Open access peer-reviewed chapter - ONLINE FIRST
Abstract
Pleural diseases are rare in the neonatal period, but sometimes are associated with significant morbidity and mortality. Congenital chylothorax is the most common type of pleural effusion in neonates. The diagnostic approach to neonatal chylothorax and neonatal pleural effusions are discussed in detail. The management of congenital chylothorax is challenging, because it includes prenatal procedures, diet, drug treatment, and surgery. Summarized treatment protocol gives information about the most important therapeutic measures, according to the postnatal age and clinical evolution. Brief description of the other types of pleural effusions is provided.
Keywords
- neonate
- pleura
- effusion
- chylothorax
- congenital
1. Introduction
Pleural diseases in the neonatal period are rare, but some of them are associated with significant morbidity and mortality. The most common neonatal pleural disease is the chylothorax – congenital and acquired. There is lack of uniform guidelines for the prenatal and postnatal treatment of this condition. The aim of this chapter is to summarize the clinical experience, provide up to date knowledge, and delineate future perspectives.
1.1 Neonatal pleural effusions
Pleural effusion is defined as fluid accumulation in the pleural space between the parietal and visceral pleura. There are many conditions in the neonatal period associated with changes of the pulmonary venous hydrostatic pressure, lymphatic pressure, blood oncotic pressure, and local tissue trauma or inflammation all of them leading to the development of pleural effusion [1]. The incidence of pleural effusions in neonates varies between 5.5/10000 to 2.2% in different clinical settings [2, 3]. The prevalence of pleural effusion is high in neonates admitted to the NICU (neonatal intensive care unit) [2].
1.2 Classification of neonatal pleural effusions
About 10–30% of neonatal pleural effusions are identified prenatally, and up to 90% are postnatally acquired [4, 5].
1.3 Prenatally acquired pleural effusions
The most common types and causes of congenital pleural effusion are as follows [6]:
Immune and nonimmune hydrops – abnormal fetal liquid collection in a minimum of two anatomic locations. Fetal hydrops could be immune-mediated (Rh incompatibility) or nonimmune (genetic syndromes, metabolic diseases, hematologic disorders (alpha thalassemia), and infections).
Chromosomal diseases – most commonly Turner and Down syndrome. Turner syndrome is a condition, when one of the X chromosomes is missing or partially missing, and in Down syndrome, there is an extra copy of chromosome 21.
Congenital pneumonia.
Congenital chylothorax.
Congenital heart failure.
Congenital nonchylous-isolated pleural effusion.
Infections – cytomegalovirus, herpes simplex virus, toxoplasmosis, and coxsackie viruses.
Pulmonary malformations – bronchopulmonary sequestration, pulmonary lymphangiectasia, pulmonary lymphatic hypoplasia, and congenital pulmonary airway malformation [7, 8].
Rare causes – obstructive uropathy [9, 10], congenital malignancies [11], thoracic hamartoma [12, 13], and intrapericardial teratomas [14].
The incidence of congenital isolated pleural effusion is about 1:12,000 to 1:15,000 [15]. Isolated nonchylous effusions without concomitant pathologic conditions are very rare [16]. The most common type of congenital isolated pleural effusion is the congenital chylous pleural effusion [17].
1.4 Postnatally acquired pleural effusions
Severe sepsis – pleural effusion could be associated very rare with severe neonatal sepsis [18].
COVID-19-related neonatal pleural effusion [19].
Parapneumonic effusions and empyema – positive pleural culture or purulent effusion with elevated white blood cells (WBC) and higher percentage of polymorphonuclears (PMN), high protein content, and presence of bacteria. Pleural effusions are mostly seen in sepsis and pneumonia, caused by
Staphylococcus aureus ,Streptococcus pneumoniae ,Streptococcus pyogenes ,Bacteroides fragilis ,Acinetobacter spp.,Enterobacter aerogenes ,Escherichia coli ,Klebsiella spp.,Pseudomonas aeruginosa , andAcinetobacter caloasceticus [20]. The development of neonatal empyema goes through three stages – exudative, fibrinopurulent, and organizational. Chest ultrasound is extremely helpful in the diagnosis and follow-up of parapneumonic effusion [21].Hemothorax – presence of blood in the pleural space.
Congestive heart failure could be complicated by bilateral pleural effusions with characteristics of a transudate – total protein content of the fluid <30 g/l and WBC <2000/mm3.
Acquired chylothorax – the most common cause is cardiothoracic surgery with an incidence of 2–3% [22], diaphragmatic hernia, and perinatal trauma due to stretching of the chest wall during resuscitation. In traumatic injury, the latent period for chyle accumulation could be 2–10 days [3, 23, 24]. The reported incidence of chylothorax after cardio-thoracic surgery in children is reported to be between 0.85 and 6.6% [25, 26]. This pathophysiological mechanism causes injury to the thoracic duct [4, 5, 27, 28].
PICC (percutaneously inserted central venous line) extravasation – the analysis of pleural fluid usually shows an increased content of glucose and triglycerides, depending on the composition of infusion solutions and low cell count. Percutaneously inserted central venous lines are widely used in all neonatal departments for prolonged venous infusion, use of vasoactive drugs (catecholamines), and parenteral nutrition. The placement is easy, but some common complications could happen such as catheter-associated infection, pericardial effusion, pleural effusion, ascites, venous thrombosis, and phlebitis [29, 30]. Some of the complications could be avoided by precise placement of the catheter. The tip should be in the superior vena cava or inferior vena cava and not advancing to the right atrium. When the catheter is used for prolonged time, regular X-ray controls should be done, because spontaneous migration of catheter is also possible. The prevalence of parenteral fluid extravasation from central venous line was reported to be 0.05–1% [31].The most common mechanisms are perforation of blood vessels during the placement procedure, retrograde passage of a central venous catheter into the lymphatic duct, erosion of veins especially in cases of spontaneous catheter migration, and, in extremely premature infants, hyperosmotic endothelial damage, leading to increased vascular permeability [32, 33, 34].
UVC (umbilical venous catheter) extravasation.
2. Diagnosis of neonatal pleural effusion
The diagnosis of pleural effusion is based on the following:
Antenatal presentation – ultrasonography is very useful for the diagnosis of hydrops fetus, congenital heart diseases, pulmonary abnormalities, and fetal pleural effusions. Long standing effusions developed prior to the 20th gestational week may result in pulmonary hypoplasia.
Clinical symptoms – respiratory distress syndrome, worsening respiratory failure, hypoxemia, diminished breathing sounds unilateral or bilateral, and dullness to percussion. Small effusions could be asymptomatic, and the pleural effusion could be incidentally diagnosed.
X-ray and ultrasound findings typical for pleural effusion – the thoracic X-rays of the newborn infants usually are made in the supine position, so the pleural effusions usually are visualized as a diffuse homogenous density over the whole lung. These findings can be very easily confirmed using an ultrasound examination, which could be provided bedside and is also very useful for follow-up of the amount of pleural fluid and, respectively, the therapeutic results, without repositioning the infant [35].
Analysis of pleural effusion fluid – appearance, pH, density, presence of red blood cells (RBC), WBC, protein content, glucose, lactate dehydrogenase (LDH), and triglycerides. Pleural effusion could be chylous and nonchylous. The nonchylous effusion could be exudate or transudate. Transudate is produced due to imbalances in hydrostatic and oncotic pressure, in neonates frequently is seen in venous hypertension or obstruction due to congenital heart disease, in pulmonary malformations, hypoalbuminemia, extravasation from venous lines.
Differential diagnosis is based mainly on the pleural fluid characteristics:
Transudate – total protein: <30 g/l, WBC: <2000/mm3, predominance of mononuclear cells.
Exudative fluid – high protein content, predominance of PMN, pathogens visible on Gram’s stain.
Chylothorax (criteria, defined by Buttiker et al. [23, 36, 37]).
Total white cell count: > 1000 cells/μl.
Lymphocyte fraction: > 80%.
Triglyceride levels: > 110 mg/dl (1.24 mmol/l).
Milky pleural fluid could be seen in the following cases [38]:
Chylothorax.
Empyema.
Leakage from the central venous line.
Milk leakage from perforated esophagus.
Trauma to the thoracic duct – after surgical interventions or following traumatic vaginal delivery in breech presentation.
3. Congenital chylothorax
3.1 Incidence
The incidence of congenital chylothorax is reported to be 1:5775 to 1:100,000 live births, 1:10,000–1:24,000, 1:7300–1:10,000, 4 per 100,000 live births [39]. This is the most common form of pleural effusion in the perinatal period [39, 40, 41, 42]. The chylothorax is defined as accumulation of chyle in the in the pleural cavity [43]. H. Linner and Stewart are the first authors who described a congenital chylothorax in newborn [44]. In 1928, the first prenatal diagnosis of congenital chylothorax was reported [45]. Congenital chylothorax could be presented prenatally by the development of hydrops fetalis in one-third of the cases and has mainly bilateral pleural involvement. The pathophysiology is based on different abnormalities of the lymphatic system – maldevelopment or obstruction [1, 3, 27, 43, 46, 47, 48]. It can be idiopathic or may be associated with different genetic diseases [49]. Anomalies and malformations can be identified in 80% of the cases [40, 42, 50, 51, 52, 53, 54]. In a systematic review of 753 cases with congenital chylothorax, chromosomal diseases were identified in 18% and associated anomalies in 29% [55]. In a clinical cohort of 62 neonates with chylothorax, congenital pleural effusions were congenital in 32 and 68% acquired. Secondary etiologies were more frequent than congenital [3]. In another clinical setting, chylothorax was the most common cause of neonatal pleural effusion (9/21, 43%), 44% in congenital and 56% in acquired. The range of occurrence age was 5–46 days for congenital chylothorax and 2–44 days for acquired [4].
3.2 Causes of congenital chylothorax
Idiopathic [56]
Congenital malformations of lymphatics.
Lymphangiomatosis.
Lymhangiectasia.
Atresia of thoracic duct.
Cystic hygroma.
Associated with syndromes. Down syndrome.
Noonan syndrome.
Autosomal dominant inherited disorder presented with abnormal facial features, congenital heart disease and growth issues, developmental delay, muscle and bone abnormalities, and lymphedema.
Turner syndrome.
Gorham-Stout syndrome [57].
Vanishing bone disease, a rare disorder of unknown etiology, presented by destruction of the osseous matrix and proliferation of vascular structures, resulting in destruction and absorption of bones.
Yellow nail syndrome.
Very rare condition defined by the presence of slow growing, yellow and dystrophic nails, lymphedema, and respiratory diseases, which may be a genetic disorder.
Other syndromes.
X-linked myotubular myopathy [52].
Missense mutation in integrin alpha and beta [58, 59].
In meta-analysis published in 2022, 217 (29%) of the cases were with associated congenital anomalies and 51% of them are of pulmonary and lymphatic origin – congenital pulmonary lymhangiectasia (20%), pulmonary hypoplasia (20%), and extrapulmonary lymphatic dysplasia (7%). Congenital heart diseases and malformations of the arteriovenous system were diagnosed in 52 cases (24%).Chromosomal aberrations were found in 118/753 cases (18%), the most common were Down, Turner, and Noonan syndromes [55]. Different anomalies of the lymphatic system could be responsible for the development of chylothorax [60, 61, 62].
3.3 Pathophysiology of congenital chylothorax
The human lymphatic system is involved in the transport of lipids to the systemic circulation and return of excess fluid, lymphocytes, and proteins from the interstitial spaces to the circulation [37, 62]. The name of the lymphatic body fluid – chyle – originates from the Greek word for juice (Chylus). It has milky appearance, undergoes alkaline reaction, and has bacteriostatic properties. Chyle contains mainly fat (phospholipids, cholesterol, and long-chain triglycerides in the form of chylomicrones), electrolytes, proteins, immunoglobulins, glucose, and lymphocytes. The protein content is over 3 g/l, and the electrolyte composition is similar to that of serum [42]. The cell count is >1000 cells/μL, and the lymphocyte count varies from 400 to 6800 mm3, mainly T lymphocytes [63, 64]. The main source of chyle are digested fatty foods in the small intestine. Dietary fats are absorbed by the intestinal enterocytes in the form of chylomicrons and transported by the lymph vessels. Lymph vessels from the lower part of the body confluence and form the thoracic duct, which is placed on the right side of the vertebral column (chylothorax is more commonly seen on the right side) [37]. Flow through the thoracic duct is highly variable, depending on the enteral feeding (14 ml/h in the fasting period and up to 100 ml/h in postprandial state) [65]. Thoracic duct flow is sensible to splanchnic and vagal stimulation. Serotonin, norepinephrine, histamine, dopamine, and acetylcholine all increase the duct contraction and chyle flow [66]. The thoracic duct transports a large volume of chyle daily, and if the flow is compromised by different reasons, a rapid accumulation of chyle could occur [65]. In case of malfunction or obstruction of the lymphatic system, the chyle accumulates and bursts through the pleura [37]. The long persisting chylothorax is associated with significant chronic loss of lymphocytes and immunoglobulins and, respectively, immunodeficiency as well as malnutrition due to loss of fats and fat-soluble vitamins. Severe hypoimmunoglobulinemia could develop [67, 68, 69]. After 14 days of chylous drainage, lymphocyte depletion was observed. In a large series of 178 infants, low lymphocyte count was associated with culture positive sepsis [5]. Chylothorax-associated infections are rare due to the bacteriostatic properties of the chyle [36]. The most serious consequences of fetal chylothorax are pulmonary hypoplasia, congestive heart failure, and hydrops [70, 71]. Hydrops effusion fetalis is presented by significant fluid accumulation in the fetus and other specific antenatal ultrasound findings, such as skin edema, pericardial and pleural effusions, ascites, and polyhydramnios. In a patient setting of 598 infants with hydrops, the cause was identified as congenital chylothorax in 3.2%; other causes were congenital cardiac malformations and heart rate abnormalities, twin-twin transfusion syndrome, anomalies, chromosomal diseases, transplacental viral infections, and fetal anemia [72]. Congenital chylothorax can cause nonimmune hydrops from a combination of increased capillary filtration rate and reduced lymphatic clearance due to disturbed vena cava blood flow or following the mass effect of the chylous effusion, which leads to compromised cardiac function [73, 74]. Hypoalbuminemia, following the loss of albumin with chyle into the pleural space, could decrease the capillary osmotic pressure and leads to the development of fetal hydrops [74]. Lymphangiectasia and other congenital lymphatic disorders can also present usually as bilateral chylothorax as a result of obstruction to the lymphatic flow. Cystic hygromas cause mass compression effect and impairment of the lymphatic drainage and venous return to the heart [75].
3.4 Clinical presentation of congenital chylothorax
Congenital chylothorax usually is diagnosed in the antenatal period as a space occupying lesion, with 50%, presenting with pleural effusion on day 1 of life [23,24]. Prenatally existing effusions could lead to pulmonary hypoplasia, and the increased intrathoracic pressure interferes with the swallowing and development of polyhydramnios [76]. One recently published meta-analysis included 753 cases from 157 publications. About 71% of the included infants were born preterm, intrauterine death occurred in 42 cases, and termination of pregnancy was reported in 13 cases. The median age of prenatal diagnosis was 28.8 (16–38) weeks, and the median age of prenatal interventions was 29.7 weeks (17–38) [56].
Postnatal clinical presentation is respiratory distress syndrome and mild to severe hypoxemia [77]. Clinical manifestation depends on the rate of chyle leakage and the duration of chylothorax. Rapid accumulation of fluid in the pleural cavity results in significantly increased positive pleural pressure and cardiorespiratory distress [38]. In the postnatal period, chylothorax impairs ventilation and oxygenation, and cardiac failure could occur due to increased venous pressure. Hypoalbuminemia and nutritional depletion are the consequences of prolonged pleural drainage and chronic loss of protein and fat. The risk of infections is increased due to the loss of lymphocytes and immunoglobulins.
3.5 Diagnosis of chylothorax
Ultrasound diagnosis of fetal pleural effusion and associated conditions such as polyhydramnios or hydrops in the most severe cases.
X-ray and ultrasound diagnosis of pleural effusion in the postnatal period.
Complex analysis of pleural fluid.
The diagnosis of chylothorax based on the analysis of pleural fluid is made according to the criteria, defined by Buttiker et al. – triglycerides above 110 mg/dl (1.24 mmol/l) and elevated cell number (> 1000 cells/μl on the fluid microscopy and > 80% lymphocytes) [23] The amount of triglycerides in the pleural fluid reflects the presence of chylomicrons, but depends strongly on the oral milk and fat intake which is the reason for diagnostic difficulties in some patients, especially premature infants. The lipoprotein electrophoresis is the golden standard for diagnosis when the other data are inconclusive (triglyceride levels in the range 0.56–1.24 mmol/l). The chylomicrons are identified on the base of their charge and mass under electrical field, and they are uncharged and remain at their original place [78]. Pleural fluid triglyceride levels <0.56 mmol/l exclude chylothorax [79]. In about 14% of congenital chylothoraces, it is possible to find a low level of triglycerides (< 1,24 mmol/l), when the age of the baby is very small and if the enteral nutrition is totally absent or is in very small amounts [80]). When the results from the pleural fluid are inconclusive, a relation pleural fluid/serum could be used: fluid/serum triglycerides>1, fluid/serum cholesterol <1, and fluid triglycerides to cholesterol ratio > 1 [23, 36, 37]. Chyle separates in three layers in standing position: chylomicrons form the upper creamy layer, the medium layer is milky, and the bottom layer contains cellular elements, predominantly lymphocytes [64]. In empyema, a clear supernatant is formed after centrifugation [49, 63, 81]. Pseudochylothorax should be included in the differential diagnosis – when long persistence of pleural effusion and cholesterol crystals are formed, but the thoracic duct is fully intact. When this is the case, the fluid could be cleared out by adding 1–2 ml of ethyl ether [78].
4. Management of neonatal pleural effusions
Pleural effusions following central venous line extravasation are treated with removal of the central venous line and chest drainage if there is a clinical indication. The resolution happens in few days. In empyema cases, the treatment consists of chest drain, eventually urokinase fibrinolysis, thoracotomy, or video-assisted thoracoscopy, especially when the treatment with chest drainage and or without fibrinolysis has failed [21].
4.1 Prenatal management of congenital chylothorax
Ultrasound diagnosis of prenatal pleural effusion.
Diagnosis of hydrops, associated anomalies, and chromosomal diseases.
Decision making about palliative or active treatment depending on the associated clinical conditions.
The active treatment requires placing of prenatal thoraco-amniotic shunting with pigtail catheter in an experienced center or fetal pleurodesis with OK-432.
Diet modification for the mother.
4.1.1 Prenatal treatment procedures
Infants with ultrasound diagnosis of chylothorax before 34th week of gestation who received prenatal therapy have better postnatal adaptation and improved postnatal outcomes [82]. Therapeutic measures in the prenatal period include maternal dietary modification [83], repeated thoracocentesis [70, 84, 85], thoraco-amniotic shunting [86], and pleurodesis with OK-432 [87, 88, 89, 90]. The results of prenatal treatment depends on the time of diagnosis, effusion volume, presence of hydrops, and high-grade lung compression. The risk of development of pulmonary hypoplasia is highest before 24th week of gestation. If the effusion is small and develops in more advanced pregnancy, expectant management is recommended [85]. Thoraco-amniotic shunting was first described by Rodeck et al. as a method to decompress the fetal lungs [91], allowing better lung development. The survival following pleuroamniotic shunting has been reported to be between 47 and 70% [92, 93, 94, 95, 96, 97]. Resolution of hydrops following intervention was associated with improved survival. Displacement of the shunt occurred in 23% of the cases [98]. Antenatal treatment was performed in 316/512 (62%) prenatally diagnosed cases, 40% pleural punctuations, 43% thoraco-amniotic shunting, and 5% both procedures [55]. Pleural punctuations prior to delivery could prevent perinatal asphyxia. Picone et al. described 44 intrauterine shunted patients with recurrent punctuations until birth [86]. Chen et al. published 17 cases with intrauterine pleural punctuations; some of them performed immediately before birth and these patients showed better postpartum adaptation [99]. A total of 87 cases were treated with fetal intrapleural instillation of OK-432. OK-432 (Picibanil) is a lyophilized preparation of a low-virulence human-derived strain of group A
4.2 Postnatal course of the disease and postnatal management
If it is possible, delivery should happen in a facility with III Level NICU.
Management in the delivery room.
If the respiratory insufficiency immediately after delivery is severe, needle aspiration of the pleural fluid should be done in delivery room, followed by thoracocentesis and continuous drainage.
Initial postnatal treatment: [56]
Asymptomatic infants with small effusions should be placed on close clinical observation.
Symptomatic infants should receive different basic therapeutic measures, depending on the clinical condition:
Oxygen therapy.
CPAP (continuous positive airway pressure) using facial mask or nasal prongs.
Noninvasive ventilation.
Intubation and mechanical ventilation.
Empiric antibiotic therapy.
Infants with nonchylous pleural effusion and significant fluid losses (greater than 6 ml/kg/hour) through the thorax drainage should receive fluid replacement with normal saline and appropriate amount of potassium. Volume loss should be calculated every 8 to 12 hours.
4.2.1 Treatment of chylothorax
Draining the chylothorax.
Needle aspirations.
Tube thoracostomy – chest tubes 10–12 fr, pigtail catheters 8.5 fr or greater. The chest tube should be inserted in the midaxillary line, 5th and 6th intercostal space, directed posteriorly and connected to low pressure suction device.
Continuous suction drainage could cause volume depletion, loss of electrolytes, proteins, albumin, immunoglobulins, and lymphocytes. After prolonged pleural drainage in chylous effusion, significant losses of fluid, electrolytes, proteins, immunoglobulins, and lymphocytes occur [103]. Meta-analysis including large number of patients reported that pleural punctions (drainages) were performed in 64% (438/681) of the cases, and the indication was hypoxemia and increased work of breathing. The mean duration of pleural drainages, documented in 225 newborns, was on average 20 days (range 1–150) [55].
Adequate ventilation.
Total parenteral nutrition – in the initial stage of treatment and after unsuccessful MCT (medium-chain triglycerides) formula diet.
Fluid therapy adjusted to the thorax drainage losses.
Albumin replacement – level should be checked once per week.
Replacement of coagulation factors – levels should be checked once per week.
Immunglobulin replacement – the target level of IgG should be 500 mg/dl, initial dosing – 400–600 mg/kg.
Diet measures Diet measures – enteral feeding with MCT (medium-chain triglycerides) formulas: this type of dietary approach could reduce the chyle flow and chylous effusions. MCT are directly absorbed in the portal vein system, bypassing the lymphatic system and reducing the volume and lipid content of the pleural fluid [46]. If the drainage of chyle continues more than a week on MCT formula, feeding trial of total parenteral nutrition should be done. MCT formulas have shown to be effective in decreasing the chyle flow and resolutions of chylous effusions [25, 104, 105]. Low fat formulas or fat-free human milk, produced with centrifugation and supplementation with median chain triglycerides, could also be used [106]. MCT formulas or total parenteral nutrition can resolve 50% of the cases [23]. Analysis of a large clinical cohort showed that mechanical ventilation was needed in 56% (381/681) and total parenteral nutrition in 44% (296/681), with mean 21 days (range 2–81). MCT diet was given in 315 cases (46%) and was initiated at the mean age of 21 days (range 7–68) and was done for mean 37 days (range 5–50 days). In 96 cases, a prenatal MCT diet of the mother was reported [55].
4.2.1.1 Medications
Octreotide is used in infants failing to respond after 1 to 2 weeks of dietary treatment. Octreotide is a synthetic somatostatin analogue, reducing the intestinal blood flow and chyle production. Use of octreotide for the management of congenital chylothorax was first reported by Young et al. from Canada [107]. In neonates, octreotide is used for the treatment of persisitent neonatal hyperinsulinism [108]. The mechanism of action is reduction in gastric, pancreatic, and intestinal secretions as well as intestinal absorption [109]. Cochrane review summarized the published data on the use of octreotide and concluded that many clinical trials generally demonstrated resolution of chylothorax after octreotide treatment. Time of initiation, dose, duration, and frequency of doses showed significant variations – subcutaneously at 10–70 μg/kg/day given in 6–24 hourly doses or as continuous intravenous infusion between 0.3 and 10 μg/kg/hour. The duration of treatment varies between 4 and 21 days and is mostly guided by clinical response [110]. Octreotide is associated with adverse effects such as arrhythmias, hyperglycemia, transient hypothyroididsm, and impairement of liver function, necrotizing enterocolitis [111], hypoxemia, and pulmonary hypertension [112]. Octreotide continues to be used as off-label medication in the management of congenital chylothorax. The initial dose of octreotide is 1 μcg/kg/h and should be increased, depending on the response by 1 μg/kg/h until a response is verified or until the dose reaches 10 μg/kg/h. The response is classified as positive if there is at least 25% reduction in output. In a case of positive response, the infusion should continue with the same rate for 7–10 days, followed by slow tampering over 1 week. If the maximal dose is not effective for 2–3 days, it should be tapered off. After closing the drainage and removing the chest tubes, enteral feeding with human milk should begin after 1 week at least [103].The treatment of chylothorax with somatostatin and octreotide (somatostatin analogue) was suggested for the first time by Goto et al. in 2003 [113]. Cleveland et al. reported a series of 13 infants treated with both drugs (somatostatin and octreotide) [114]. After that, a lot of data about somatostatin and octreotide treatment were accumulated. The mean duration of octreotide treatment in 138 infants was 22 days (range 3–151 in 76 patients), and the mean age at the start of the therapy was between 2 and 109 days. These medications could be applied intravenously or subcutaneously. The initial intravenous dosage should be 3–4 μg/kg/h, and the maximum dosage 6–12 μg/kg/h. The initial dose of subcutaneous injection could be between 1 and 40 μg/kg/day and the maximal dose 24–70 μg/kg/24 h [55]. In a cohort reported by Cannizarro et al., three newborns were treated with somatostatin, and the start dose was 3.5 μg/kg/h and was gradually increased to 12 μg/kg/h [115]. The medication could be given subcutaneously at the same dose at 6- to 8-hour intervals. Adverse effects of octreotide have been reported in 14% of infants with chylothorax [116]. Octreotide reduces the insulin release, so close monitoring of blood glucose is needed. A systematic review of 753 patients with congenital chylothorax reported that, of the 138 infants, treated with octreotide, 78% had resolution of chylothorax without the need for surgical intervention [55]. In a large case series of 178 infants with chylous effusions, 172 were treated with thorax drainage and nutritional measures, and six infants were not treated. About 45 infants were treated with octreotide, and 21 patients underwent surgery. There was no additional benefit of octreotide over dietary measures [5]. Another systematic review reported that octreotide is safe and effective intervention, showing decrease or cessation of chylous drainage in 50% of the cases [117].
Sildenafil (phosphodiesterase 5 blocker) could be effective for the treatment of pulmonary hypertension and has the potential to enhance the lymphatic vessel growth and/or remodeling, resolving the lymphatic obstruction and chylothorax [56];
Sirolimus (rapamycin) – this is a macrolide compound, inhibiting (mTOR) kinase. It is used to treat vascular malformations and has the potential to slow the growth of abnormal lymphatic vessels. Effective treatment of chylothoraces in older children and adults was described, but the dosing information for neonates and infants is very limited. In a recent study, age-appropriate dosing regimens for neonates and infants were identified [118].
Propanolol (beta blocker) [119, 120, 121] – evidence is still insufficient to recommend routine use in newborn infants.
4.2.1.2 Surgical interventions
Redirection of chyle – pleuroperitoneal shunt and diaphragmatic fenestration.
Obstruction of chyle flow into the chest (thoracic duct ligation or embolization) – after lymphoangiography and locating of the rupture site of ductus thoracicus, a definitive surgical management could be performed – direct ligation of the thoracic duct [23, 24, 78].
Pleurodesis – a procedure to obliterate the pleural space. The pleural cavity should be drained, and after that, a chemical substance is instilled causing inflammation and fibrosis. The following agents have been used in infants: iodopovidone, fibrin glue,
Streptococcus pyogenes A3 (OK-432), tetracycline derivatives (oxytetracycline doxycycline), talc, and other agents [122, 123, 124, 125, 126, 127, 128, 129]. Fetal drainage plus subsequent pleurodesis with OK-432 was shown as a promising approach with 67% survival [55].
4.2.2 Summary about the management of chylothorax in newborn infants
4.2.2.1 Prenatal intervention
Ultrasound diagnosis of pleural effusion/hydrops fetalis [55].
Diagnosis of chromosomal diseases/malformations.
Decision about active or palliative treatment.
Consider prenatal thoraco-amniotic shunting or pleural punctuations.
Consider pleurodesis (OK-432).
4.2.2.2 Birth
Active treatment or palliative care.
Respiratory support.
Pleural drainage.
4.2.2.3 Diagnosis of congenital chylothorax
Lymphocytes >80%.
High level of triglyceride.
Document fluid losses to estimate fluid balance and electrolyte, protein, and immunoglobulin losses.
4.2.2.4 Weeks 1–4
Treatment strategies in confirmed cases.
Start with total parenteral nutrition.
Removing the pigtail catheter placed antenatal or placement of new pleural drainage.
Initiate MCT diet very slowly, depending on pleural fluid and maintain the drainages.
If pleural fluid increases, go back to total parenteral nutrition.
4.2.2.5 Weeks 5 and 6
MCT diet until full enteral nutrition.
If not possible, begin octreotide treatment intravenously or subcutaneously.
If not successful, consider surgical treatment: pleurodesis or surgical ligation of the thoracic duct or both.
Antibiotics for prophylaxis/treatment.
Immunoglobulins every 2–4 weeks to maintain the physiological levels.
4.2.2.6 Practice points
Prenatal interventions in experienced perinatal centers could improve survival in severe fetal chylothorax.
The therapeutic approach should be stepwise, depending on chylothorax severity and treatment risks.
4.2.2.7 Prognosis of congenital chylothorax
The neonatal chylothorax is associated with high mortality rate (20–60% and 30–70%), especially when associated with other comorbidities [42, 56, 130]. The highest mortality rate was observed in patients with hydrops fetalis, severe congenital conditions, and serious lymphatic abnormalities. Risk factors for death in acquired chylothorax are prematurity and infection [42]. In 462 cases (68%), the resolution of the chylothorax was complete, and in 34/44 cases following intrauterine intervention, time of complete regression was at mean 28 days (1–148). In those treated prenatally, resolving of the pleural effusion was noted around 24 weeks of gestation (19–26) [55].
4.2.2.8 Follow-up
About 133 neonates with chylothorax were followed up for 1–144, mean 14.7 months. The longest clinical observation included six cases followed up to the age of 12 [131]. Recurrence of pleural effusions was not reported. Long-term observations revealed two cases with later development of interstitial infiltrations, one – bronchial asthma, one – pulmonary obstructive disease, and one with pleural fibrosis.
5. Discussion
Neonatal pleural pathology is relatively rare, but some of the clinical cases impose significant diagnostic and therapeutic challenges. The most common type of neonatal pleural effusion is chylothorax. Important clinical issue is the fact that the majority of infants with congenital chylothorax have a significant comorbidity, presented by chromosomal diseases and malformations. This requires more complex clinical approach including the efforts of obstetricians, neonatologists, pediatric surgeons, and clinical genetics specialists. Precise diagnosis of accompanying conditions is very important, regarding the indications for prenatal interventions and the extent of postnatal management. The treatment of nonchylous effusions is easier, but the therapeutic protocol especially for congenital chylothorax is more complicated. There is a general agreement in the literature and clinical practice in different clinical settings about the necessity of a prenatal procedures in some cases, stepwise postnatal approach with a clear priority of pleural drainage and dietary measures. Medical treatment should include preferably drugs with a greater experience of use in the neonatal period, such as octreotide. Octreotide treatment is associated with good clinical response in the majority of treated infants, and the medication is safe, when close clinical observation about the side effects is ensured. There are slight differences in opinions about the maximal intravenous dose of octreotide (10 or 12 μg/kg/h), but they are not clinically significant. Surgical treatment and chemical pleurodesis should be reserved for more resistant cases and should be performed in experienced pediatric surgical departments.
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