Congenital Chylothorax in Preterm Infants – A New Approach in Dietary Treatment with Skimmed Breast Milk


 BackgroundCongenital chylothorax (CC) is a rare but potentially life-threatening condition in newborns. It is defined as an accumulation of chyle in the pleural cavity. The few publications regarding medical management and therapeutic dietary intervention motivated us to share our experience.MethodsNeonates diagnosed with congenital chylothorax and treated at Innsbruck Medical University Hospital between 2013 and 2019 (n = 5, gestational age: 36 3/7, 32 5/7, 36 4/7, 35 0/7, 35 4/7) were eligible for this report. The cornerstones of treatment for chylothorax conventionally consist of chest tube drainage (CTD), respiratory support, dietary restriction of long-chain triglycerides (LCT) or total parenteral nutrition (TPN). In further course the introduction of a medium-chain triglyceride (MCT)-based formula followed by an overlapping switch to a formula with low LCT and high MCT, containing the essential long-chain fatty acids (LCFA), is attempted. As soon as possible, the change is made to breast milk feeding or breastfeeding. In two patients we used fat-modified (skimmed) breast milk to avoid discontinuation of breast milk feeding.ResultsThe early introduction of LCFA in the form of breast milk after resolution of chylothorax was associated with favourable outcome (no recurrence of pleural effusion and adequate weight gain).ConclusionThe first-line therapy of chylothorax is a combination of respiratory stabilization and dietary modification. The purpose of this report is to point out the feasibility of a fast change from LCT fat-free nutrition to full-fat nutrition once the chylothorax has dissolved, especially the early introduction of breast milk feeding / breastfeeding in infants with chylothorax.


Abstract Background
Congenital chylothorax (CC) is a rare but potentially life-threatening condition in newborns. It is de ned as an accumulation of chyle in the pleural cavity. The few publications regarding medical management and therapeutic dietary intervention motivated us to share our experience.
The cornerstones of treatment for chylothorax conventionally consist of chest tube drainage (CTD), respiratory support, dietary restriction of long-chain triglycerides (LCT) or total parenteral nutrition (TPN).
In further course the introduction of a medium-chain triglyceride (MCT)-based formula followed by an overlapping switch to a formula with low LCT and high MCT, containing the essential long-chain fatty acids (LCFA), is attempted. As soon as possible, the change is made to breast milk feeding or breastfeeding. In two patients we used fat-modi ed (skimmed) breast milk to avoid discontinuation of breast milk feeding.

Results
The early introduction of LCFA in the form of breast milk after resolution of chylothorax was associated with favourable outcome (no recurrence of pleural effusion and adequate weight gain).

Conclusion
The rst-line therapy of chylothorax is a combination of respiratory stabilization and dietary modi cation.
The purpose of this report is to point out the feasibility of a fast change from LCT fat-free nutrition to fullfat nutrition once the chylothorax has dissolved, especially the early introduction of breast milk feeding / breastfeeding in infants with chylothorax.

Background
Congenital chylothorax, the accumulation of chyle (lymphatic uid of intestinal origin) in the pleural space, is a rare -1:5.000-10.000 live births -but potentially life-threatening condition and requires multimodal management strategies .
Treatment is typically stepwise, starting with stabilization of the respiratory situation via chest tube drainage (CTD) and respiratory support. Nutrition management for chylothorax includes adhering to a regime where the fat source is primarily medium-chain triglyceride (MCT). As breast milk (BM) contains [ 1 ] high concentrations of long-chain triglycerides (LCT), patients are usually transitioned to an MCTcontaining formula like Monogen®, which is a milk protein-based powdered formula that is low in fat (25% of calories), of which 90% is in the form of MCTs [2]. MCTs are transported directly into the portal circulation, contributing little to chylomicron formation and minimizing the volume of lymph owing along the thoracic duct [3]. However, breast milk (BM) contains the appropriate nutritional components and digestive enzymes, but also immunologically effective and protective components like antibodies, lysozyme, neuregulin-4 and lactoferrin. Completely weaning children with chylothorax off breast milk means the loss of these components, which are essential for an enhanced neurological development.
Moreover, special milk formulas are not freely available in developing countries and are far too expensive, so that the use of fat-free human milk was already reported by Chan in 2007 [4]. The use of skimmed milk was found to be equivalent or even better to specialized formulae and can be a therapeutic option [5]. Octreotide, a long-acting analogue of somatostatin, is an additional strategy in the treatment of chylothorax, because it inhibits lymphatic uid production by acting on somatostatin receptors in the splanchnic vessels [6].
Considering the importance of breast milk feeding, especially in preterm infants [7], we used skimmed breast milk (SBM) to avoid its discontinuation. Further, we report the early introduction of long-chain fatty acids (LCFA) in the form of breast milk after resolution of chylothorax with favorable outcome in neonates with congenital chylothorax.

Methods
Neonates diagnosed with congenital chylothorax and treated between 2013 and 2019 at Innsbruck Medical University Hospital (n = 5) were eligible for this report.
In two patients we administered skimmed breast milk, which is de ned as the nearly fat-free fraction of breast milk and can be produced via centrifugation or spontaneous separation. We decided to use a centrifugation-based method because it was shown to be more effective at separating fat in human milk.
BM was expressed and stored at 0°-4 °C in a refrigerator for maximal 24 hours until it was processed at the local human milk bank. Expressed breast milk (EBM) was then transferred to sterile conical centrifuge tubes (Falcon TM 50 ml polypropylene conical tubes) and centrifuged for 10 minutes at 2000 rpm and 5 °C (Centrifuge 5810R®, Eppendorf). Separation of the fat fraction and the skimmed portion was clearly visible (shown in Fig. 1). Aspiration of the fat-free fraction was performed with a syringe and an attached sampling straw. Skimmed breast milk was either stored at 0°-4 °C and fed within 24 hours from the time BM was expressed or stored at ≤ -18 °C for at least 24 hours and used thereafter. After thawing, SBM was used within 24 hours and not frozen again [8].

Patient 1 (36 + 4 weeks):
A diet with an MCT-based formula (Monogen®) was started on the rst day of life (DOL). However, even with total parenteral nutrition (TPN), the chyle amount did not decrease. On day 16, therapy with somatostatin (octreotide) was initiated and slowly increased to a peak dose of 5 µg/kg/h. This was a female neonate with con rmed RAF1 mutation (Noonan syndrome). Ligation of a persistent ductus arteriosus Botalli at the age of 28 days revealed congenital lymphatic system malformations and subsequently a chylothorax. The patient was on parenteral nutrition for ve days, and somatostatin was additionally given at a maximal dose of 10 µg/kg/h for 24 days (cumulative dose 8.31 mg). Since day 42, when pleural effusions resolved, the patient was fed with skimmed breast milk and reached full enteral feeding ten days later.
A summary of patient characteristics and CC management at the NICU Innsbruck is given below (shown in Fig. 2).

Discussion
Congenital chylothorax is an uncommon but serious entity in neonates. Due to the rarity of this disorder a universal consensus on management of CC is unavailable and current dietary treatment recommendations are based on individual case reports or case series [9]. Over a period of seven years we identi ed a total of ve preterm infants with congenital chylothorax.
The accumulation of lymphatic uid with high levels of triglycerides (> 110 mg/dl), proteins (> 20 g/L), and lymphocytes (> 80% of cells) implicates large losses of nutrients and immune cells and put patients at risk of malnutrition and impair their immune system [10]. So, when dealing with the effusion, nutritional management is a key issue and a balance is needed between achieving su cient caloric intake and minimizing chyle production. Moreover, a rapid conversion to regular alimentation (preferably breast feeding) is especially important for preterm infants as the growing brain is strongly dependent on the supply of balanced fatty acid nutrition [11]. Enteral feeding with MCT bypasses the intestinal lymphatic system, as they are absorbed directly into the portal venous system. Thus, therapy of chylothorax calls for MCT-based nutrition with adequate LCFA supplementation, as they are needed as essential part and precursors for membranes and other metabolic processes. This reduces the chyle ow.
However, even the intake of sterile water can stimulate chyle ow by 20% [12]. Therefore, total parenteral nutrition should be applied until the pleural effusions have resolved [13]. Thereafter, diet needs to be cleared of long-chain fatty acids over several weeks or even months. Thus, chylothorax is considered an absolute contraindication for breastfeeding as human milk has a high long-chain fatty acid content [14]. The dietary management of our ve patients consisted of TPN, which was performed until pleural effusions resolved (mean 12.4 days). To avoid a prolonged parenteral nutrition and its possible adverse effects including a high risk of sepsis, nutritional support was provided in the form of adequate caloric intake and enteral feedings were gradually introduced using a low-fat formula. Basic F® was given to Patient 2 (for 22 days), to Patient 3 (for seven days) and to Patient 4 (for ten days), respectively. LCFA like clinoleic acid and vitamins (Vitalipid®, Soluvit®) were substituted once a week. In further course the introduction of a medium-chain triglyceride (MCT)-based formula containing some LCFA (16% of energy) was attempted. Patient 1 immediately received Monogen®, Patient 2 at the 29th DOL and Patient 3 at the 21st DOL. About 80% of infants with chylothorax respond to conservative dietary management [15].
Nevertheless, chylothorax did not resolve in any of our patients under this regime, and therefore treatment with somatostatin was started additionally. The initial dose varied from 0.5 to 1 µg/kg/h and the maximum dose applied was 15 µg/kg/h. In human milk somatostatin is found in high concentrations, thus contributing a direct bene cial effect toward reducing lymph production when human milk is continued in infants with chylothorax [16]. If breast milk feeding is continued, medication with octreotide could be avoided and uncommon but potentially life-threatening side-effects like necrotizing enterocolitis (NEC) [17], pulmonary hypertension or aggravation of bronchopulmonary dysplasia (BPD) might possibly be prevented [18].
Breast milk has proven to have bene cial effects and is strongly recommended for all infants, particularly for preterm infants because of its nutritional, immunologic and psychosocial advantages [19]. Abstaining from breast milk causes infants to not be optimally protected against serious diseases of preterm infants like gastrointestinal infections or NEC. Furthermore, a chylothorax diagnosis can be disappointing for parents, especially for those who had intended to provide breast milk as the primary form of nutrition for their infant. Consequently, the mother-child interaction may suffer because of the missing physical contact. Against this background, we aimed to successfully introduce a dietary regimen of fat-modi ed breast milk forti ed with additional fat, calories, and essential fatty acids that can provide the immune, nutritional and bonding bene ts of breast milk without exacerbating chylous effusions. Accordingly, in Patients 4 and 5 we administered skimmed breast milk instead of an MCT-based formula after resolution of chylothorax on day 40 and 42, respectively. The literature shows reports on several cases of successful use of fat-free (skimmed) breast milk [4,[20][21][22][23]. More and more clinics worldwide are introducing skimmed breast milk instead of special fat-free nutrition. This can be provided via centrifugation (at minimum 2500 rcf for 15 min; which is approx. 3000-3500 rpm depending on the centrifuge) or by placing the milk in the refrigerator and leaving it undisturbed until the fat fraction and the transparent, uid skimmed portion spontaneously separate, so that it is also practicable after discharge. Skimmed milk has had the long-chain fatty acids removed (fat content is less than 0.1%), is lower in calories, essential fatty acids and fat-soluble vitamins, which have to be parenterally replaced. However, it retains levels of electrolytes, protein and lactose that are similar to those of normal breast milk, and it can thus be assumed that the immunologically protective components of breast milk that are contained in proteins are largely preserved during the procedure. [4] Conclusion The therapy regimen practiced at our institution for congenital chylothorax, including the use of fat-free human milk, was successful in all ve patients, meaning no further re-accumulation of pleural uid and an adequate weight gain. From patient to patient we improved our treatment strategy, and with the last two patients we feel we achieved a good plan to suit the wishes of mother and child.
The use of skimmed breast milk offers bene ts to mothers who wish to resume breast feeding after resolution of chylothorax and has proven positive effects, above all in preterm infants as optimal nutrition with protective components superior to formula feeding.

Consent for publication
The manuscript does not contain any individual person's data in any form (no individual details, images or videos).

Availability of data and materials
The datasets during and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests" in this section.

Funding
No funding was obtained for our study.
Author Contributions MH, KW, MH, JK and UKK treated the patients at the neonatal intensive care unit. DK, AH and SSB provided expertise for nutritional advice. MH, KW, MH, JK, UKK and DK drafted the manuscripts, collected data on the patients, and reviewed the literature for data on other known patients suffering from congenital chylothorax. All authors critically reviewed the manuscript and approved the nal version. Figure 1 Clearly visible separation of fat and fat-free fraction after centrifugation.