Successful Management of Gysella Muniz, MD,​a Jennifer Hidalgo-Campos, MD,​b Maria del Carmen Valdivia-Tapia, MD,​b NaderChylothorax Shaikh, MD, MPH,a​ Nilton Yhuri Carreazo, With MDb,​c : Case Report in 2 Pediatric Patients abstract Chylothorax is defined as the accumulation of chyle within the pleural space. Originally described in 1917 by Pisek, it is the most common cause of pleural effusion in the neonatal period. The leading cause of chylothorax is laceration of the thoracic duct during surgery, which occurs in 0.85% to 6.6% of children undergoing cardiothoracic surgery. Few authors of reports in the literature have looked at etilefrine, a relatively unknown sympathomimetic, as an option for the medical treatment of chylothorax. In this case report, we review the clinical course of 2 infants with type III aDivision of General Academic Pediatrics, University of Pittsburgh School of Medicine and Children’s Hospital esophageal atresia who developed chylothorax after thoracic surgery and of Pittsburgh of University of Pittsburgh Medical Center, were successfully treated with intravenous etilefrine after failing initial Pittsburgh, Pennsylvania; bHospital de Emergencias c dietary and pharmacological management. Pediatricas, Lima, Perú; and Escuela de Medicina, Universidad Peruana de Ciencias Aplicadas, Lima, Perú PATIENT INFORMATION Dr Muniz conceptualized and drafted the initial Case 1 manuscript; Drs Hidalgo-Campos, Valdivia-Tapia, oxygen desaturations. Radiography of and Carreazo were involved in the management the chest revealed obliteration of the of both patients and conceptualized the initial right costodiaphragmatic angle, and manuscript; Dr Shaikh supervised the design and Case 1 involved a late preterm female transthoracic ultrasound revealed critically reviewed the manuscript; and all authors born to a 24-year-old gravida 2 para 2 a 50 mL loculated fluid collection approved the final manuscript as submitted and agree to be accountable for all aspects of the work. mother at 35 0/7 weeks of gestational that was drained after chest tube age (birth weight 2040 g) via normal insertion. Fluid analysis revealed DOI: https://​doi.​org/​10.​1542/​peds.​2016-​3309 spontaneous vaginal delivery who triglycerides of 19 mg/dL, total Accepted for publication Jan 10, 2018 was prenatally diagnosed with type III protein of 3 g/dL, lactate Address correspondence to Nilton Yhuri Carreazo, MD, Avenida General Garzon 685, Jesus Maria, Lima esophageal atresia and imperforated dehydrogenase of 356 U/L, and white3 anus with associated recto-vaginal blood cell count of 360 cells per mm 11, Peru. E-mail: [email protected] fistula. She underwent anoplasty and (80% polymorphonuclear cells). The PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, fistula closure without complications chest tube was removed after 5 days 1098-4275). on day 3 of life. At 10 days of life with no detected output and resolution Copyright © 2018 by the American Academy of (DOLs), she underwent esophageal of clinical symptoms. Enteral nutrition Pediatrics repair with an end-to-end esophageal was restarted. FINANCIAL DISCLOSURE: The authors have anastomosis along with closure of the indicated they have no financial relationships At DOL 37 the patient presented with relevant to this article to disclose. tracheoesophageal fistula (TEF). On recurrent apneic episodes requiring postsurgical day 7, an esophageal- FUNDING: No external funding. mechanical ventilation. Transthoracic pleural fistula along with moderate POTENTIAL CONFLICT OF INTEREST: The authors ultrasound revealed a 55 mL right stenosis of the esophageal anastomosis have indicated they have no potential conflicts of pleural effusion (Fig 1). A chest tube interest to disclose. was observed. was placed and the milky pleural fluid Two weeks after TEF closure (DOL that was retrieved was characteristic To cite: Muniz G, Hidalgo-Campos J, Valdivia-Tapia 25), total parenteral nutrition (TPN) of chylothorax with a triglyceride MdC, et al. Successful Management of Chylothorax was discontinued and enteral feeds level of 548 mg/dL, total cholesterol With Etilefrine: Case Report in 2 Pediatric Patients. Pediatrics. 2018;141(5):e20163309 with infant formula were started. level of 43 mg/dL, white blood3 cell The patient quickly developed signs count of 22170 cells per mm (95% of respiratory distress and frequent mononuclear cells), glucose level of Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 141, number 5, May 2018:e20163309 CASE REPORT μ

220 mg/dL, and total protein level After increasing the rate to 1 g/kg – of 4.16 g/dL. Bacterial culture of per hour, HR increased to 150 to the chylothorax did not reveal a 170 beats per minute (75th 95th – pathogen, and TPN was restarted. percentile), and MAP was between 60 and 80 mmHg (70th 90th μ Enteral nutrition with medium chain percentile). Once the infusion rate triglyceride (MCT) infant formula was weaned down to 0.5 g/kg (Monogen) was restarted on DOL 43. per hour, HR stayed between the Chest tube output increased from 21 25th and 75th percentile and MAP to 40 mL/kg per day to a maximum of between the 75th and 90th percentile FIGURE 1 80 mL/kg per day on DOL 51. Enteral until therapy discontinuation. Chest radiograph of case 1 at postoperative μ day 27. IP-NEO, inpatient-neonatology. feeds were stopped, and octreotide Chest tube output decreased was administered at a dose of 0.5 g/kg μ to 0 after 4 days of treatment, per hour increasing to a maximum and mechanical ventilation was of 4 g/kg per hour (Supplemental discontinued at this point. MCT defect, ventricular septal defect, and Fig 2). A mild decrease in the output formula was started, and after 7 days a patent ductus arteriosus). On DOL was noticed, but after 3 days the of treatment with etilefrine, TPN was 10, an esophageal repair with an end- octreotide drip was discontinued discontinued. The etilefrine drip was to-end esophageal anastomosis was because of the prohibitive cost of discontinued at postoperative day 58. this medication. Chest tube output performed along with TEF closure. (CaseTable 2 1). at that point was 96 mL/kg per day. TPN was given for a total of 15 days, On DOL 60, while the patient was and MCT formula was started at DOL still not taking enteral feedings, the 12. Two days after patent ductus chest tube output increased to 147 Case 2 involved a term male arteriosus ligation was performed mL/kg per day, and intravenous infant born via cesarean section (DOL 44), milky chest tube output μ etilefrine infusion was started at 0.6 because of breech presentation was noticed (25 mL/kg per day). ’ g/kg per hour (Table 1). At the time to an 18-year-old gravida 1 para Fluid analysis was compatible with of initiation of therapy, the patient s 1 mother with limited prenatal chyle (triglycerides 228 mg/dL). – rate (HR) was between 120 care. The infant was transferred Bacterial culture did not reveal a and 160 beats per minute (25th 75th from an outside hospital at DOL 5 pathogen. Intravenous etilefrine drip percentile), and the mean arterial after being diagnosed with type III was started along with MCT formula – blood pressure (MAP) was between esophageal atresia with associated (Supplemental Fig 2). Basal HR and 46 to 52 mmHg (5 50th percentile). cardiovascular defects (atrial septal MAP were 105 to 140 beats per TABLE 1 Clinical Progress and Chest Tube Output in Case 1 Postoperative d Intake Medication Chest Tube Output 15 TPN (breast milk 7 mL/kg per d) — 14 mL/kg per d 27 NPO – TPN — 21 mL/kg per d 33 MCTs 6 mL/kg per d — 40 mL/kg per d 37 MCTs 31 mL/kg per d — 124 mL/kg per d 38 MCTs discontinued NPO – TPN — 91 mL/kg per d 41 NPO – TPN Octreotide 0.5 μg/kg per h 83 mL/kg per d 42 NPO – TPN Octreotide 1.5 μg/kg per h 101 mL/kg per d 43 NPO – TPN Octreotide 5 μg/kg per h 85 mL/kg per d 44 NPO – TPN Octreotide 4 μg/kg per h 25 mL/kg per d 45 NPO – TPN Octreotide 4 μg/kg per h 20 mL/kg per d 46 NPO – TPN No octreotide available 90 mL/kg per d 47 NPO – TPN No octreotide available 140 mL/kg per d 50 NPO – TPN Etilefrine 0.6 μg/kg per h 147 mL/kg per d 51 NPO – TPN Etilefrine 1 μg/kg per h 180 mL/kg per d 52 NPO – TPN Etilefrine 0.5 μg/kg per h 90 mL/kg per d 53 NPO – TPN Etilefrine 0.3 μg/kg per h 0 54 MCTs 64 mL/kg per d Etilefrine 0.3 μg/kg per h 0 55 MCTs 75 mL/kg per d Etilefrine 0.2 μg/kg per h 0 56 MCTs 80 mL/kg per d; TPN discontinued Etilefrine 0.2 μg/kg per h 0 58 MCTs 95 mL/kg per d Etilefrine discontinued 0

NPO, nil per os; —, not applicable.

Downloaded from www.aappublications.org/news by guest on October 2, 2021 2 MUNIZ et al TABLE 2 Clinical Progress and Chest Tube Output in Case 2 Postoperative d Intake Medication Chest Tube Output 2 MCTs 90 mL/kg per d Etilefrine 0.5 μg/kg per h 25 mL/kg per d 3 MCTs 90 mL/kg per d Etilefrine 0.5 μg/kg per h 25 mL/kg per d 4 MCTs 90 mL/kg per d Etilefrine 0.5 μg/kg per h 12.5 mL/kg per d 5 MCTs 90 mL/kg per d Etilefrine 0.5 μg/kg per h 0 6 MCTs 100 mL/kg per d Etilefrine 0.5 μg/kg per h 0 7 MCTs 110 mL/kg per d Etilefrine 0.3 μg/kg per h 0 8 MCTs 110 mL/kg per d Etilefrine 0.3 μg/kg per h 0 9 MCTs 110 mL/kg per d Etilefrine discontinued 0

– – minute (5th 50th percentile) and 50 surgery. The authors of some of the thoracic duct is also available ∼ to 60 mmHg (10th 50th percentile), data estimate the appearance of in case of medical treatment failure, respectively. After therapy initiation, symptoms 0 to 10 days between although this is usually considered – HR was documented between 145 the thoracic duct injury and the7 as a secondary option and is usually11 and 180 beats per minute (75th 95th development of chylothorax. associated with a high failure rate. percentile), and MAP increased to Interestingly, the concept of thoracic Dietary modifications, such as the a maximum of 120 mmHg (˃90th duct injury as the main cause of use of a fat-free diet along with percentile). Both parameters postoperative chylothorax has been 8 MCTs, which are directly absorbed returned to basal levels after recently challenged by Savla et al. through the venous portal system etilefrine was discontinued. Chest These authors found, using lymphatic bypassing the lymphatics, help tube output ceased after 4 days, and imaging, that only the minority of decrease chyle production. The use of etilefrine was discontinued 7 days cases of postoperative chylothorax TPN, if available, is another efficient after treatment initiation (Table 2). were the result of injury to the therapeutic intervention that will DISCUSSION thoracic duct. help decrease5,12​ chyle production and The diagnosis is confirmed by leakage. ‍ In the first case described, observation of the presence of the patient was first started on TPN Chylothorax is the most common and then transitioned to Monogen, a chylomicrons or triglyceride4 levels cause of pleural1 effusion in being ˃110 mg/dL. Both of our low-fat infant formula that contains neonates. Caused by the disruption patients had levels well above this 80% MCTs. The second patient was of the thoracic duct or secondary cutoff value. Another characteristic is immediately started on MCT formula to increased pressure within the presence of leukocyte cell count along with etilefrine drip. the superior vena cava, chyle being ˃1000, with more than 90% Octreotide is a widely used and accumulates in the pleural space lymphocytic predominance. As a effective medication in the treatment causing different degrees of 2 diagnostic intervention, a trial of fatty of chylothorax. With a 2- to 6-hour respiratory symptoms. foods by mouth or via nasogastric half-life, this synthetic somatostatin The general incidence of chylothorax tube can be done to observe a analog decreases chyle production dramatic change in color, as well as by inhibiting gastric, pancreatic, after cardiothoracic surgeries3 11 is between 0.9% and 6.6%. the presence of triglycerides and 9 and intestinal secretions. Some More specifically, the repair of chylomicrons in the pleural fluid. of its secondary effects reported Given the lack of resources, diagnosis in children include hyperglycemia, congenital cardiac anomalies4 has an incidence risk of 2.8% and an was based on clinical data (analysis hypothyroidism, nausea, diarrhea, of the pleural fluid analysis and chest necrotizing enterocolitis, and liver incidence risk ranging from 0.2% 5 13 to 10% after esophageal surgeries. radiography). No other diagnostic dysfunction. Given the cost of Its development is associated tests (eg, dynamic contrast- octreotide, the use of it might be with increased morbidity and enhanced magnetic resonance prohibitive in many countries mortality, prolonged mechanical lymphangiography and intranodal worldwide. This imposes the need of ventilation, increased frequency in lymphangiography) were used. establishing other affordable and safe options in the treatment of pediatric infections, malnutrition,6 and venous The treatment of this condition patients. thrombosis. requires dietary modifications and – The clinician should suspect this therapeutic agents like octreotide Although there is no Food and Drug diagnosis on the basis of the presence and etilefrine9,10​ that can decrease chyle Administration approved indication of milky or, less frequently, bloody production. ‍ Surgical treatment of this medication, etilefrine is chest tube output after thoracic and, more specifically, the ligation commonly used in the treatment Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 141, number 5, May 2018 3 5. Chalret du Rieu M, Baulieux J, Rode A, Mabrut JY. Management of of postural , syncope, The use of etilefrine could be a novel α β postoperative chylothorax [published and sickle cell priapism. With this option in the conservative treatment correction appears in J Visc Surg. sympathomimetic, both and of postoperative chylothorax in 2012;149(1):e80]. J Visc Surg. receptors are pediatric patients, but given the 2011;148(5):e346–e352 stimulated, arterial and venous lack of data, more prospective trials 6. Mery CM, Moffett BS, Khan MS, et al. tone are improved, and14 myocardial are needed to establish its cost- Incidence and treatment of chylothorax activity is enhanced. Smooth effectiveness, efficacy, and safety in after in children: muscle contraction within the the pediatric population. analysis of a large multi-institution thoracic duct causes a decrease database. J Thorac Cardiovasc Surg. in chyle flow, therefore decreasing In our 2 patients, etilefrine 2014;147(2):678–686.e1 caused a significant reduction or stopping the effusion10,15​ into 7. Bauman ME, Moher C, Bruce AK, Kuhle the pleural space. ‍ Potential in chyle output 3 days after S, Kaur S, Massicotte MP. Chylothorax side effects include palpitations, starting treatment, and complete in children with congenital heart ventricular , chest pain, resolution was observed after disease: incidence of thrombosis. Thromb Res. 2013;132(2):e83 e85 pectoris, and , 4 days of treatment with no – which have been described in significant side effects. 8. Savla JJ, Itkin M, Rossano JW, Dori Y. adults taking etilefrine by mouth. ACKNOWLEDGMENT Post-operative chylothorax in patients If intravenous infusion is too with congenital heart disease. J Am Coll Cardiol. 2017;69(19):2410–2422 rapid, , tremor,14 and piloerection may occur. We thank Dr Judy Martin for her 9. Soto-Mar tinez M, Massie J. valuable suggestions and review Chylothorax: diagnosis and To the best of our knowledge, of the article. management in children. Paediatr there are no reports of etilefrine ABBREVIATIONS Respir Rev. 2009;10(4):199–207 use in the treatment of children 10. Ismail SR, Kabbani MS, Najm HK, and/or neonates with chylothorax. Shaath GA, Jijeh AM, Hijazi OM. Impact Of the <8 articles published in the DOL: day of life of chylothorax on the early post literature in which authors describe operative outcome after pediatric HR: heart rate etilefrine as a therapeutic option, cardiovascular surgery. J Saudi Heart MAP: mean arterial blood only a few of the authors discuss in Assoc. 2014;26(2):87–92 pressure more detail its use and only report MCT: medium chain triglyceride 11. Hung WP, Wang JN, Chang HK, Wu JM. outcomes in adult patients. Ohkura 16 TEF: tracheoesophageal fistula Octreotide therapy in two children with et al presented a case report of intractable postoperative chylothorax. TPN: total parenteral nutrition 2 patients who developed post Int J Cardiol. 2011;146(3):e63–e65 esophagectomy chylothorax and REFERENCES 12. Lee H, Gumpeni R, Jain M, Taiwar were successfully managed with a 1. van Straaten HL, Gerards LJ, Krediet A. Chylothorax: a review of current combination of octreotide, etilefrine,15,17​ TG. Chylothorax in the neonatal period. management strategies. J Respir Dis. 2008;29(8):325 333 and pleurodesis. Guillem et al ‍ Eur J Pediatr. 1993;152(1):2–5 – published both a case report of 13. Tutor JD. Chylothorax in infants 2. Beghetti M, La Scala G, Belli D, 3 patients and a case series of 10 and children. Pediatrics. Bugmann P, Kalangos A, Le Coultre patients with thoracic or abdominal 2014;133(4):722 733 C. Etiology and management of – chyle leaks after thoracic surgical pediatric chylothorax. 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Downloaded from www.aappublications.org/news by guest on October 2, 2021 Successful Management of Chylothorax With Etilefrine: Case Report in 2 Pediatric Patients Gysella Muniz, Jennifer Hidalgo-Campos, Maria del Carmen Valdivia-Tapia, Nader Shaikh and Nilton Yhuri Carreazo Pediatrics 2018;141; DOI: 10.1542/peds.2016-3309 originally published online April 27, 2018;

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