Ashcroft Reprinted KW, et al., a severe CDH. CDH can also be identified with CT scan eds.with Philadelphia: permission WBof Elsevier. Saunders, 302. Reprinted by permission. esizeand ultrasound, that this is butthe isresult most of easily decreased identified blood on flowchest tox-ray. the left side of the heart from compression or changes in the pul- 91,120 monary vessels.Management Eghtesady and and Treatment colleagues state that the arteriolesother liver contribute and spleen todeformities. increased38 reactivityHeart anomalies and resistance in infants of mostCurrent common prenatal cardiac management defect associated options with for CDH the fetus is a smallwith 85 thewith pulmonary CDH that vessels are not and part to pulmonaryof the CDH hypertension. syndrome include It is leftCDH ventricle are expanding and that, with in themost development infants with of this new defect, therapies, the 121 thehypoplastic amount left of lungheart hypoplasiasyndrome, andatrial the septal responsiveness defect, ventricular of the outcomealthough ismost fatal. remain experimental, with variable success. circulationseptal defect, that tetralogy determine of Fallot, the prognosis Ebstein’s foranomaly, the infant and withcoarc- a TherePPHN are istwo a serioustypes of and prenatal often treatmentlife-threatening options complica for the- 108 CDH,tation ofnot the the aorta. size 9,27,38,40of the diaphragmaticThere is evidence defect. that the hernia tionfetus seen with in CDH: infants a withtracheal CDH. occlusion Abnormal procedure vascularity and of fetal the canInfants cause malformationswith late migration of the heartof the and abdominal can cause contentsit to be pulmonarysurgery. Tracheal bed and occlusion ongoing involves hypoxia plugging contribute the tracheato ongoing via a intosmall. the Researchers thorax may hypothesizenot show any that signs this of isrespiratory the result dis of- persistentclip or “plug” fetal while circulation, the fetus which is in utero,createsbefore a vicious 25 weeks cycle ges- of tressdecreased at birth, blood but flow at several to the days left sideof age of showthe heart signs from of intesti com-- hypoxemiatation. Occlusion that further of the precipitates trachea keeps pulmonary the fetal hypertensionlung fluid in nalpression obstruction, or changes vomiting, in the andpulmonary respiratory vessels. distress9,40 Eghtesadyfollowing (Figurethe affected 2C-37). lung The and shunting allows for within lung thegrowth. heart,50 secondaryThe plug toor feedings.and colleagues These infantsstate that likely the experienced most common late migration cardiac defectof the theclip highis removed pulmonary at delivery pressures before that are the characteristic umbilical cord of infants is cut 91 abdominalassociated with contents CDH with is a nearlysmall left normal ventricle lung and development. that, in most withusing PPHN,an EXIT causes (ex utero hypoxemia,intrapartum which treatment) responds procedure.poorly to 122 infantsMultiple with thistheories defect, exist the outcomein the literature is fatal.41 supporting sur- oxygenThe EXIT or vasodilatorprocedure involvesagents. the The partial combination delivery of of the PPHN, fetus factantPPHN deficiency is a serious or andalterations often life-threatening in surfactant productioncomplication in poorvia a oxygenation,cesarean delivery hypoplasia with maintenance of the left ventricle,of fetal circulation and per- infantsseen in withinfants CDH. with SeveralCDH. Abnormalstudies have vascularity demonstrated of the thatpul- sistentwhile aductal bronchoscopy shunting isin done the infantto remove with theCDH balloon. presents The a 123 theremonary is abed possible and ongoing delay in hypoxia structural contribute growth to and ongoing functional per- significantbaby is intubated, management given surfactant,challenge. and ventilated before the maturationsistent fetal or circulation, development which of the creates Type IIa viciouscells that cycle manu of- umbilical cord is cut and the delivery is completed.51 113,114 facturehypoxemia surfactant that further and precipitatessurfactant components.pulmonary hypertension Other Harrison andDiagnosis colleagues and Clinical initially Presentation showed that tracheal researchers(Figure 16). have The demonstratedshunting within that the infants heart, withsecondary CDH to have the obstructionInfants with reduces CDH the often,pulmonary but nothypoplasia always, associated present with anhigh altered pulmonary ability pressuresto respond that to exogenousare characteristic surfactant, of infants espe- respiratoryCDH in fetal symptoms. lamb models In 95 and percent later ofin neonateshuman fetuses with CDH, using ciallywith PPHN,in the case causes of increasedhypoxemia, pressure which in responds the right poorly ventricle to theboth presentation a plug and a consiststracheal clip.of cyanosis,52 The tracheal respiratory occlusion distress, pro- 115,116 oroxygen in the or presence vasodilator of iNO. agents.42 WigglesworthThe combination and ofcolleagues PPHN, mediastinalcedure has beenshift, refined, shifted mostheart recentlysounds, withabsent the breath development sounds 91 hypothesizepoor oxygenation, that thehypoplasia respiratory of the epithelium left ventricle, in andthe persis-infant overof a fetoscopicthe side of approach. the hernia, Called and scaphoidFetendo, abdomen.this approach In usesthe withtent ductalCDH shuntingmust reach in the a certaininfant with stage CDH of developmentpresents a signif- for othersmall instruments5 percent, the and symptoms a detachable appear balloon later, withto occlude vomiting, the 124 theicant endocrine management factors challenge. that stimulate43 surfactant production abdominaltrachea without pain, removing and respiratory the fetus distress. from the womb.In the Itmildest is cur- 117 91 to work. Lotze and colleagues compared infants with and casesrently ofbeing CDH, investigated the symptom on fetuses is feeding less thanintolerance. 24 weeks Thesegesta- without CDHDiagnosis treated andwith Clinical exogenous Presentation surfactant and found otherwisetion with severeasymptomatic CDH in infantsan NIH-sponsored often become trial. symptomatic53 O’Toole thatInfants those withwith CDH CDH were often, still but surfactant not always, deficient present even with after followingand colleagues the initial found feeding. that even though tracheal ligation treatment.respiratory Theysymptoms. hypothesize In 95 thatpercent the changesof neonates to the with lung CDH, epi- reversesThe ultrasoundthe lung hypoplasia presentation in infants of most with lung CDH, anomalies the proce- is a theliumthe presentation that were consists associated of cyanosis, with lung respiratory hypoplasia distress, might medi- have compresseddure has detrimental or deviated hearteffects or anon area the ofdevelopment abnormal echo of- 94 causedastinal shift, prolonged shifted postnatal heart sounds, surfactant absent deficiency. breath sounds This over may the be genicitysurfactant. in54 theIn thorax.other fetal On lamb fetal studies ultrasound, with tracheal the differential ligation, anside additional of the hernia, factor andcontributing scaphoid to abdomen. the high 9morbidityIn the other and diagnosisO’Toole andincludes colleagues CDH, found cystic that masses, the procedure and cardiovascular allows for mortality in some neonates with CDH.115 abnormalities.125,126 The antenatal ultrasound diagnosis of

N EONATAL N ETWORK 2C-34 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics 20 NOVEMBER/DECEMBER 2004, VOL. 23, NO. 6 CDH is challenging because the features of bowel, lung, and and premature labor and delivery following the procedure. liver appear similar on ultrasound.127 In fact, not all CDHs Only fetuses with livers in the abdomen were considered for are evident on antenatal ultrasound which also hinders diag- surgery, and the researchers found it difficult to determine noses.128 When a CDH is large, it presents on ultrasound as which fetuses were favorable candidates for in utero repair.136 abdominal contents in the chest, mediastinal shift, abnormal Farmer noted that even with successful in utero repair of the abdominal anatomy, and an abnormal stomach position.87,129 CDH, postnatal outcomes did not improve when compared Polyhydramnios is often present on ultrasound in infants with those of infants whose CDHs were repaired after birth.133 with CDH and may be a predictive factor of a severe CDH.128 Antenatal steroids are currently given to mothers of infants CDH can also be identified with CT scan and ultrasound, but with CDH at 34–36 weeks gestation.137 One small study is most easily identified on chest x-ray. involving three mothers of infants with CDH who received antenatal steroids over ten weeks showed that the infants had Management and Treatment easier postnatal courses, but the outcomes and side effects of Current prenatal management options for the fetus with prolonged steroid treatment are unknown. Positive outcomes CDH are expanding with the development of new therapies, from this treatment could dramatically improve postnatal out- although most remain experimental, with variable success. comes in these infants, but more human trials are needed.138 There are two types of prenatal treatment options for the fetus The medical and surgical management of infants with with CDH: a tracheal occlusion procedure and . CDH is focused on maintaining oxygenation by minimizing Tracheal occlusion involves plugging the trachea via a clip PPHN and on stabilizing the respiratory and cardiovascular or “plug” while the fetus is in utero, before 25 weeks gesta- systems prior to surgery to promote a normal transition to tion. Occlusion of the trachea keeps the fetal lung fluid in the postnatal circulation. JG presented us with the challenge of affected lung and allows for lung growth.130 The plug or clip an infant who did not respond to any of the normal treatment is removed at delivery before the umbilical cord is cut using strategies for PPHN. He failed to respond to high-frequency an EXIT (ex utero intrapartum treatment) procedure. The oscillation, surfactant, iNO, and ECLS and required the use EXIT procedure involves the partial delivery of the fetus via of vasodilators that are not normally given to these infants. a cesarean delivery with maintenance of fetal circulation while Past management strategies for the infant with CDH a bronchoscopy is done to remove the balloon. The baby is focused on aggressive hyperventilation and alkalinization, intubated, given surfactant, and ventilated before the umbili- which contributed to pneumothorax, chronic lung disease, cal cord is cut and the delivery is completed.131 Harrison and and neurologic complications. Current management focuses colleagues initially showed that tracheal obstruction reduces on “gentle ventilation” or permissive hypercapnea, which the pulmonary hypoplasia associated with CDH in fetal lamb minimizes trauma to the hypoplastic lungs; allows for gentle models and later in human fetuses using both a plug and a tra- lung expansion; and uses high-frequency oscillating ventila- cheal clip.132 The tracheal occlusion procedure has been refined, tion, surfactant replacement therapy, and iNO to promote most recently with the development of a fetoscopic approach. oxygenation.91 iNO selectively reduces pulmonary vascular Called Fetendo, this approach uses small instruments and a resistance without decreasing systemic blood pressure.139 detachable balloon to occlude the trachea without removing Artificial and bovine surfactants have been used with variable the fetus from the womb. It is currently being investigated success in the CDH population. If the lungs of infants with on fetuses less than 24 weeks gestation with severe CDH in CDH are hypoplastic and immature, then surfactant should an NIH-sponsored trial.133 O’Toole and colleagues found that relieve the respiratory distress, but this outcome has not even though tracheal ligation reverses the lung hypoplasia in always been observed.140 infants with CDH, the procedure has detrimental effects on Drug therapies for infants with CDH have included vasodila- the development of surfactant.134 In other fetal lamb studies tors such as tolazoline,91,139 prostaglandin,141 sildenafil,142,145,146 with tracheal ligation, O’Toole and colleagues found that the and phenoxybenzamine.143 However, these can result in pro- procedure allows for better lung growth and development, found systemic hypotension, thus limiting their use. These but prevents fetal respirations and the movement of fetal lung drugs may not benefit infants if the major underlying problem fluid, resulting in severe surfactant deficiency. These research- is pulmonary hypoplasia; in fact, the infants’ conditions may ers could not find evidence to support normal lung function in worsen because of the systemic vasodilator effects.144 lamb fetuses following this treatment and recommend that this Liquid ventilation is an experimental ventilation strategy procedure remain experimental.134 The techniques for tracheal that uses a perfluorocarbon liquid that fills the lungs assisting occlusion have yet to be perfected, and the results of tracheal in gas exchange, thus decreasing the surface tension of the occlusion are mixed.132 lungs and recruiting unventilated alveoli. This treatment has Antenatal repair of a CDH has been shown to reverse pul- proven effective in fetal animal studies but has seen limited monary hypoplasia and pulmonary vascular abnormalities, use in neonates.147 ECLS is a proven therapy for neonatal but it is technically difficult and the risks to the mother and respiratory failure resulting from meconium aspiration and fetus are high, with a significant incidence ofin utero death sepsis, but its use in infants with CDH is controversial. ECLS

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-35 provides a “rest” for the lungs while supporting cardiac sequestration, the clinical presentation is acute respiratory function and supplying well-oxygenated blood to the body, distress.91 This is likely related to the presence of the CDH. allowing the pulmonary vascular resistance to fall.148 ECLS The spectrum of respiratory symptoms associated with these provides time for the lungs to rest and for the pulmonary combined lesions varies, depending on their location, their hypertension to decrease, but it will not change the under- size, and the degree of lung hypoplasia. An infant presenting lying lung hypoplasia or elevated pulmonary vascular resis- with a CDH with a large shunt between an ELS and the aorta tance.148,149 With pulmonary hypoplasia, little lung growth may be at risk for cardiac failure.90 If the infant has both a can be expected in the three- to four-week period feasible for CDH and an ELS, then, because of the sequestration, man- ECLS.150 Hansen and colleagues observe that the outcomes agement must focus on respiratory distress and prevention of of infants with CDH treated with ECLS are based on the cardiac failure. degree of lung hypoplasia and the severity of the pulmonary JG presented with a combined lesion, but the most serious vascular disease.88 presentation was the CDH and PPHN. The ELS did not Repair of the CDH was previously considered a surgical become problematic and was not resected at the time of the emergency; the infant was rushed to surgery and often dete- CDH repair. Although there was flow between the ELS and riorated because of PPHN.151 Current strategies involve sta- the aberrant vessel, the flow did not result in cardiac failure. bilizing the infant with intensive medical therapies and in the The surgical team determined that resecting the ELS in the most severe cases, ECLS before surgical repair of the defect.116 absence of congestive heart failure symptoms would be too The argument of whether to repair on or off circuit for those risky in view of JG’s PPHN and previous course. infants requiring preoperative ECLS is an ongoing one. The major risk of on-circuit repair is , but the benefits IMPLICATIONS FOR NURSING include respiratory and cardiac support in the initial postopera- JG was a challenge to nurse because of his degree of PPHN tive period when some infants recovering from CDH surgery and his requirement for new treatment strategies and experi- revert to severe pulmonary hypertension.151 During on-circuit mental drug therapies. His ELS, which was initially felt to repair, antiheparin agents, electrocautery, and blood products be a complication, required neither intervention nor further are used to control bleeding. Most centers that do ECLS prefer investigations and became a secondary concern to his CDH to reduce the risk of hemmorhage by weaning the patient from and PPHN. ECLS support and then repairing the CDH.116 JG’s case has provided us with experience with new treat- ment strategies and management techniques that we had not Complications and Prognosis previously used in our hospital. Already, another infant born Long-term complications experienced by infants with with a left-sided CDH and severe PPHN has benefited from CDHs include feeding intolerance; vomiting and gastroin- our experience with JG. Our use of IV sildenafil in combi- testinal reflux; and long-term respiratory difficulties includ- nation with other vasodilator therapies reduced pulmonary ing pneumothoraces, bronchopulmonary dysplasia (BPD), vascular resistance in JG’s case, but this was accompanied by and reherniation. Infants with CDH who presented with severe hypotension. This experience provided us with the PPHN in the neonatal period have the risk of recurrent pul- necessary dose titrations, weaning schedules, and clinical data monary hypertension. Despite ongoing growth of the lungs to support IV sildenafil use in severe PPHN cases in which and a decrease in abnormal muscularization of the pulmo- oral sildenafil cannot be used. nary vascular bed over time, these pulmonary vessels remain Infants with CDH and PPHN require ongoing assessment reactive to stimuli that can precipitate postrepair-pulmonary and monitoring for subtle signs of changes in their condi- hypertension. Some of the most severely compromised tions that might indicate an exacerbation of PPHN. Nurses patients develop severe BPD and may die several weeks or caring for infants with CDH who have PPHN must be aware months after birth. Other infants require long-term oxygen of the factors that can aggravate PPHN and utilize strate- therapy. Infants with late-presentation CDH do well, with gies to prevent or reduce these stimuli. Nurses must also be normal growth, minimal symptoms, and minimal changes on aware that infants with a CDH that has been repaired have chest x-ray.91 Survival rates of infants with CDH range from the potential for recurrent PPHN for a significant period fol- 50 percent for those most severely affected to 100 percent for lowing their repair. those with minimal respiratory symptoms.152 Originally published: Harris K. 2004. Extralobar sequestration with congenital diaphragmatic hernia: A complicated case study. Neonatal ELS AND CDH: COMBINED PRESENTATION Network 23(6): 7–24. Used with permission of Springer Publishing It is often difficult to distinguish an infant with a dia- Company, LLC, www.springerpub.com/nn. phragmatic hernia from one with a diaphragmatic hernia The author discloses no relevant financial interests or affiliations with any commercial interests. and an ELS based on presentation alone. Unless the infant with CDH/ELS presents with cardiac failure as a result of shunting between the aorta or the supplying vessel(s) and the

2C-36 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics infant’s heart rate increased with intubation and needle aspi- Congenital Chylothorax: ration. Apgar scores were 1, 3, 4, and 6 at 1, 5, 10, and 15 minutes, respectively. A Case Study Clinical Summary: Day of Life (DOL) 1 Carey Gaede, MSN, RN, NNP-BC Respiratory. H.E. was transported­ to the NICU and ini- tially placed on a ventilator, (synchronized intermittent man- leural effusions occur when a large amount of free fluid datory ventilation) pressure control mode, with a rate of 50 accumulates in the pleural space.153 A chylothorax is breaths per minute, peak inspiratory pressure of 32 cmH O, P 2 caused by chyle-containing lymphatic fluid draining into the positive end-expiratory pressure of 6 cmH2O, and a pressure 154 pleural cavity. This is the most common type of pleural control setting of 26 cmH2O. A right chest tube was inserted, effusion observed during the neonatal period and is two and an initial chest x-ray was obtained, demonstrating bilat- times more likely to occur in males than in females. Though eral pneumothoraces and probably left uncommon, pleural effusions may cause significant respira- (Figure 2C-38). Therefore, a second chest tube was placed in tory compromise, and 50 percent of infants with a chylotho- the left pleural space. Both the right and left chest tubes freely rax develop symptoms of respiratory distress within 24 hours drained blood-tinged fluid. H.E.’s initial arterial blood gas of birth.155 The following case study summarizes the course at one hour of age in 50 percent oxygen demonstrated sig- of a 33-week-gestation neonate with bilateral congenital nificant respiratory acidosis: pH 7.05, PaCO2 85.1 mmHg, pleural effusions (chylothoraces). A review of the etiology, PaO2 68.5 mmHg, HCO3 23 mEq/liter, and base deficit radiographic and laboratory diagnosis, and management of −10.1 mEq/liter. An umbilical arterial catheter (UAC) was chylothorax follows the case study. placed following the admission x-ray. A follow-up arterial blood gas (ABG) was obtained in 50 percent oxygen without CASE STUDY improvement. Preterm male infant H.E. was born weighing 2,460 g at The infant was placed on high-frequency oscillating ven- 335/7 weeks gestation to a 24-year-old, gravida 2, para 1, tilation (HFOV). After ventilator adjustments, morphine Caucasian mother. Maternal blood work was unremarkable, for pain, and administration of pancuronium (Pavulon) and an ultrasound at 18 weeks gestation was normal, without to induce paralysis, H.E. improved, with the following pleural effusions. The mother’s blood type was A+. The ABG on 30 percent oxygen: pH 7.27, PaCO2 53 mmHg, mother presented in preterm labor at 33 weeks gestation PaO 52.4 mmHg, HCO 22.6 mEq/liter, and base deficit 4/7 2 3 at an outlying rural hospital. She was transported to a tertiary −5.4 mEq/liter. At this time, the chest tube fluid was sent level maternal and newborn services hospital after magnesium for the following studies: culture (bacterial and viral), Gram’s sulfate was started. The mother’s Group B β-hemolytic strep- stain, protein, and cell count. Throughout the first night, a tococcus (GBS) status was unknown, and she was treated total of 44 mL was drained from H.E.’s right chest tube and with ampicillin to prepare for delivery, along with betametha- 99 mL from his two left chest tubes. The initial chest tube sone. The morning after the mother’s arrival at the unit, a fluid revealed a glucose level of 4.8 mcmol/liter, total protein fetal ultrasound was performed; it revealed significant bilat- of 26 g/liter, and 96–99 percent lymphocytes. The high lym- eral pleural effusions. Because of the large bilateral pleural phocyte count is indicative of a congenital chylothorax.156,157 effusions and the baby’s gestation, the mother’s labor was Figure 2C-39, taken at 18 hours of age, demonstrates a induced with oxytocin (Pitocin); the amniotic membranes pleural effusion on the right side most prominent in the right ruptured spontaneously two hours prior to delivery. During lower costophrenic angle, free air in the pleural space on the labor, variable decelerations and decreased variability were left, and a small heart size suggestive of intravascular volume noted. depletion and/or compression from the free air in the pleural The infant was delivered vaginally with the NICU team space. present. H.E. had no respiratory effort at birth, and his heart Cardiovascular. The initial cardiovascular exam was normal: rate was <100 beats per minute (bpm). The infant was intu- blood pressure 68/45, mean 53 mmHg, capillary refill time bated immediately, and simultaneous bilateral needle aspira- <3 seconds, heart rate 153 bpm, no audible heart murmur. tion of the chest was performed with a 25-gauge butterfly An initial echocardiogram was done at 12 hours of age to needle. A total of 70 mL of fluid was aspirated from the left evaluate for congestive heart failure, look at cardiac function, chest, and 125 mL was aspirated from the right side. The and check for any pericardial effusions. The echocardiogram fluid was a light yellow color initially and then became tinged showed right ventricular enlargement with elevated right with blood, with air noted. A left chest tube was placed in ventricular pressures, which indicates persistent pulmonary the delivery room and was attached to a Heimlich valve for hypertension of the newborn (PPHN). Around the same transport. Chest compressions were not required because the time (12 hours of age), H.E. developed hypotension that did

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-37 FIGURE 2C-38 n Admission x-ray of 33-week-gestation male infant obtained after 70 mL of fluid was aspirated from the left pleural space and 125 mL of fluid from the right pleural space. X-ray interpretation 1. Technique: Able to visualize vertebrae and soft tissue. Overall quality good. 2. Rotation: The infant is not rotated in the anterior-posterior plane, but is rotated laterally to the right, causing a small right curve in the spine. Therefore, the heart appears to be shifted slightly to the left. 3. Artifacts: Spotted artifact on upper chest caused by cloth diaper. There is a temperature probe attached to the skin in the lower left abdomen and two cardiorespiratory monitor leads attached to the skin in the upper right chest outside the rib margin and lower left abdomen. Umbilical cord clamp across the pelvis. 4. Tubes: Endotracheal tube tip is high, just above the clavicles. There are two chest tubes in place: one on the right side and one on the left. No intravenous or arterial catheters are present. 5. Bony Structures: Clavicles, vertebrae, and ribs are intact, without fracture. 6. Soft Tissue: Soft tissue, generous around chest, indicates edema. 7. Degree of Inspiration: The lungs are expanded to the level of the ninth rib. 8. Thymus: Visualized in the center of the chest, with elevation of left lobe secondary to free air. 9. Lung Fields: a. Density—Focal area of density on the right represents compressed right lung secondary to free air mixed with chyle in the pleural space. Triangular density on the left represents lifted lobe of the thymus secondary to pneumomediastinum. There is most likely free air in the left pleural space. The left diaphragm is elevated into the chest, obscuring the left costophrenic angle. This area looks hazy and may also represent pleural fluid. b. Symmetry—The lung fields are not symmetric, as noted earlier. c. Infiltrates—There are no significant areas of focal infiltrates. d. Fluid—There is no fluid in the fissures, although pleural fluid is present on the right and probably left lower lung field. e. Bronchograms—None visualized.

f. Atelectasis—Right lung is collapsed approximately 50 percent. g. Effusions—Pleural fluid mixed with free air on the right as well as lower left. No fluid noted in the fissures. h. Carina—Not observed; unable to visualize mainstem bronchi secondary to dense overlying of thymus and mediastinum. i. Vascularity—No congestion evident. j. Free Air—Free air on right, compressing lung. Free air on left, lifting thymus and sharply outlining thymus and heart borders. 10. Heart: The heart is shifted to the left (due to infant positioning) and occupies approximately 40 percent of the chest. 11. Abdomen: Large stomach bubble; small amount of small-bowel gas on the left side; no bowel gas on the right side or in the rectum. Interpretation: A 33-week-gestation male infant with bilateral pleural effusions and pneumothoraces (right larger than left) and left pneumomediastinum.

not respond to a fluid bolus. He was started on dopamine and H.E.’s blood type was A+, and a direct Coombs test was dobutamine drips, with minimal response after 24 hours, so negative. hydrocortisone was started and given for a total of five days. Neurologic. The infant had poor tone from birth, etiology Infectious Disease/. On admission, H.E. was unkown, and did not demonstrate appropriate responsiveness evaluated for sepsis secondary to the mother’s unknown GBS to handling. He was treated with pancuronium (Pavulon) for status and the infant’s severe respiratory distress. Blood and a total of 36 hours. At 16 hours of age, an initial cranial ultra- pleural fluid cultures were obtained, and ampicillin and genta- sound was performed and showed no evidence of intracranial mycin therapy was begun. The initial complete blood count bleeding or hypoxic-ischemic injury. By the time of transfer, (CBC) included a white blood cell count of 29,000/mm3, H.E.’s tone was improved. with 52 percent segmented neutrophils, 3 percent bands, Fluids/Electrolytes/Nutrition. H.E. was initially treated 32 percent lymphocytes, 9 percent monocytes, and 1 percent with 10 mL/kg of normal saline to replace fluid drained from eosinophils. The initial hemoglobin was 180 g/liter, and the the pleural space. The infant was given nothing by mouth hematocrit was 0.519. The platelet count was 341,000 mm3. (placed NPO), and total parenteral nutrition (TPN) and intralipids (IL) were started on admission, with total fluids at

2C-38 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-39 n X-ray of 33-week-gestation male infant with TABLE 2C-5 n Chemistry Values for H.E. (Case Study) congenital chylothorax at 18 hours of age. 12 hours 30 hours 96 hours Normal The endotracheal tube is in good position at T2; the UAC tip is at of age of age of age Values* T7. There is one right chest tube and two left chest tubes as well (SI units) (SI units) (SI units) (SI units) as a nasogastric tube with its tip in the stomach. The lungs are expanded to the ninth rib, and the right lung field demonstrates a triangular area of density in the lower right consistent with pleural g/dL 1.6 1.2 4.3 3.5–5.4 effusion. There is also a streaky density in the right perihilar area, (g/liter) (16) (12) (43) (35–54) probably consistent with pleural fluid. The left chest is hyperlucent, Blood Urea particularly in the lower left, with a sharply demarcated left heart Nitrogen (BUN) border as evidence of free air in the left pleural space. The heart size mg/dL normal 37 53 3–12 is small (compressed or fluid depleted). The bowel gas pattern is (millimoles/liter) (13.2) (18.9) (1.1–4.3) normal. Calcium mg/dL 7.6 9.2 7.6 –10.4 (millimoles/liter) normal (1.9) (2.3) (1.9–2.6) Chloride mEq/liter 95 103 102 96–106 (millimoles/liter) (95) (103) (102) (96–106) Creatinine mg/dL 0.8 0.5 0.3–1.2 (micromoles/liter) normal (71) (44) (27–106) Phosphorus mg/dL 3.9 4.3–9.3 (millimoles/liter) n/a n/a (1.26) (1.4–3) Potassium mEq/liter normal 3.3 4.1 3.9–5.9 (millimoles/liter) (3.3) (4.1) (3.9–5.9) Protein Total g/dL 3.1 2.1 5.7 4.6 –7.4 (g/liter) (31) (21) (57) (46 –74) Sodium mEq/liter 124 130 136 134 –150 (millimoles/liter) (124) (130) (136) (134 –150) * term newborn

Genetics. On initial exam, H.E. had mild dysmorphic features, consisting of a small face, abnormally placed and posteriorly rotated ears, and very long fingers and toes. Blood for chromosome studies was drawn on admission and were normal. Differential Diagnoses. At this point, the differential Interpretation: Right pleural effusion and left pneumothorax. diagnoses under consideration included congenital chylotho- rax, sepsis (viral and bacterial), congenital pleural effusions, respiratory distress syndrome, pneumothoraces, and chro- 80 mL/kg/day. Over the first 16 hours, H.E.’s urine output mosomal abnormality. Immune-mediated hydrops fetalis was was 0.42 mL/kg/hour. At 16 hours of age, the total fluids not considered a likely etiology because H.E. was not anemic were increased to 140 mL/kg/day. and no blood group incompatibilities or evidence of hemoly- At 12 hours of age, H.E.’s chemistry panel showed the sis was identified. Because of the composition of the pleural following abnormal levels for total protein, albumin, sodium, fluid, with its predominance of lymphocytes, congenital chy- and chloride (Table 2C-5). The lab values reflect the loss of lothorax was the main diagnosis under consideration. electrolytes, protein, and fluid in the large amount of pleural fluid drainage, which is a common finding in congenital Clinical Summary: DOL 2–DOL 4 chylothorax. Because low protein levels can promote fluid Respiratory. By 48 hours of age, the two left chest tubes movement into the lungs, pleural space, or tissues, albumin had minimal drainage (15 mL) compared with the right chest infusions were started for a total of six doses to increase H.E.’s tube (99 mL). A decision was made to discontinue the left serum albumin level. chest tubes at this time. A total of 245 mL had drained from the left side since birth. H.E. remained stable on the HFOV.

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-39 FIGURE 2C-40 n X-ray of 33-week-gestation male infant with FIGURE 2C-41 n X-ray of 33-week-gestation male infant with congenital chylothorax at 104 hours of age. congenital chylothorax at 165 hours of age. The infant is intubated, with the tip of the endotracheal tube just above The infant is intubated, with the tip of the endotracheal tube at the the level of the carina. The right chest tube is in place, and the left carina (T5). There is mild blunting of both costophrenic angles. chest tubes have been removed since the previous x-ray (see Figure Streaky infiltrates appear on the right side. The left side appears 2C-39). The UAC is just above the diaphragm at T8. The nasogastric denser, with a poorly defined heart border, and the heart is enlarged. tube is in the stomach. The right-sided pleural effusion extends from the top of the right thorax to the base of the lung along the peripheral lung edge. The left lung field is fairly well aerated, with some area of atelectasis in the left upper lobe and a small pleural effusion in the left lower lobe at the costophrenic angle. Bowel gas throughout the small and large intestines is increased.

Interpretation: Infiltrates on right side and an enlarged heart.

discontinued on DOL 6. H.E. remained on dobutamine at 5 mcg/kg/minute at the time of transfer to the referral center on DOL 10. A follow-up echocardiogram on DOL 3 showed right ventricular pressure at near-systemic levels, indicating that PPHN was no longer present. Infectious Disease/Hematology. The blood and pleural fluid cultures were negative, so the ampicillin and gentamycin were discontinued at 48 hours of age. H.E.’s hemoglobin and hematocrit were stable at 14.9 g and 42.9 percent. Neurologic. On DOL 3, an electroencephalogram was performed. It showed a near-burst suppression pattern, which can be indicative of perinatal asphyxia. A pediatric neurologist Interpretation: Large right pleural effusion, new left-sided pleural effusion, atelectasis. Infant was started on enteral feedings on DOL 4. was consulted. Fluids/Electrolytes/Nutrition. H.E. remained NPO and received intravenous TPN and IL. Electrolytes on DOL 4 are presented in Table 2C-5. Urine output on DOL 4 was Ventilator settings were weaned per ABG results. At 48 hours, 1.8 mL/kg/hour, a significant drop from DOL 3, when an analysis of the chest tube drainage revealed a cholesterol it was 4.2 mL/kg/hour. Close monitoring of electrolytes level of 18 mg/dL (0.47 millimoles/liter), an albumin level continued. of 12 g/liter, a triglyceride level of 0.23 millimoles/liter, and a lymphocyte count of 0.91. Lymphocyte predominance and Clinical Summary: DOL 5–DOL 10 a cholesterol level of <100 mg/dL (<2.59 millimoles/liter) Respiratory. On DOL 5, the infant’s right pleural effu- are indicative of a chylothorax.158 The fact that H.E. had not sion was more prominent, and a small left pleural effusion started enteral feedings was the likely cause of the low triglyc- was noted on x-ray (Figure 2C-40). H.E.’s right chest tube eride level.156 drained 174 mL on DOL 5; however, he had been weaned to Cardiovascular. H.E.’s blood pressures were stable after a minimal setting on the HFOV, and his ABGs were stable. a short course of hydrocortisone, and the dopamine was H.E. was extubated to a high-flow nasal cannula on DOL 5.

2C-40 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-42 n X-ray of 33-week-gestation male infant with FIGURE 2C-43 n X-ray of 33-week-gestation male infant with congenital chylothorax at 176 hours of age. congenital chylothorax and continued clinical The infant is intubated, with the tip of the endotracheal tube at T2. deterioration on DOL 10. There is perihilar streaking on the right and a prominent right lower The infant is intubated, with the tip of the endotracheal tube at T1. The lung pleural effusion. Pleural fluid is evident on the left with possible right chest tube is in place. There is increased density throughout left lower lung free air as evidenced by the sharp border along the both lung fields consistent with increased pleural fluid. There are diaphragm. significant pleural effusions in the right lower lung field as well as the left upper lung field as substantiated by heavy areas of density in both of these locations. In addition, there are infiltrates consistent with pleural fluid throughout the right lung, particularly the right upper lobe, and in the left lower costophrenic angle.

Interpretation: Continued pleural effusions on the right and left sides coinciding with worsening respiratory status. Interpretation: Significant increase in pleural fluid bilaterally.

Minimal enteral feedings of breast milk had been started on DOL 4, which may have correlated with increasing pleural of fluid on the left. The infant had a new chest tube placed effusions on DOL 5. on the left side to facilitate drainage. Because of the contin- H.E. remained on the high-flow nasal cannula until ued reaccumulation of pleural fluid and the potential need DOL 7, when he developed worsening respiratory distress for nitric oxide and a surgical consultation for treatment of and significant respiratory acidosis requiring reintubation. chylothorax, on DOL 10, H.E. was transferred to a regional The infant was initially placed on SIMV at a rate of 35, and neonatal referral center for further evaluation. a chest x-ray was obtained (Figure 2C-41). The right chest tube continued to drain excessive amounts of pleural fluid, Clinical Summary: DOL 11–DOL 69 totaling 90 mL for the day. Interventions at this time included At the referral center, H.E. remained on the HFOV replacement of the right chest tube for better drainage and a until DOL 21, when he was successfully weaned to SIMV. sepsis evaluation with particular concern for . A However, the bilateral chest tubes remained in place, and CBC, blood culture, and tracheal aspirates were obtained, H.E. continued to have copious amounts of drainage from and antibiotics were initiated. The cultures were negative, them. and the antibiotics were discontinued on DOL 10. Pleural Over the next two weeks, H.E. was weaned to a nasal fluid remained on the right side even after the right chest cannula. Small enteral feedings were started again with tube was replaced (Figure 2C-42). The infant’s respiratory Portagen (Mead Johnson Nutritionals, Evansville, Indiana). status continued to deteriorate, and his oxygen requirement H.E. tolerated the feedings well (no emesis), and they were increased to 70 percent. Enteral feedings, which had been advanced slowly to full volume. H.E. still had a chest tube increased to 60 mL/kg/day, were discontinued. H.E. was on the right side for continued reaccumulation of fluid. placed back on the HFOV on DOL 8. From birth through Chromosome studies were repeated, specifically testing for DOL 9, a total of 1,060 mL of pleural fluid had been drained Noonan’s syndrome. Chromosome studies were negative. from H.E.’s right and left chest tubes. Fluid continued to reaccumulate in H.E.’s right lung, and On DOL 10, the infant’s chest x-ray (Figure 2C-43) showed a computed tomography scan was performed, confirming continued pleural fluid on the right and a reaccumulation the diagnosis of congenital chylothorax. On DOL 55, after

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-41 FIGURE 2C-44 n Development of the lymphatic system. FIGURE 2C-45 n Development of the lymphatic system. Left side of an eight-week embryo, showing the primary lymph sacs. Left: Ventral view of the lymphatic system at nine weeks, showing the paired thoracic ducts. Right: Formation of the thoracic duct and the right lymphatic duct later in the fetal period.

From: Moore K, and Persaud TVN. 2003. The Developing Human: Clinically Oriented Embryology, 7th ed. Philadelphia: Saunders, 377. Reprinted by permission.

From: Moore K, and Persaud TVN. 2003. The Developing Human: conservative management strategies failed to treat the chylo- Clinically Oriented Embryology, 7th ed. Philadelphia: Saunders, 377. Reprinted by permission. thorax, a thoracotomy was done on the right side, and the pleural space was stripped. This procedure was effective, and no new reaccumulations appeared on the right side. However, new fluid began accumulating on the left side of H.E.’s lung, vessels develop in a manner similar to that of the blood vessels and on DOL 68, the same procedure was performed on the and join the primitive lymph sacs. At approximately nine left side. weeks gestation, there are two large lymphatic vessels (the By 69 days, H.E. was tolerating full feedings of Portagen right and left thoracic ducts); these merge to form one vessel every three hours through a feeding tube. Portagen was used later in the fetal period (Figure 2C-45). When these two large because it is 85 percent medium-chain triglycerides (MCTs), vessels merge to form one thoracic duct, a number of factors which is the diet recommended for conservative treatment can influence final vessel formation.161 Therefore, anatomic of congenital chylothorax (see “Management” later in this connections between the lymphatic and venous systems may article). At 69 days, H.E. remained tachypneic and was differ from infant to infant.157 Furthermore, failure of the unable to bottle feed. many connections to form between the embryonic lymphatic channels may result in congenital malformations of the lym- ETIOLOGY AND PATHOPHYSIOLOGY phatic system and alterations in lymphatic drainage.162 The etiology for congenital chylothorax is not well under- Figure 2C-46 shows the anatomic pathway of the thoracic stood, but it is thought to occur secondary to trauma to the duct. Throughout the course of the thoracic duct, there are thoracic duct during delivery or a congenital malformation of many connections between the collateral lymphatic vessels the lymphatic vessels of the chest.159 Congenital chylothorax and the veins. These connections transport chyle and non- has been associated with genetic such as Noonan syn- chyle lymphatic fluid into the circulation to be absorbed in drome and .155,160 This association supports the body. The multiple connections communicate among its etiology as an altered anatomic arrangement of the lym- the azygos lumbar and intercostal veins and the inferior vena phatic system resulting from these genetic disorders. cava; after leaving the mediastinum, the thoracic duct obtains The lymphatic system begins to develop by the end of the additional lymph from the pleura and lungs. Pulmonary fluid sixth embryonic week; by the eighth week, six primary lymph enters the lymphatic vessels at the alveolar ducts and drains sacs emerge as buds from the adjacent developing veins.156,161 over the outside of the lungs into the interlobular lymphat- Also emerging are two jugular lymph sacs, two iliac lymph ics. The fluid then moves into the right and left bronchome- sacs, a retroperitoneal lymph sac, and one cisterna chyli. Figure diastinal trunks, which empty into the subclavian vein, the 2C-44 shows these embryonic lymph sacs. The lymphatic internal jugular veins, or the thoracic duct (Figure 2C-47).

2C-42 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics FIGURE 2C-46 n Anatomic pathway of the thoracic duct from its of interstitial fluid to continually move into the pleural space. origin, the cisterna chyli, and its major anatomic Figure 2C-48 demonstrates the avenues for fluid exchange relationships. within the pleural cavity. Normally, only a few millimeters of fluid are present in each pleural cavity; when the quantity of fluid increases, the extra fluid is removed by the lymphatic vessels that connect directly to the pleural cavity. Abnormal amounts of fluid may enter the pleural space, causing effu- sions by one of two mechanisms: transudation from the vas- cular space secondary to inflammation of the surfaces of the pleural cavity or blockage of lymphatic drainage from the pleural space.153 Pleural effusion in congenital chylothorax is caused by (1) an obstruction of the lymphatic drainage from the pleural cavity,153 (2) a thoracic duct atresia, or (3) congen- ital fistulas.160 Congenital fistulas result from a failed connec- tion of the lymphatic channels to the main lymphatic network, which causes oozing of chyle into the pleural space.165 Severe pleural effusions occurring early in gestation may cause the fetus to have significant pulmonary hypoplasia. Figure 2C-49 demonstrates this phenomenon. The large fluid-filled pleural space compresses or collapses the lung, interfering with lung development if this occurs early in gestation. In addition, large or bilateral congenital pleural effusions can increase intrathoracic pressure and cause fetal esophageal dysfunction, impairing swallowing, and resul- tant polyhydramnios; they can also cause compression of the central veins, resulting in ascites or general hydrops.129 Postnatally, when large amounts of lymphatic fluid and chyle are lost to the pleural space, the newborn may experience From: Valentine V, and Raffin T. 1992. The management of chylothorax. Chest 102(2): 586. Reprinted with permission from the American severe nutritional deficiencies in protein, fat, vitamins, elec- College of Chest Physicians. trolytes, immunoglobulins, and free water. Such losses may adversely affect growth and cause immunosuppression.158

The pleural fluid is removed by the posterior intercostal lymphatics.156 Prenatal Course Chyle is a yellow or milky-colored type of lymphatic fluid Antenatally, pleural effusions are identified in fetuses that contains fat from the cells of the intestine. It contains through ultrasound. Fetuses with congenital pleural effusions lymph, along with erythrocytes, electrolytes, proteins, some may have associated polyhydramnios; hydrops fetalis; and pres- enzymes, a high concentration of triglycerides after the ence of intrathoracic fluid, edema, and sometimes ascites.166 initiation of enteral feedings, and a large number of lym- The differential diagnoses for pleural effusions detected pre- phocytes.158,163 Table 2C-6 summarizes the biochemical char- natally include nonimmune hydrops, hydrops fetalis, heart acteristics of chyle. The vessels of the lymphatic system collect failure, Turner syndrome, and .159,163,166 the chylous lymphatic fluid from the intestinal area and trans- port it to the thoracic duct. The thoracic duct then transports Postnatal Course the chyle from the lower body as well as the lymphatic fluid After birth, infants with congenital chylothorax can present from other areas of the body to the systemic circulation.6,12 with different levels of respiratory distress. They may be Extrinsic factors such as arterial pulsations, tissue hydrostatic symptomatic immediately after birth, within 24 hours, or not pressure, and pressure on the cisterna chyli affect the flow of until some time during the first week of life.155,167 The size of the lymphatic fluid through the vessels and out of the pleural the chylothorax determines the severity of the symptoms.158 space.156,163 Chyle flows in and out of the thoracic duct and A congenital chylothorax should be considered as a cause for moves in an upward direction secondary to the valves of the respiratory distress if an infant presents in the delivery room thoracic duct. The flow increases considerably after eating and is unable to be ventilated, has diminished thorax move- and drinking and decreases with starvation.163 ments, and has diminished breath sounds on auscultation.157 Fluids move in and out of the pleural cavity through the There may also be a shift of the apical heartbeat away from porous, serous pleural membrane, which allows small amounts the side of the effusion.155

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-43 FIGURE 2C-47 n Lymphatic drainage of the lung.

• Lymphatic vessels originate in the subpleural (superficial) and deep lymphatic plexuses. • The subpleural lymphatic plexus is superficial, lying deep to the visceral pleura, and drains lymph from the surface of the lung to the bronchopulmonary (hilar) nodes. • The deep lymphatic plexus is in the lung and follows the bronchi and pulmonary vessels to the pulmonary and then bronchopulmonary nodes located at the root of the lung. • All lymph from the lungs enters the inferior (carinal) and superior tracheobronchial nodes and then continues to the right and left bronchomediastinal trunks to drain into the venous system via the right lymphatic and thoracic ducts; lymph from the left inferior lobe passes largely to the right side. • Lymph from the parietal pleura drains into the lymph nodes of the thoracic wall. From: Agur A, and Dalley A. 2005. Grant’s Atlas of Anatomy, 11th ed. Philadelphia: Lippincott Williams & Wilkins, 43. Reprinted by permission.

DIAGNOSIS chylothorax.166 An amniocentesis can be done to identify any Antenatal diagnosis enables the NICU team to be prepared chromosomal abnormalities, and fetal blood can be obtained for the delivery and the need for immediate thoracentesis in to evaluate the hemoglobin and total protein content in the delivery room.162 The antenatal workup of the mother the blood. A low serum protein level that occurs secondary and fetus may include fetal karyotype determination, maternal to fluid loss in the pleural space may promote fluid move- screening and viral studies, fetal echocardiography, ment out of the vascular space and into surrounding tissues. a complete ultrasound to look for associated anomalies, and Cultures would help determine if infection is the underlying diagnostic thoracentesis.162,166 A high number of lymph cells cause of the chylothorax.166 Repeated ultrasounds allow for in the thoracentesis fluid leads to a diagnosis of congenital close monitoring of the fetus and the pleural effusions. Once

2C-44 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics TABLE 2C-6 n Biochemical and Diagnostic Features of Chylous compressed lungs is restricted. Because fluid blocks more of Effusions156,157,175 the x-ray beam than air, on x-ray, the areas containing pleural Feature Chyle Characteristic fluid will be more opaque or denser than normal. Bilateral Appearance Clear or serous pulmonary hypoplasia may be noted on x-ray as a result of Milky after introduction of feedings fetal lung compression.5 Once pleural fluid is removed, free Odor Odorless air may enter the pleural spacing, causing pneumothorax, which will be evident on chest x-ray as hyperlucent areas Specific gravity 1.012–1.025 (dark) in the lung fields. Cell count Lymphocytes predominate (>90 percent) To confirm the diagnosis of a chylothorax in the postnatal Culture Sterile period, fluid aspirated from the pleural space needs to be Triglycerides Usually >110 mg/dL after fat-containing sent for diagnostic testing. The aspirated fluid may appear feedings are started May be <50 mg/dL if infant is NPO milky and with fat globules on microscopic examination if it was aspirated after enteral feeding has been established due Lipoprotein analysis Chylomicrons present to the fat content in formula and breast milk. It may appear Protein and electrolytes Same as in plasma straw colored in infants who have not been fed enterally.5 The analysis (with minimal fat intake) will show an increased triglyceride level of >110 mg/dL (1.24 millimoles/liter)156 and an absolute cell count >1,000 cells/microliter with lym- the infant is admitted to the NICU, a chest x-ray confirms the phocyte domination.164 See Table 2C-6 for a summary of the presence of a pleural effusion; however, analysis of the fluid diagnostic characteristics of chyle. from thoracentesis is necessary to confirm the diagnosis of a chylothorax.129 On x-ray, pleural effusions usually present as MANAGEMENT unilateral or bilateral accumulations that appear opaque (see Management of the fetus identified with congenital Figure 2C-40). The adjacent diaphragm may be depressed, chylothorax involves close fetal surveillance, early delivery and the mediastinum may be displaced away from the side of if indicated (preferably when the infant is >32 weeks gesta- the pleural effusion.159 In infants with bilateral fluid accumu- tion), and consideration of fetal surgery if the infant is <32 lations, the chest may appear completely opacified because weeks gestation. Prenatal surgical interventions to decrease the pleural space is filled with fluid and the aeration of the the pleural effusion and thereby lessen the risk of pulmonary hypoplasia include transabdominal fetal thoracentesis and placement of a pleural-amniotic shunt.160 FIGURE 2C-48 n Dynamics of fluid exchange in the intrapleural space. FIGURE 2C-49 n Mechanism by which fluid (or air) in the pleural space can collapse or compress the lung—in this case, the right lung.

From: Guyton A, and Hall J. 2011. Pulmonary circulation; pulmonary From: Agur A, and Dailey A. 2005. Grant’s Atlas of Anatomy, 11th ed. edema; pleural fluid. In Textbook of Medical Physiology, 12th ed. Philadelphia: Lippincott Williams & Wilkins, 28. Reprinted by Philadelphia: Saunders, 483. Reprinted by permission. permission.

Neonatal Radiology Basics Lung Pathology: Embryologic Abnormalities 2C-45 Postnatal management of a congenital chylothorax can be option chosen, a chest tube is inserted, and povidone-iodine, divided into two categories: conservative and surgical.156 The either 4 percent or 10 percent, is intrapleurally instilled goal of management is to minimize chyle formation while through the tube. It is believed that iodine initiates an maintaining adequate nutrition.169 However, optimal treat- inflammatory response, causing pleural adhesion.172 Because ment guidelines have not been developed.162 Conservative frequent use of iodine can impair thyroid function, thyroid management includes intermittent drainage of the effusion function tests must be monitored closely.170 by thoracentesis or continuous drainage by chest tube, respi- Octreotide is an analog of somatostatin that causes mild ratory support to improve oxygenation and ventilation, and vasoconstriction of the splanchnic vessels and reduces sero- a specialty diet including oral MCTs as the primary source tonin secretions and endocrine secretions from the gastric, of fat to minimize chyle formation.156,162,163 Drainage of the pancreatic, and intestinal areas.173 Octreotide decreases intes- pleural effusion, either by thoracentesis or chest tube, is nec- tinal absorption of the endocrine secretions of the pancreas, essary to promote expansion of the lungs and promote gas stomach, and intestine, slowing gastrointestinal transit time. exchange. Chest tubes should remain in place in anticipation Octreotide also regulates water and electrolyte transport across of reaccumulation and continuous drainage of pleural fluid, the gut.174 Rasiah and colleagues reported on the adminis- which needs to be accurately monitored. Large amounts of tration of octreotide treatment to a 34-week gestational age chyle may drain daily, depleting electrolytes, protein, fat, and infant with congenital chylothorax. The infant experienced lymphocytes. To avoid conditions of nutritional depletion high amounts of chest drainage. To avoid surgery, a ten-day and immunodeficiency, the neonate’s weight should be mon- course of an octreotide infusion was administered on a trial itored closely, along with serum albumin, total protein, abso- basis. After administration, the infant demonstrated immedi- lute lymphocyte count, and electrolyte levels.156 Nutritional ate respiratory improvement, and a reduction of chyle flow losses should be anticipated and replaced based on serum was observed.171 The infant was also able to tolerate normal values and amount of lymphatic drainage. cow’s milk formula 2 weeks after the octreotide treatment. Infant formula that contains oral MCTs is recommended because the MCTs are absorbed straight into the portal SUMMARY venous system, bypassing the intestinal lymph system, where Congenital chylothorax, an uncommon cause of respira- they would exacerbate the chylothorax. Providing MCTs as tory distress in the neonate, is diagnosed initially by prenatal the fat source for the newborn’s diet will decrease the amount ultrasound or postnatal x-ray and definitively by evaluation of of lymph flow, which may decrease lymph flow in the thoracic the fluid in the pleural space. The etiology is not well under- duct.163 Success with the MCT diet has not been consistent, stood, and reaccumulation of fluid can occur. Thoracentesis possibly because any oral intake can increase lymph flow.156 and chest tube placement may be required to support respi- If flow does not diminish or in cases of excessive chyle pro- ratory status. Conservative treatment, which may be tried duction despite diet and pleural drainage, feedings should be for up to five weeks, includes diet and should be attempted discontinued. TPN should be started to prevent malnutrition before surgical intervention. Nutritional status, along with and electrolyte imbalances.163 fluids and electrolytes, needs to be monitored closely. Generally, conservative management is undertaken for four to five weeks, while maintaining nutritional status, Originally published: Gaede C. 2006. Congenital chylothorax: A case study. 160 Neonatal Network 25(5): 371–381. Used with permission of Springer before surgery is considered. Many cases of congenital Publishing Company, LLC, www.springerpub.com/nn. chylothorax resolve spontaneously over time.162 When con- Disclosure servative management fails and pleural drainage continues, The author discloses no relevant financial interests or affiliations with any commercial interests. ligation of the thoracic duct may be considered. A thoracot- omy is performed, and the thoracic duct is ligated just above the aortic hiatus T8–T12.156 Other surgical options include: REFERENCES (1) a pleuroperitoneal shunt and placement of a catheter in 1. Savic B, et al. 1979. Lung sequestration: Report of seven cases and the pleural space leading to the peritoneal cavity to permit review of 540 published cases. Thorax 34(1): 96–101. fluid to be displaced from the pleural space to the peritoneal 2. Landing BH, and Dixon LG. 1979. 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2C-50 Lung Pathology: Embryologic Abnormalities Neonatal Radiology Basics