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 esophageal atresia who developed chylothorax after thoracic surgery and were successfully treated with intravenous etilefrine after failing initial dietary and pharmacological management.
- DOL —
- day of life
- HR —
- heart rate
- MAP —
- mean arterial blood pressure
- MCT —
- medium chain triglyceride
- TEF —
- tracheoesophageal fistula
- TPN —
- total parenteral nutrition
Patient Information
Case 1
Case 1 involved a late preterm female born to a 24-year-old gravida 2 para 2 mother at 35 0/7 weeks of gestational age (birth weight 2040 g) via normal spontaneous vaginal delivery who was prenatally diagnosed with type III esophageal atresia and imperforated anus with associated recto-vaginal fistula. She underwent anoplasty and fistula closure without complications on day 3 of life. At 10 days of life (DOLs), she underwent esophageal repair with an end-to-end esophageal anastomosis along with closure of the tracheoesophageal fistula (TEF). On postsurgical day 7, an esophageal-pleural fistula along with moderate stenosis of the esophageal anastomosis was observed.
Two weeks after TEF closure (DOL 25), total parenteral nutrition (TPN) was discontinued and enteral feeds with infant formula were started. The patient quickly developed signs of respiratory distress and frequent oxygen desaturations. Radiography of the chest revealed obliteration of the right costodiaphragmatic angle, and transthoracic ultrasound revealed a 50 mL loculated fluid collection that was drained after chest tube insertion. Fluid analysis revealed triglycerides of 19 mg/dL, total protein of 3 g/dL, lactate dehydrogenase of 356 U/L, and white blood cell count of 360 cells per mm3 (80% polymorphonuclear cells). The chest tube was removed after 5 days with no detected output and resolution of clinical symptoms. Enteral nutrition was restarted.
At DOL 37 the patient presented with recurrent apneic episodes requiring mechanical ventilation. Transthoracic ultrasound revealed a 55 mL right pleural effusion (Fig 1). A chest tube was placed and the milky pleural fluid that was retrieved was characteristic of chylothorax with a triglyceride level of 548 mg/dL, total cholesterol level of 43 mg/dL, white blood cell count of 22 170 cells per mm3 (95% mononuclear cells), glucose level of 220 mg/dL, and total protein level of 4.16 g/dL. Bacterial culture of the chylothorax did not reveal a pathogen, and TPN was restarted.
Chest radiograph of case 1 at postoperative day 27. IP-NEO, inpatient-neonatology.
Enteral nutrition with medium chain triglyceride (MCT) infant formula (Monogen) was restarted on DOL 43. Chest tube output increased from 21 to 40 mL/kg per day to a maximum of 80 mL/kg per day on DOL 51. Enteral feeds were stopped, and octreotide was administered at a dose of 0.5 μg/kg per hour increasing to a maximum of 4 μg/kg per hour (Supplemental Fig 2). A mild decrease in the output was noticed, but after 3 days the octreotide drip was discontinued because of the prohibitive cost of this medication. Chest tube output at that point was 96 mL/kg per day. On DOL 60, while the patient was still not taking enteral feedings, the chest tube output increased to 147 mL/kg per day, and intravenous etilefrine infusion was started at 0.6 μg/kg per hour (Table 1). At the time of initiation of therapy, the patient’s heart rate (HR) was between 120 and 160 beats per minute (25th–75th percentile), and the mean arterial blood pressure (MAP) was between 46 to 52 mm Hg (5–50th percentile). After increasing the rate to 1 μg/kg per hour, HR increased to 150 to 170 beats per minute (75th–95th percentile), and MAP was between 60 and 80 mm Hg (70th–90th percentile). Once the infusion rate was weaned down to 0.5 μg/kg per hour, HR stayed between the 25th and 75th percentile and MAP between the 75th and 90th percentile until therapy discontinuation.
Clinical Progress and Chest Tube Output in Case 1
Chest tube output decreased to 0 after 4 days of treatment, and mechanical ventilation was discontinued at this point. MCT formula was started, and after 7 days of treatment with etilefrine, TPN was discontinued. The etilefrine drip was discontinued at postoperative day 58. (Table 1).
Case 2
Case 2 involved a term male infant born via cesarean section because of breech presentation to an 18-year-old gravida 1 para 1 mother with limited prenatal care. The infant was transferred from an outside hospital at DOL 5 after being diagnosed with type III esophageal atresia with associated cardiovascular defects (atrial septal defect, ventricular septal defect, and a patent ductus arteriosus). On DOL 10, an esophageal repair with an end-to-end esophageal anastomosis was performed along with TEF closure. TPN was given for a total of 15 days, and MCT formula was started at DOL 12. Two days after patent ductus arteriosus ligation was performed (DOL 44), milky chest tube output was noticed (25 mL/kg per day). Fluid analysis was compatible with chyle (triglycerides 228 mg/dL). Bacterial culture did not reveal a pathogen. Intravenous etilefrine drip was started along with MCT formula (Supplemental Fig 2). Basal HR and MAP were 105 to 140 beats per minute (5th–50th percentile) and 50 to 60 mm Hg (10th–50th percentile), respectively. After therapy initiation, HR was documented between 145 and 180 beats per minute (75th–95th percentile), and MAP increased to a maximum of 120 mm Hg (˃90th percentile). Both parameters returned to basal levels after etilefrine was discontinued. Chest tube output ceased after 4 days, and etilefrine was discontinued 7 days after treatment initiation (Table 2).
Clinical Progress and Chest Tube Output in Case 2
Discussion
Chylothorax is the most common cause of pleural effusion in neonates.1 Caused by the disruption of the thoracic duct or secondary to increased pressure within the superior vena cava, chyle accumulates in the pleural space causing different degrees of respiratory symptoms.2
The general incidence of chylothorax after cardiothoracic surgeries is between 0.9% and 6.6%.3 More specifically, the repair of congenital cardiac anomalies has an incidence risk of 2.8%4 and an incidence risk ranging from 0.2% to 10% after esophageal surgeries.5 Its development is associated with increased morbidity and mortality, prolonged mechanical ventilation, increased frequency in infections, malnutrition, and venous thrombosis.6
The clinician should suspect this diagnosis on the basis of the presence of milky or, less frequently, bloody chest tube output after thoracic surgery. The authors of some data estimate the appearance of symptoms ∼0 to 10 days between the thoracic duct injury and the development of chylothorax.7 Interestingly, the concept of thoracic duct injury as the main cause of postoperative chylothorax has been recently challenged by Savla et al.8 These authors found, using lymphatic imaging, that only the minority of cases of postoperative chylothorax were the result of injury to the thoracic duct.
The diagnosis is confirmed by observation of the presence of chylomicrons or triglyceride levels being ˃110 mg/dL.4 Both of our patients had levels well above this cutoff value. Another characteristic is the presence of leukocyte cell count being ˃1000, with more than 90% lymphocytic predominance. As a diagnostic intervention, a trial of fatty foods by mouth or via nasogastric tube can be done to observe a dramatic change in color, as well as the presence of triglycerides and chylomicrons in the pleural fluid.9 Given the lack of resources, diagnosis was based on clinical data (analysis of the pleural fluid analysis and chest radiography). No other diagnostic tests (eg, dynamic contrast-enhanced magnetic resonance lymphangiography and intranodal lymphangiography) were used.
The treatment of this condition requires dietary modifications and therapeutic agents like octreotide and etilefrine that can decrease chyle production.9,10 Surgical treatment and, more specifically, the ligation of the thoracic duct is also available in case of medical treatment failure, although this is usually considered as a secondary option and is usually associated with a high failure rate.11
Dietary modifications, such as the use of a fat-free diet along with MCTs, which are directly absorbed through the venous portal system bypassing the lymphatics, help decrease chyle production. The use of TPN, if available, is another efficient therapeutic intervention that will help decrease chyle production and leakage.5,12 In the first case described, the patient was first started on TPN and then transitioned to Monogen, a low-fat infant formula that contains 80% MCTs. The second patient was immediately started on MCT formula along with etilefrine drip.
Octreotide is a widely used and effective medication in the treatment of chylothorax. With a 2- to 6-hour half-life, this synthetic somatostatin analog decreases chyle production by inhibiting gastric, pancreatic, and intestinal secretions.11 Some of its secondary effects reported in children include hyperglycemia, hypothyroidism, nausea, diarrhea, necrotizing enterocolitis, and liver dysfunction.13 Given the cost of octreotide, the use of it might be prohibitive in many countries worldwide. This imposes the need of establishing other affordable and safe options in the treatment of pediatric patients.
Although there is no Food and Drug Administration–approved indication of this medication, etilefrine is commonly used in the treatment of postural hypotension, syncope, and sickle cell priapism. With this sympathomimetic, both α and β adrenergic receptors are stimulated, arterial and venous tone are improved, and myocardial activity is enhanced.14 Smooth muscle contraction within the thoracic duct causes a decrease in chyle flow, therefore decreasing or stopping the effusion into the pleural space.10,15 Potential side effects include palpitations, ventricular arrhythmias, chest pain, angina pectoris, and hypertension, which have been described in adults taking etilefrine by mouth. If intravenous infusion is too rapid, tachycardia, tremor, and piloerection may occur.14
To the best of our knowledge, there are no reports of etilefrine use in the treatment of children and/or neonates with chylothorax. Of the <8 articles published in the literature in which authors describe etilefrine as a therapeutic option, only a few of the authors discuss in more detail its use and only report outcomes in adult patients. Ohkura et al16 presented a case report of 2 patients who developed post esophagectomy chylothorax and were successfully managed with a combination of octreotide, etilefrine, and pleurodesis. Guillem et al15,17 published both a case report of 3 patients and a case series of 10 patients with thoracic or abdominal chyle leaks after thoracic surgical procedures. In this last case series, a total of 11 etilefrine intravenous infusions were given (patient 10 required a second infusion cycle after reoperation). One patient with postoperative heart failure required infusion withdrawal because of an interaction with other sympathomimetic drugs (dopamine and dobutamine), and another patient required reduced doses, without stopping the infusion, because of an increased HR and blood pressure.
The use of etilefrine could be a novel option in the conservative treatment of postoperative chylothorax in pediatric patients, but given the lack of data, more prospective trials are needed to establish its cost-effectiveness, efficacy, and safety in the pediatric population.
In our 2 patients, etilefrine caused a significant reduction in chyle output 3 days after starting treatment, and complete resolution was observed after 4 days of treatment with no significant side effects.
Acknowledgment
We thank Dr Judy Martin for her valuable suggestions and review of the article.
Footnotes
- Accepted January 10, 2018.
- Address correspondence to Nilton Yhuri Carreazo, MD, Avenida General Garzon 685, Jesus Maria, Lima 11, Peru. E-mail: yhuroc{at}gmail.com
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
References
- Copyright © 2018 by the American Academy of Pediatrics
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