INTRODUCTION
Neonatal chylothorax is the most common cause of pleural effusion. Although its prevalence in neonates is rare, chylothorax is a fatal condition with a mortality rate of 28% and is associated with multiple complications, such as lung hypoplasia, immunocompromise, heart failure, and fetal hydrops [1,2]. The causes of neonatal chylothorax vary widely. Cases identified as congenital chylothorax are attributable to diseases, such as lymphatic flow disorders, whereas other cases of neonatal chylothorax are acquired through a traumatic origin, such as thoracic surgery or central venous catheterization, or by a non-traumatic origin, such as amyloidosis or malignancy [3].
While the majority of patients show favorable outcomes with conventional therapies, such as fasting with total parenteral nutrition or intravenous octreotide, secondary therapeutic measures, such as pleurodesis, thoracic duct ligation, and pleurectomy, should be considered in refractory cases [4]. Chemical pleurodesis is a viable therapeutic option for refractory neonatal chylothorax owing to its minimally invasive nature compared to surgical interventions, making it preferable for neonates or infants. Commonly utilized pleurodesis agents include OK-432, talc, and povidone-iodine; however, a consensus has yet to be reached on which reagent demonstrates the most therapeutic efficacy [2].
Recently, a hypertonic glucose solution has been proposed as an alternative reagent for chemical pleurodesis. Multiple adult cases of malignant pleural effusion or postoperative chylothorax have been reported to respond to chemical pleurodesis using a hypertonic glucose solution [5,6]. Additionally, there have been reports of neonatal postoperative chylothorax successfully treated with hypertonic glucose pleurodesis [7]. However, the number of reported cases of neonatal chylothorax treated with hypertonic glucose pleurodesis is insufficient for large sample studies. We present two cases of preterm neonates diagnosed with chylothorax that were initially refractory to conventional therapy but were successfully treated with 50% glucose pleurodesis.
CASE REPORTS
1. Case 1
The patient was a female infant delivered via cesarean section at 24+5 weeks of gestation because of preterm labor, weighing 585 g. The infant exhibited respiratory distress and hypoxia after delivery and required intubation and surfactant administration. She was receiving mechanical ventilation and intravenous dexamethasone for severe bronchopulmonary dysplasia. Despite intravenous ibuprofen treatment, a persistently large patent ductus arteriosus necessitated surgical ligation at 17 days of life (DOL). Postoperative chest radiography revealed no pleural effusion. The infant was extubated at 59 DOL.
At 68 DOL, when the infant reached a postmenstrual age of 34+2 weeks and a weight of 1,600 g, with full enteric feeding of 110 mL/kg/day, the patient showed signs of tachypnea, chest retraction, and respiratory acidosis, prompting reintubation. Subsequent chest radiography revealed left pleural effusion (Figure 1A-C). A chest tube was inserted at 69 DOL. Pleural fluid analysis confirmed chylothorax, with triglyceride levels of 505 mg/dL and 31.6% chylomicrons. Nil per os status was maintained thereafter; however, chest tube drainage persisted at up to 14.2 mL/kg/day. Consequently, intravenous octreotide infusion began at an initial rate of 1 μg/kg/hr at 86 DOL. Despite increasing the octreotide dosage to 9 μg/kg/hr, daily chest tube drainage reached 265 mL (131.8 mL/kg/day) at 94 DOL (Figure 2A).
Given the persistent chylothorax, chemical pleurodesis was performed at 100 DOL using a hypertonic dextrose solution. Ten milliliters of 50% dextrose solution mixed with 1 mL of 1% lidocaine was injected into the left thorax, and the chest tube was clamped for 2 hours. After the injection of 50% dextrose, the patient showed transient signs of pain and labored breathing, which resolved after intravenous fentanyl infusion. An hour after the injection of 50% dextrose, the patient exhibited hypotension with a mean blood pressure of <35 mm Hg. A bolus of 10 mL/kg isotonic sodium chloride solution was administered intravenously, and the mean blood pressure was restored to >40 mm Hg.
Follow-up chest radiography showed a decreased chylothorax (Figure 1D). The procedure was repeated at 112 and 120 DOL because of recurrence at 109 DOL (Figure 1E). No additional signs of pain, respiratory distress, or hypotension were observed during repeated chemical pleurodeses. Subsequent radiography confirmed the resolution of the chylothorax (Figure 1F). The chest tube was removed on 137 DOL, and the infant was discharged on 162 DOL with home oxygen at 0.2 L/min, showing no signs of chylothorax recurrence.
2. Case 2
The patient was a female infant with prenatal signs indicative of fetal hydrops. Prenatal ultrasonography performed at 34+5 weeks of gestation revealed bilateral pleural effusion, skin edema, and polyhydramnios, with an amniotic fluid index of 399 mm. The following day, the mother developed signs of premature rupture of membranes, and the infant was delivered via emergency cesarean section with a birth weight of 3,040 g. The infant’s initial Apgar score was 2/10. The patient was cyanotic and exhibited bradycardia with a heart rate lower than 60 bpm, along with no signs of chest or limb movement or irregular respiration. Positive pressure ventilation via a T-piece resuscitator was commenced, but there was no immediate improvement in bradycardia. Thus, immediate intubation was performed, and the heart rate increased to >100 bpm. The infant was kept on positive pressure ventilation and transferred to the neonatal intensive care unit. Since prenatal thoracocentesis was not feasible because of urgent delivery, postnatal ultrasound confirmed persistent bilateral pleural effusion, with measurements of 1.77 cm depth in the left thorax and 0.63 cm in the right thorax (Figure 3A, B). Bilateral chest tube insertion was successfully performed, resulting in improved oxygenation (Figure 3C, D). The initial chest tube drainage volumes were 140 and 75 mL from the left and right sides, respectively. The pleural fluid was yellowish and mildly turbid, with lymphocyte dominance (93%), leading to a diagnosis of chylothorax. No bacterial growth was observed in initial pleural fluid cultures.
The infant was gradually weaned from mechanical ventilation and extubated at 6 DOL. Despite being maintained on nil per os since birth, both pleural effusions persisted, prompting the initiation of octreotide infusion at an initial rate of 1 μg/kg/hr at 5 DOL. The octreotide dose was gradually increased to 10 μg/kg/hr by 20 DOL, reducing right-sided chest tube drainage to 20 mL per day. However, left-sided drainage persisted at >80 mL daily (32.1 mL/kg/day). Consequently, chemical pleurodesis was initiated at 21 DOL and continued for 3 consecutive days. A 10 mL dose of 50% dextrose solution mixed with 1 mL of 1% lidocaine was injected into the left thorax, and the chest tube was clamped for 2 hours. During the procedure, the patient exhibited signs of pain and tachycardia, which resolved after a single-dose intravenous injection of 0.05 mg/kg morphine. Additionally, there was a single event of hypotension, with the mean blood pressure falling below 40 mm Hg, which resolved with an intravenous bolus of 10 mL/kg isotonic sodium chloride solution. Subsequent pleurodesis was performed on 27 DOL, after which the daily chest tube drainage volume decreased to 10 mL (Figure 2B). Follow-up radiographs showed resolution of the chylothorax (Figure 3E); the left and right chest tubes were successfully removed at 34 and 36 DOL, respectively. The infant was discharged at 42 DOL without supplemental oxygen (Figure 3F). Genetic analysis later revealed a heterozygous mutation in EPHB4, confirming the diagnosis of lymphatic malformation-7.
DISCUSSION
These two cases demonstrate that hypertonic glucose pleurodesis is effective in treating patients with refractory neonatal chylothorax [2,8]. The first patient was a premature female infant born at a gestational age of 24+5 weeks who developed traumatic chylothorax at 68 DOL after patent ductus arteriosus ligation. The patient showed no improvement with conventional therapeutic measures, such as intravenous octreotide; therefore, she underwent three sessions of 50% glucose pleurodesis at 100, 112, and 120 DOL. The second patient was a premature female infant born at a gestational age of 34+5 weeks who was diagnosed with congenital chylothorax by prenatal ultrasound. After failing to respond to total parenteral nutrition and intravenous octreotide, the patient underwent consecutive sessions of 50% glucose pleurodesis on 21 to 23 DOL and 28 DOL. A temporal relation between the resolution of chylothorax and the administration of 50% glucose pleurodesis was observed in both cases, as the amount of pleural drainage halved within 72 hours of initiating pleurodesis.
Neonatal chylothorax is a rare yet potentially fatal respiratory condition that can result in various life-threatening complications. Prompt therapeutic measures should be taken if the patient presents with symptoms of respiratory distress at diagnosis. Pleural drainage via needle aspiration or a chest tube must be performed, and the patient should be provided with respiratory support via mechanical ventilation, if necessary [2,8]. To reduce pleural effusion and allow time for the lymphatic vessels to heal, a medium-chain triglyceride diet or total parenteral nutrition is recommended. Intravenous or subcutaneous octreotide administration can also be beneficial, as it reduces splanchnic blood flow and lymphatic flow to the thoracic duct. In some cases, other pharmacologic agents, such as midodrine and propranolol, have been reported to effectively treat neonatal chylothorax; however, the level of evidence supporting their use remains debated [8]. It is essential that multi-system evaluations be conducted regularly to assess the risks of complications, such as malnutrition, heart failure, lung hypoplasia, and infections. Loss of protein due to chylothorax can be substantial in severe cases; therefore, replacement with 5% albumin, immunoglobulin, and antithrombin should be considered [2,8].
While most neonates with chylothorax respond to first-line treatments, such as fasting, total parenteral nutrition, or intravenous octreotide, patients identified as refractory should be considered for invasive measures, such as chemical pleurodesis or thoracic duct ligation. There is no consensus on the criteria for defining refractory chylothorax. Rocha et al. [8] proposed a stepwise algorithm for treating neonatal chylothorax, in which patients were deemed refractory if pleural drainage persisted at over 10 mL/kg/day for more than 1 week despite first-line therapy. Other studies recommend surgical intervention if pleural drainage persists at over 50 mL/kg/day or continues for more than 4 weeks [9]. In our cases, we deemed both patients refractory as pleural drainage exceeded 30 mL/kg/day, despite increasing the intravenous octreotide dosage to 9 μg/kg/hr.
Chemical pleurodesis may be preferred over thoracic surgery because of its less invasive nature. Bellini et al. [2] reviewed published cases of neonatal congenital chylothorax and reported that 23% of cases required chemical pleurodesis or surgery. Of the 116 patients who underwent chemical pleurodesis, 62% received OK-4322). However, the therapeutic superiority of different pleurodesis agents has yet to be established, and the search for alternative agents is ongoing. Hypertonic glucose solution has been reported to effectively treat pleural effusion in adults, making it a promising candidate for pleurodesis [5,6]. The mechanism of action of hypertonic glucose pleurodesis is not fully understood. However, it is hypothesized that osmotic damage and the inflammatory response induced by the agent result in pleural adhesion [5]. In a double-blind clinical trial conducted by Talebzadeh et al. [5], adult patients with malignant pleural effusion were randomized and treated with chemical pleurodesis using either bleomycin or 50% dextrose. The study found no statistically significant differences between the two groups in terms of recurrence rates, chest tube retention time, or hospitalization period, suggesting that 50% dextrose is a plausible alternative to conventional pleurodesis agents, such as bleomycin [5].
The risk of adverse effects should also be considered when selecting appropriate pleurodesis agents. The reported adverse effects of commonly used pleurodesis agents, such as povidone-iodine and OK-432, include chest pain, hypotension, respiratory distress, and atrial tachyarrhythmia [9,10]. Talebzadeh et al. [5] reported that, apart from transient hyperglycemia, the frequency of adverse effects in patients treated with 50% dextrose did not significantly differ from that in bleomycintreated patients. Talebzadeh et al. [5] also noted that the relatively low cost of 50% glucose rendered it a viable treatment option. In our cases, both infants exhibited pain, respiratory distress, and hypotension as post-procedural side effects. Respiratory distress in both infants was transient, and hypotension resolved with intravenous isotonic sodium chloride solution administration. The inflammatory response induced by the hypertonic glucose solution may have caused focal atelectasis and vasodilation, leading to the aforementioned side effects.
While the first patient, who underwent intermittent pleurodesis over 3 weeks (100 to 120 DOL), had the chest tube removed after 37 days, the second patient, who received consecutive pleurodesis over 3 days, was comparatively rapidly weaned from pleural drainage within 14 days. This finding suggests a superior therapeutic efficacy of consecutive pleurodesis over intermittent pleurodesis. However, given that the first patient had a lower gestational age and more severe comorbidities than those of the second, slower recovery was expected in the first case. Largescale comparative studies should be conducted to determine the optimal pleurodesis protocol that yields the best therapeutic effect.
In the second case, the date when the maximum dose of intravenous octreotide was reached (20 DOL) coincided with the commencement of 50% glucose pleurodesis (21 DOL). Therefore, the subsequent reduction in pleural drainage may not be solely attributable to the efficacy of hypertonic glucose pleurodesis. To accurately assess the efficacy of hypertonic glucose pleurodesis, it may be critical to strictly discern nonresponsive cases of neonatal chylothorax by allowing a longer follow-up period after reaching the maximal octreotide dosage.
In conclusion, we present two rare cases of chylothorax in preterm infants who were successfully treated with 50% glucose pleurodesis with minimal adverse effects. Similarly treated cases should be collected to compare the therapeutic efficacy of hypertonic glucose solution with that of other pleurodesis agents or to determine the optimal protocol for hypertonic glucose pleurodesis.
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