Chylothorax in Infants and Children

abstractChylothorax, the accumulation of chyle in the pleural space, is a rel-atively rare cause of pleural effusion in children. It can cause signif-icant respiratory morbidity, as well as lead to malnutrition andimmunodeficiency. Thus, a chylothorax requires timely diagnosisand treatment. This review will first discuss the anatomy and phys-iology of the lymphatic system and discuss various causes that canlead to development of a chylothorax in infants and children. Then,methods of diagnosis and treatment will be reviewed. Finally, compli-cations of chylothorax will be reviewed. Pediatrics 2014;133:722–733

AUTHOR: James D. Tutor, MD

Program in Pediatric Pulmonary Medicine, University ofTennessee Health Science Center; Le Bonheur Children’s Hospital;and St. Jude Children’s Research Hospital, Memphis, Tennessee

KEY WORDSchylothorax, infants, children

www.pediatrics.org/cgi/doi/10.1542/peds.2013-2072

doi:10.1542/peds.2013-2072

Accepted for publication Oct 2, 2013

Address correspondence to James D. Tutor, MD, Division ofPulmonology, Department of Pediatrics, Le Bonheur Children’sHospital, 50 North Dunlap St, Memphis, TN 38103. E-mail:jtutor@uthsc.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The author has indicated he has nofinancial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The author has indicated hehas no potential conflicts of interest to disclose.

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Chylothorax, the accumulation of chylein the pleural space, occurs after dis-ruption of the thoracic duct.1 The in-cidence of chylothorax in children isunknown. Although a rare cause ofpleural effusion in most children,2 it isthe most common form of pleural ef-fusion in neonates.3 It can result insignificant respiratory morbidity andimmunodeficiency in infants and chil-dren if not diagnosed and treated.

Here, the anatomy and physiology ofthe lymphatic system will be re-viewed, as well as some of the variouscauses of chylothorax in infants andchildren. Current methods of di-agnosis and management, and someassociated complications, will bereviewed.

ANATOMY AND PHYSIOLOGY OFTHE LYMPHATIC SYSTEM

The human lymphatic system has 3main functions: (1) transport lipids andlipid-soluble vitamins to the systemiccirculation; (2) collect and return ex-cess fluid and extravasated proteinsfrom the interstitial spaces to the cir-culation; and (3) return lymphocytes tothe circulation.1,2

From the lacteals, the chyle is trans-ported to the cisterna chyli, whichoverlies the anterior surface of thesecond lumbar vertebra.4 The ductpasses through the esophageal hiatusof the diaphragm into the thoraciccavity, ascends extrapleurally in theposterior mediastinum to the right ofthe vertebral column, and lies betweenthe azygous vein and the descendingaorta, in close proximity to the esoph-agus and the pericardium. At the fourthto sixth thoracic vertebrae, the ductcrosses to the left of the vertebralcolumn and continues cephalic to en-ter the superior mediastinum betweenthe aortic arch and the subclavian ar-tery and the left side of the esophagus.Once past the thoracic inlet, it arches 3to 5 cm above the clavicle and passes

anterior to the subclavian artery, ver-tebral artery, and thyrocervical trunkto terminate near the left jugular andsubclavian veins.1 Many anatomic var-iations can exist in all portions of thethoracic duct.5,6

Chyle is a noninflammatory, alkaline,and bacteriostatic fluid composedmainly of fat, cholesterol, electrolytes,proteins, glucose, and abundant lym-phocytes (Table 1).2 The protein contentof chyle is usually .3 g/L, and theelectrolyte composition is similar tothat of serum.7 The lymphocyte countranges from 400 to 6800/mm3, withmost being T lymphocytes.8 Chyle ap-pears as a milky, opalescent fluid thatseparates into 3 layers upon standing:a creamy uppermost layer containingchylomicrons, a milky intermediatelayer, and a dependent layer containingcellular elements, most of which aresmall lymphocytes.9 Chyle may beslightly turbid if an individual has noteaten recently because its lipid contentwill be reduced.1 The thoracic ducttransports between 1.5 and 2.5 L ofchyle daily (maximum 4 L/day ina healthy adult). Flow varies dependingon the diet, medications, intestinalfunction, and physical activity, and itcan increase by two- to 10-fold for 2 to 3

hours after ingestion of fat, and by 20%after drinking water.2,7

CAUSES OF CHYLOTHORAX

There are several causes of chylothoraxin infants and children (Table 2), whichvary according to the age of the child ormechanism of injury to the thoracic

TABLE 1 Components of Chyle2,108

Component Amount

pH 7.4–7.8Absolute cell count .1000 cells/LLymphocytes 400–6800/mm3

Erythrocytes 50–600/mm3

Calories 200 kcal/LTotal fat 0.4–0.6 g/dLCholesterol 65–220 mg/dLTriglycerides . 110 mg/dL

(.1.1 mmol/L)Chylomicrons PresentTotal protein 2–6 g/dLAlbumin 1.2–4.1 g/dLGlobulin 1.1–3.1 g/dLGlucose 2.7–11 mmol/LSodium 104–108 mmol/LPotassium 3.8–5.0 mmol/LChloride 85–130 mmol/LCalcium 3.4–6.0 mmol/LPhosphate 0.8–4.2 mmol/L

TABLE 2 Causes of Chylothorax in Children

I. Congenital chylothoraxA. Congenital lymphatic malformations1. Lymphangiomatosis2. Lymphangiectasia3. Atresia of thoracic duct.

B. Associated with syndromes1. Down syndrome2. Noonan syndrome3. Turner syndrome4. Gorham-Stout syndrome5. X-linked myotubular myopathy6. Missense mutation in integrin a9b1

7. Hydrops fetalis8. Yellow nail syndrome

II. TraumaticA. Associated with surgeries for1. Excision of lymph nodes2. Congenital heart disease3. Scoliosis4. Vascular ring5. Diaphragmatic hernia

B. Invasive diagnostic and therapeuticprocedures1. Subclavian vein catheterization

C. Other trauma1. Blunt force or penetrating trauma to the

chest2. Hyperexpansion or stretching of chest wall

or thoracic spine3. Coughing4. Vomiting5. Child birth6. Child abuse

III. High central venous pressureA. Thrombosis of superior vena cavaB. Post-Fontan surgery

IV. Associated with tumorsA. NeurogenicB. LymphomaC. TeratomaD. WilmsE. OvarianF. Kaposi sarcoma

V. MiscellaneousA. Granulomatous infections1. Tuberculosis2. Histoplasmosis3. Sarcoidosis

B. Other1. Staphylococcal discitis2. Henoch-Schönlein purpura

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duct. It may result from congenitalabnormalities of the lymphatics, whichdo not always present in the neonatalperiod.2

Pulmonary lymphangiomas and lym-phangiectasia are the 2 major lym-phatic abnormalities associated withchylothorax,2 but absence or atresia ofthe thoracic duct can also lead to thisproblem.10 Pulmonary lymphangioma-tosis is a focal proliferation of welldifferentiated lymphatic tissues oftenassociated with lymphatic abnormali-ties in other organs, whereas pulmo-nary lymphangiectasia is diffusedilatation of the interlobular and sub-pleural lymphatics.2 Lymphangiomasusually present by 2 years of age, butthey may not be recognized untiladulthood. If they occur in the head,neck, or axial skeleton, they can extendinto the mediastinum. About 1% oflymphangiomas are confined to thechest.2 Lymphangiectasia can be a pri-mary condition that is often fatal innewborns, or it can be secondary toother conditions, such as congenitalheart disease or pulmonary venousobstruction, where there is abnormaldrainage or an increase in lymph pro-duction.2 Diagnosis of pulmonary lym-phangiomatosis and lymphangiectasiacan be made by lymphoscintigraphy,11

computerized tomography,12 or MRI.13

Lung biopsy is often necessary forconfirmation.14,15 Lymphangiomas aretreated with surgical excision or sclero-therapy.14 There are reports of the suc-cessful use of radiotherapy for casesin which chylothorax was refractory tosurgical management.16,17

Chylothorax can be a manifestation ofDown,18–21 Turner,18–20 and Noonansyndromes.18–20,22–24 Congenital andpulmonary lymphangiectasia occurin these syndromes.2 Other syndromesassociatedwith chylothorax are X-linkedmyotubular myopathy,25 missense mu-tation in integrina9b1,26,27 and Gorham-Stout syndrome.28–34 Members of the

integrin family of adhesion receptorsmediate both cell–cell and cell–matrixinteractions and have been shownto play vital roles in embryonic de-velopment, wound healing, and otherbiologic processes. Gorham-Stout dis-ease, characterized by proliferation ofvascular structures within bones,leads to osteolytic lesions evidenton radiography. It has no known in-heritance pattern. Chylothorax is as-sociated with the disease, possiblyrelated to dysplasia of lymphatic ves-sels at the pleura. Children are morecommonly affected than adults, andpresenting symptoms may includecough, dyspnea, and pain. The pres-ence of chylothorax is associated withworsened prognosis.35 Anecdotal re-ports suggest that interferona2b maybe trialed in the treatment of thisdisease.31,35 Chylothorax can occur inthe presence of hydrops fetalis.36,37 Ithas been seen in a newborn infantwith nonimmune hydrops fetalis andyellow nail syndrome.38

Trauma can cause chylothorax by rup-ture or laceration of the thoracic duct.2

It occurs as a postoperative complica-tion after various surgeries involvingstructures in the neck and thorax.39–44

Other surgeries that can be complicatedby chylothorax in children include thosefor treatment of scoliosis,45–48 vascularrings,49,50 and diaphragmatic hernia.51

In children, the reported incidence ofchylothorax after cardiothoracic sur-gery is between 0.85% and 6.6%.39,52–54

Another traumatic cause of chylothoraxis laceration of the thoracic duct dur-ing catheterization of the subclavianvein.55,56

Noniatrogenic trauma can lead to thedevelopment of chylothorax. These in-cludeblunt force orpenetrating traumato the chest,57–61 sudden hyperexten-sion, or stretching of the chest wall orthoracic spine with fracture of a verte-bra,2 severe coughing or vomiting,62

and the force of child birth.2,63 Child

abuse, such as heavy blows to the backor stomach, can cause rupture of thethoracic duct, leading to the de-velopment of chylothorax.64–66 Chylo-thorax due to closed trauma is usuallyon the right side, with the site of rup-ture most commonly in the region ofthe ninth or 10th thoracic vertebra.67

Venous thrombus or obstruction in thesuperior vena cava or subclavian veinmay lead to rupture of the thoracicduct.55,56,68 Chylothorax can complicateinnominate vein69 or left subclavianvein thrombosis70 and the Fontan pro-cedure.71–73

Chylothorax can be associated withvarious tumors and malignancies(neurogenic,74,75 lymphoma,2 teratoma,2

Wilms,76 ovarian,77 andKaposi sarcoma78).Lymphoma is the most common tumorassociated with chylothorax (60% to70% of cases),2 and it may be the pre-senting symptom.7,79,80 The presenceof a nontraumatic chylothorax is anindication for a diligent search for alymphoma.1

Granulomatous infections such as tu-berculosis,81–83 histoplasmosis,84 andsarcoidosis85 can be associated withthe development of chylothorax attrib-utable to lymphadenopathy obstruct-ing the thoracic duct. Other etiologiesinclude staphylococcal discitis86 andHenoch-Schönlein purpura.87

CLINICAL MANIFESTATIONS OFCHYLOTHORAX

The initial symptoms of chylothorax areusually related to accumulation of fluidin the pleural space.1,2 Patients canbe asymptomatic; however, dyspnea,cough, and chest discomfort developwith time.2 Pleuritic chest pain and fe-ver are rare.1 With traumatic chylo-thorax, a latent period of 2 to 10 daysusually occurs between the traumaand the onset of the pleural effusion.67

Lymph collects extrapleurally in themediastinum after the thoracic duct

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disruption, forms a chyloma, and pro-duces a posterior mediastinal mass.6

The mediastinal pleura ruptures, chylegains access to the pleural space, anddyspnea is produced by the chylecompressing the lung.1 Rapid accu-mulation of a large volume of fluid canlead to adverse hemodynamic compli-cations with significant cardiorespira-tory difficulties, such as hypotension,cyanosis, and significant respiratorydistress.1,2 In patients with non-traumatic chylothorax, symptom onsetis gradual.1 Congenital chylothoraxpresenting antenatally can act asa space-occupying lesion and restrictnormal development of the lungs.2 Atbirth, the infant develops respiratorydistress; 50% of patients have symp-toms within the first 24 hours, whereas75% have symptoms by the end of thefirst week.88 On physical examination,there is bilateral or unilateral dullnessto percussion, and poor air entry.89

Among patients with chronic chylo-thorax, muscle wasting, weight loss,and other signs of malnutrition can bepresent.1 The patients may be com-promised immunologically becauseof lymphocyte depletion and hypo-gammaglobulinemia.1,14

DIAGNOSIS OF CHYLOTHORAX

A chest radiograph can reveal pleuralfluid and assess the size and location ofthe effusion. Use of lateral decubitusradiographs or ultrasound can de-termine whether there is free fluid inthe pleural space or whether it is or-ganized.90

Chyle obtained on thoracentesis iswhite, odorless, and milky in appear-ance. When this type offluid is obtained,thedifferentiation is between empyemaand pseudochylothorax with a chyliformpleural effusion. A pseudochylothoraxis a long-standing (mean 5 years)pleural effusion that is turbid or milky,containing large amounts of cholesterolor lecithin-globulincomplexes(chyliform).

It does not result from disruption of thethoracic duct.1 The visceral pleura ina pseudochylothorax is thickened andmay be calcified, whereas with chylo-thorax there is acute onset and thepleural surfaces are normal.91 Themilkiness of the fluid from an empyemais caused by suspended white bloodcells. If the fluid is centrifuged, thesupernatant will be clear. Chylous andchyliform pleural fluids remain opaqueafter centrifugation. If cholesterolcrystals are responsible for the tur-bidity, theymay be easily demonstratedby examination of the pleural fluidsediment.1 If the turbidity is because ofhigh levels of cholesterol, it will clearwith the addition of 1 to 2 mL ethylether. If it is due to chylomicrons orlecithin complexes, the fluid will notclear.92

The best way to diagnose chylothorax isby measuring the triglyceride andcholesterol levels in the pleural fluid.1 Ifthe triglyceride level is above 110 mg/dL and the ratio of the pleural fluid toserum cholesterol is ,1.0, the di-agnosis is established. In a pseudochy-lothorax, the ratio will exceed 1.0.93 Ifthere is still doubt about whether thepleural effusion is a chylothorax ora pseudochylothorax, the fluid shouldbe analyzed for chylomicrons by lipo-protein analysis. Demonstration ofchylomicrons confirms the diagnosisof chylothorax.94 With congenital chy-lothorax, the pleural fluid is serous andbecomes chylous when milk feedingsare started.88 Pleural fluid triglycerideand lipoprotein analysis should beperformed in all newbornswith pleuraleffusion.1,88

OTHER INVESTIGATIONS

Once chylothorax has been diagnosed,other radiologic studies will likely beneeded to further investigate the lym-phatic system. Studies to outline thelymphatic vessels, identify the site ofchyle leakage, and determine the cause

of thechylothoraxshouldbeperformed.Imaging studies such as computerizedtomography scans, lymphangiography,and lymphoscintigraphy can be help-ful.2 Occasionally, MRI is used, partic-ularly if the mediastinum needs to beimaged.2

Lymphangiography and lymphoscintig-raphy both require the administrationof a contrast agent. This can be done byinterstitial (intradermalorsubcutaneous)administration, administration into a can-nulated lymphatic vessel, intravenous in-jection, or injection into a lymphnode.95–97

Lymphangiography implies the admin-istration of an iodinated contrast agentinto a cannulated lymph vessel. A simul-taneous chest radiograph or computer-ized tomography scan will delineate thelymphatic anatomy. The sensitivity oflymphangiography can be low becauseit is difficult to visualize the entirelength of the thoracic duct because ofpoor mixing of oily contrast mediumand chyle.2 Successful identificationrates of up to 81% have been reportedin adults.98 Limitations include the tech-nical skills needed to cannulate lymphvessels, pain, infection, respiratory dis-tress, and damage to the lymphatics.2

Thus, many medical centers no longerperform lymphangiograms.1 An alter-native is lymphoscintigraphy, a fasterand less traumatic nuclear imagingtechnique that utilizes filtered 99mTc in-jected intradermally or subcutaneouslyas a contrast agent.2,99

Computerized tomography can beuseful to image the mediastinum, es-pecially if nontraumatic chylothorax issuspected,andcandetectsmallamountsofcontrastmaterial in thepleural space.2

It has been used in at least 1 case to aidin the diagnosis of lymphangiomatosisin a child.12

Magnetic resonance lymphographyinvolves interstitial or intravenous in-jection of gadolinium-based contrastagents. This technique has been usedin adults with good delineation of

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lymphatic vessels.100,101 MRI has beenused in at least 1 case of disseminatedlymphangiomatosis in a child to helpassess the extent of the disease.13

If direct visualization of a chyle leakpoint is needed, thoracoscopy can beuseful. It also allows for biopsies of anysuspect areas.2

MEDICAL MANAGEMENT OFCHYLOTHORAX

The goals of management of chylo-thorax are relief of respiratory symp-toms by drainage of the pleural fluid,prevention of recurrence by treat-ment of the underlying cause, andprevention/treatment of malnutritionand immunodeficiency (Fig 1).

The initial step is aspiration of thepleural fluid for diagnostic purposes. Ifthe effusion is large and compromisingrespiration, or if the effusion is likely toreoccur, then a chest tube should beinserted for continuous drainage of thepleural space.Quantificationofdrainage

is useful to guide treatment of fluidimbalances.2 Some centers use dailydrainage as a guide for clinical im-provement or failure (,10 mL/kg perday of pleural drainage is consideredto be an improvement;.10 mL/kg perday of pleural drainage is consideredto be a failure after 4 weeks of non-surgical management).52 In severely illpatients, assisted ventilation may benecessary. The use of positive end-expiratory pressure ventilation maytamponade the injured duct, helpingto decrease chyle flow.102–104 There is1 report of the successful use of high-frequency oscillatory ventilation inseverely ill neonates with congenitalchylothoraces.105

There are several nonsurgical methods(dietary modifications and/or adjunc-tivemedications) thathavebeenused totry to prevent or treat chylothoraxreoccurrence if the leak does notspontaneously resolve. Most seriesperformed in children recommend upto a 2- to 4-week trial of nonsurgical

therapies before surgery is consid-ered.2 Nonoperative management ofchylothorax in children is successful in.80% of reported cases, includingthose patients with chylothorax aftercardiothoracic surgery.5,39,52–54,106,107

To reduce the flow of chyle through thethoracic duct while waiting for spon-taneous healing to occur, a fat-free dietwith the addition of medium-chain tri-glycerides is instituted. Medium-chaintriglycerides with saturated fatty acidsof 8 to 12 carbon chain lengths areabsorbed directly into the portal ve-nous system, bypassing lymphaticdrainage.2 Several enteral formulasare available commercially that con-tain a high percentage of medium-chain triglycerides but also containsome long-chain fatty acids as well:Optimental (Abbott Nutrition, Columbus,OH), Peptamen (Nestle Health Science,Vevey, Switzerland), Peptamen AF (NestleHealth Science), Peptamen 1.5 (NestleHealth Science), Perative (Abbott Nutri-tion), Portagen (Mead Johnson Nutrition,

FIGURE 1Algorithm for evaluation and treatment of chylothorax in children.

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Glenview, IL), Monagen (Nutricia,Gaithersburg, MD), Enfaport (MeadJohnson Nutrition), Pregestimil (MeadJohnson Nutrition), Vital HN (AbbottNutrition), Vital HN 1.5 (Abbott Nutri-tion), and Vivonex TEN (Nestle HealthScience). Medium-chain triglycerideformulas do not contain essential fattyacids, so those will need to be supple-mented if these formulas are used for.3 weeks.108 There is a report of thesuccessful use of an enteral formulacontaining long-chain triglycerides,109

and a report of the combined use oflow-fat breast milk and octreotide, totreat postoperative chylothorax.110 Amore aggressive option is completeenteric rest by using total parenteralnutrition.54 There are several intra-venous lipid emulsions that are de-signed to be delivered directly into theblood stream: Intralipid and Liposyn.They do not travel through the lymphsystem and do not contribute to chyleflow. They also provide essential fattyacids. In adults, enteral nutrition maybe effective if chyle output is ,1000mL/day. A low fat semielemental for-mula may be effective if chyle output is,500 mL/day. An elemental formulamay be required if chyle output is.500mL/day. Parenteral nutrition will berequired if chyle output is .1000 mL/day in adults, or if patients are notresponding to a modified oral or en-teral regimen, or if they are havingincreased chyle output on enteralnutrition.108 Whether enteral or par-enteral nutrition is chosen, the calo-ries, electrolytes, and volume must atleast match those lost in the chyleoutput. In a group of 51 children withchylothorax, the use of conservativeenteral or parenteral therapy for 1to 3 weeks resulted in resolution ofthe chylothorax in 41 (80%) of thechildren.52

Somatostatin is an endogenous hor-mone with actions that include effectson the gastrointestinal tract. Octreotide

is a synthetic, long-acting somatostatinanalog. These agents, whose mecha-nism(s) of action is(are) not clear, havebeen used in the management of chy-lothorax with varying results.2 It may bethat they cause a reduction in intestinalblood flow by vasoconstriction of thesplanchnic circulation, with reductionof lymphatic fluid production.111,112 Al-ternately, the lymphatic vessels mayhave somatostatin receptors, and theirstimulation could result in decreasedlymphatic flow.113 These agents alsodecrease gastrointestinal motility, anddecrease the volume of gastric, pan-creatic, and biliary secretions, whichin turn decreases lymphatic flow.114–116

In comparison with somatostatin,octreotide has a longer half-life, greaterpotency, and the option of subcutaneousadministration.115,116 Either drug can begiven as a continuous intravenous in-fusion or as an intravenous bolus twicedaily. The starting dose of somatostatinis 3.5 mg/kg per hour, which can be in-creased to 10 mg/kg per hour.111 Thedose for octreotide in children hasranged from 0.3 to 1.0 mg/kg perhour.117,118 The optimal timing of in-troduction and duration of treatment isunknown.2 Side effects of somatostatinand octreotide include hyperglycemia,hypothyroidism,119 cramps, nausea, di-arrhea, renal impairment, necrotizingenterocolitis,120 and liverdysfunction.115,116

A case of anaphylaxis has been re-ported in a child after the use of octreo-tide.121 Shah and Sinn122 reported theuse of octreotide in 6 patients withcongenital chylothorax by using a doserange of 0.5 to 10 mg/kg per hour.Octreotide was started at amedian ageof 13.5 days (range, 8 to 22 days) andwas given for a median of 20 days(range, 12 to 27 days). Five of the 6patients had resolution of their chylo-thoraces with this therapy. Roehret al116 performed a systematic litera-ture review of the use of somatostatinand octreotide in 35 children with pri-mary or secondary chylothorax. Most

studies reported a significant de-crease in chylous drainage within 5to 6 days of starting octreotide or so-matostatin. A 2010 Cochrane report123

described the use of octreotide in 20neonates with chylothorax. Fourteen ofthe case reports described successfulresolution of chylothorax, 4 reportedno resolution, and 1 reported equivocalresults. No practice recommendationwas made based on this evidence.Horvers et al124 reported on the use ofoctreotide in 7 patients with congenitalchylothorax. Pleural effusions eventu-ally decreased in all patients after ad-ministration of 5 to 6 mg octreotide/kgperminute, but the authors felt that thedecrease might reflect the naturalhistory of congenital chylothorax and,hence, no clear, consistent effect ofoctreotide was identified. They notedthat pulmonary hypertension was acommon problem in the patient group.A randomized, controlled, multicentertrial is needed to assess the safety andefficacy of octreotide and somatostatinuse in the treatment of chylothorax inchildren.123,124

Other agents used in the treatment ofchylothorax include nitric oxide andetilefrine. A case report described theuse of nitric oxide in a neonate whodeveloped a chylothorax after surgeryfor congenital heart disease.125 At aninhaled nitric oxide dose of 20 ppm, thechest tube drainage markedly de-creased and finally ceased 8 days later.Nitric oxide was discontinued 19 daysafter initiation with no recurrence ofthe chylothorax. The authors proposedthat functional venous obstruction dueto the patient’s moderate pulmonaryhypertension was a contributor to thepersistence of the chylous leak. Thenitric oxide caused a decrease in pul-monary artery pressure and decreasedsystemic venous pressures by aug-menting forward flow through the rightside of the heart. Etilefrine is a sympa-thomimetic drug that has been used

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in a small number of adults for themanagement of postoperative chylo-thorax with no side effects. It causessystemic smooth muscle contractionand is thought to decrease chyle flowby constriction of the thoracic duct.126,127

SURGICAL MANAGEMENT OFCHYLOTHORAX

Surgery should be considered whenmedical management of chylothoraxhas failed toreducechyleflowandallowhealing of the duct. There is no con-sensus on the timing of surgery.2 Somerecommend surgery if the effusionpersists for more than 2 weeks. Othersregard a particular volume, such as.100 mL per year of age in children, asan indication for surgery.128–130 Mostrecommend an extended period (3 to 4weeks) of conservative managementbefore proceeding to surgical treat-ment.52,106 If there is a well identifiedsite of chyle leak and high flow thatprecludes spontaneous healing, a casefor earlier surgery can be made.131

Successful surgery can shorten hos-pitalization and reduce the risks ofmalnutrition and immunosuppres-sion.2

There are several procedures that canbe used for the treatment of chylo-thorax. If the site of rupture of thethoracic duct can be identified bylymphangiography, direct surgical li-gation of the duct represents a de-finitive treatment of chylothorax.9,52,132

Thoracoscopy has a low rate of com-plications and is cost-effective.133,134

Pego-Fernandez et al134 performedthoracic duct ligation via thoracoscopyin 14 children with chylothorax aftercardiac surgery and reported that itwas successful in 12 (86%). Nathet al132 performed duct ligation in 20pediatric patients with chylothorax af-ter cardiothoracic surgery. They weresuccessful in 16 patients (80%), butnoted that patients with thrombus ofupper body venous vessels or prolonged

chest tube drainage were more likelyto fail and/or die. They recommendedthat duct ligation be done within 2weeks of recognizing the chylothorax. Ifneeded to visualize the thoracic ductand the site of leakage during surgery,the patient can be given a 200-mLmixture of milk and cream a few hoursbefore surgery, or an intraoperativeinjection of 1% Evans blue dye.131,135,136

If the site of leakage cannot be identi-fied, a mass ligation of the thoracicduct and its surrounding tissue is donearound the aorta, azygos vein, andesophagus, adjacent to the vertebralbody,137 or by ligation of the cisternchyli.138

Another procedure used to managechylothorax isobliterationof thepleuralspace, either chemically or surgically.Various agents, such as tetracycline,talc, bleomycin, fibrin glue, andpovidone-iodine, have been used.139–143

Povidone-iodine 10% dermique dilutedwith saline or povidone-iodine 4%scrub was instilled directly througha chest tube into the pleural space ina group of 4 neonates with chylo-thoraces. Systemic analgesia wasachieved with a morphinomimetic(fentanyl or sufentanil), and sedationwas provided with intravenousmidazolam. Thyroid function was re-ported to be normal before and afterinstillation of povidone-iodine in 3 ofthe infants; it was not checked in thefourth infant.139 The intrapleural ad-ministration of talc can lead to thedevelopment of the acute respiratorydistress syndrome.1 OK-432, an inactivepreparation of Streptococcus pyogenes,has also been used as an effectivesclerosing agent in neonates.144,145 OK-432-induced pleurodesis has beenused as an antenatal treatment ofsevere chylothorax associated withnonimmunologic hydrops fetalis.146,147

Pleurodesis is performed with thoracos-copy, although the sclerosing agent canbe instilled through a chest tube.

Pleurodesis has effectively been usedin cases where medical therapies forchylothorax failed and direct surgicalduct ligation was not performed.148

A third surgical method to managechylothorax is the placement of a pleu-roperitoneal shunt. This provides a wayof draining chyle from thepleural spacewithout losing the fluid. The shunts area 1-way subcutaneous connection be-tween the pleura and the peritoneumthat can be inserted with local anes-thesia.1,2 They have been used in chil-dren whose chylothoraces have beenrefractory to treatment with dietarymanagement, thoracentesis, or tubethoracostomy, and are reported to be75% to 90% effective.129,149–151 Aftera shunt is implanted, the lymphaticdefect closes spontaneously in mostcases and the shunt can be removed 30to 90 days after insertion.149 Murphyet al129 recommended placing theshunt if drainage from the chylothoraxpersisted beyond 5 days. Shunts havealso been used to treat chylothoracesin preterm infants and in fetuses.37,151

There are case reports of 2 other sep-arate methods that have been used tomanage chylothorax. Fluoroscopicallyguided percutaneous embolization ofthe thoracic duct has been used tomanage chylothorax.152,153 There arealso reports of autoinfusion of chylo-thorax fluid in patients who were un-dergoing hemodialysis.154,155

COMPLICATIONS OF CHYLOTHORAX

Several complications can occur inassociation with the development ofchylothorax. These include malnutri-tion, hyponatremia, fluid imbalance,respiratory distress, increased risk ofthrombosis,156 and secondary immu-nodeficiency.2 In 1 reported case ofselenium deficiency because of loss ofselenium in chylous fluid, myopathyassociated with severe cardiomyopa-thy developed.157

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Chylothorax leads to hypogammaglo-bulinemia and lymphopenia.158–162 In 16children who developed chylothoracesafter cardiac surgery, there weredecreases in the absolute numbers ofB lymphocytes (CD19+), T lymphocytes(CD3+), helper T-cells (CD4+), andsuppressor/cytotoxic T-cells (CD8+),but a normal CD4+:CD8+ ratio.159 Theabsolute number of natural killer cells(CD16+) and metabolic activity ofpolymorphonuclear leukocytes wasnormal. In another study of 5 childrenwith chylothorax, 2 had reduced abso-lute numbers and percentage of CD3+T-lymphocytes, and all the children haddecreased numbers and percentage ofCD4+ T-lymphocytes.158 The percentageof CD8+ lymphocytes was normal in allpatients and the CD4+:CD8+ ratio wasreversed. Because of this secondaryimmunodeficiency, children with chy-lothorax are at risk for developmentof infections. Of 7 infants with congen-ital chylothorax due to nonimmunehydrops fetalis, 4 (57%) developed

nosocomial infections.162 In 2 childrenwho developed chylothorax after sur-gery for congenital heart disease, in-travenous immunoglobulin G was givenprophylactically, after the developmentof the chylothorax or early in the courseof septicemia.160 In a later study of 8children with hypogammaglobulinemiaand lymphopenia attributable to chy-lothorax, intravenous immunoglobulinG administration did not lead to dis-cernible protection from infectiouscomplications.161

CONCLUSIONS

Chylothorax is a rare cause of pleuraleffusion in children except during theneonatal period, when it is the mostcommon cause. Diagnosis is made bymeasurement of the triglyceride level,determination of the pleural fluid toserum cholesterol ratio, and demon-stration of chylomicrons in the pleuralfluid. There are multiple etiologies ofchylothorax in children. Knowledge of

the anatomy and physiology of thelymphatic system, particularly thethoracic duct, is vital for assessmentand management. Initial treatmentinvolves drainage of the effusion, di-etary modifications, and other medicaltherapies to diminish chyle flow so thatthe thoracic duct can heal. Somato-statin and octreotide are of variableusefulness. Failure of medical man-agement, particularly if the childdevelops complications from the chy-lothorax, should result in early surgicalintervention. There are several surgicalprocedures that have been effective inthe treatment of chylothorax. Theprognosis of children who developchylothorax depends on the etiology ofthe effusion, its response to medical/surgical therapies, and the complica-tions that result from the chylothorax.

ACKNOWLEDGMENTThe author thanks Andrea B. Patters forher editorial assistance with the prep-aration of this article.

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BIRTHPLACE OF BUDDHA: I enjoy ecclesiastical architecture and the architec-tural history of religions. While I have visited many innumerable temples,churches, pilgrimage sites, shrines, and Buddhist temples, I have not known forsure which one marked the birthplace of Buddha. The most commonly accepteddate for Buddha’s lifespan is 563-483 BC, but the exact date of his birth andwhereabouts of his birthplace are not known; much of what we know of his earlylife comes from oral histories. As reported on CNN (World: November 25, 2013),scientists have uncovered archaeological evidence to suggest that Buddha wasmost likely born in the sixth century BC in current Nepal. Scientists excavating inNepal (at a site believed by many to be Buddha’s birthplace) have uncovered anancient Buddhist shrine dating back to that time. The Lumbini site in Nepal, in anarea bordering India and the Siwalik Range of the Himalayas, has long beenassociated with Buddha, and pilgrims routinely visited the site through the 16thcentury. Currently, there is a temple at the site built over earlier Buddhist tem-ples. A sandstone pillar found here in the late 19th century has an inscriptionstating that Emperor Ashoka visited this early temple in the third century BCbecause it was the birthplace of Buddha. Scientists have now found evidence thatthe third century temple was built over an even earlier temple. Carbon dating ofpost-hole fragments date the earliest structure to the sixth century BC. In-terestingly, the structure most likely was open in the middle and had a centraltree – consistent with the tradition that Buddha’s mother gave birth to him whileholding onto a tree branch. It would appear that belief, customs, and scienceactually may all agree. I for one am excited about these recent archaeologicaldiscoveries and hope to be able to visit the site soon.

Noted by WVR, MD

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