The use of high dose octreotide in management of neonatal chylothorax: Review

1 Introduction

Chylothorax is characterized as an abnormal condition in which lymphatic fluid collects in the pleural space [1]. In neonates, chylothorax is a rare medical condition [2]. Despite its low incidence, high mortality rates of approximately 64% are reported. The etiology of chylothorax is vast in nature and scope and ranges from congenital abnormalities to post-surgical complications such as lymphangiectasis, subclavian vein thrombosis, thoracic duct injuries, and tumors. Chylothorax is associated with significant loss of lymph and, coincidingly, a serious loss of antibodies, coagulation factors, fluid, lymphocytes, and protein [3]. Chylothorax can be acquired or manifest as a congenital condition, which is identified by the presence of an idiopathic lesion.

Upon diagnosis of congenital chylothorax, first-line management is based on dietary modifications such as aggressive fasting accompanied by total parenteral nutrition with formulas enriched with medium-chain triglyceride [4]. A majority of neonates with chylothorax experience pleural effusion, further contributing to respiratory distress. As a result, neonates require both chest drainage as well as respiratory support. Recently, pharmacological options, such as use of somatostatin and octreotide, have been studied. However, the impact of somatostatin and octreotide treatment on the clinical outcomes of neonates diagnosed with chylothorax remains a rather controversial topic. Octreotide, a somatostatin analog, is a more widely used therapy for neonates with chylothorax since it has a longer half-life than somatostatin and does not necessitate continuous administration [5]. However, despite recommendations for treatment of chylothorax, uniform guidelines have not yet been developed and implemented for use among neonatal patient populations diagnosed with chylothorax.

2 Results and discussion

The incidence of congenital chylothorax ranges from one in every 5,800 to 24,000 neonatal patients [6, 7]. Previous research has found that administering octreotide to newborns with acquired or congenital chylothorax was a safe and effective treatment regimen [8–10]. Across the studies included in our review, octreotide was deemed an effective course of treatment in approximately 47% of patients with chylothorax.

The effectiveness of octreotide in treating acquired chylothorax (33.3%) compared to congenital chylothorax (53.3%) was not statistically significantly different. This finding corroborates the results of two independent large systematic reviews, which demonstrated that octreotide is the most suitable tool by which to treat chylothorax in neonatal patient populations. One meta-analysis that assessed 19 case reports found that 14 cases reported successful resolution, four demonstrated no improvement, and one case exhibited equivocal results using octreotide [11]. Octreotide should therefore serve as an adjunctive treatment therapy among pre-term as well as full-term neonates with acquired and congenital chylothorax [12].

Despite the effectiveness of octreotide, octreotide treatment is associated with mild adverse effects thus never requiring treatment to be discontinued. However, there has been a lack of consistency regarding the optimal dosage and route of administration for octreotide throughout the literature. Octreotide can be administered intravenously or subcutaneously. Infants on low-dose octreotide treatments have had successful clinical outcomes; low-dose octreotide (2μg/kg/h) therapy does not require intubation and neonatal patients typically do not experience any side effects. Shah and Sinn tested a starting dose of octreotide at 0.5–1μg/g/h and increased it by 1-2μg/kg/h increments until a dose of 10μg/kg/day was reached. This led to the resolution of chylothorax in five neonates and resistance to octreotide in one neonatal patient [13]. After receiving a 5-6μg/kg/min dose of octreotide, pleural effusions decreased in neonatal patients with chylothorax [14]. Four out of seven patients experienced persistent pulmonary hypertension and a mortality of 30% was reported.

Yin and colleagues further investigated the influence of octreotide treatment therapy on neonates with congenital chylothorax by determining the effects of somatostatin or octreotide on health outcomes. Out of 14 neonates with congenital chylothorax, neonates who were treated with either 3.5–7μg/kg/h of somatostatin before 2016 or 1–6μg/kg/h of octreotide after January 2016 were compared to neonates receiving traditional treatment over a three year period, from 2013 to 2016. Findings revealed that 71.4% of neonates showed signs of a bilateral presentation of pleural effusion while 28.6% of neonates demonstrated a unilateral presentation of pleural effusion. Additional findings revealed that 12 of the 14 neonatal patients survived until discharge; however, two neonates died within three days following birth. This varies from reports of a 64% mortality rate among neonates with chylothorax. Chest tubes were implemented for an average duration of 14 days and none of the neonates required thoracic duct ligation or pleurodesis surgery. There was a reduction in the need for ventilation support in 12 of the neonates following the administration of somatostatin or octreotide treatment.

Although doses varied, the maximum doses were 10 vs. 7.5μg/kg/h. Other studies reported that octreotide can be increased to 15μg/kg/h while, in other cases, the maximum dose has been 24μg/kg/h. Neonatal patients treated with such high doses of octreotide have not been previously reported. Octreotide, especially when taken in higher doses, may also be correlated with major side effects, including cutaneous flushing, hyperglycemia, ileus, liver dysfunction, loose stools, nausea, necrotizing enterocolitis, transient abdominal distention, and transient hypothyroidism. Contrary to findings from Saito and colleagues, no significant side effects were reported in infants who were administered high-dose octreotide therapy (20μg/kg/h). These findings were also supported by another case report by Alhasoon who examined the effects of using high doses of Octreotide (20μg/kg/h).

These findings vary from previous research findings that have reported multiple side effects among neonates from octreotide treatment such as hyperglycemia, necrotizing enterocolitis, pulmonary hypertension, severe hypotension, transient hypothyroidism, and transient mild cholestasis. In addition to necrotizing enterocolitis and transient hypothyroidism, gastrointestinal intolerance was a side effect of octreotide treatment in neonatal patients with chylothorax. Both high dose and long-term octreotide treatment along with administration of skim milk fortified with medium-chain triglycerides resolved chylothorax in 33-week old pre-term neonatal patients [15]. Hence, high doses of octreotide can be safely used as a therapeutic option if administered carefully. Early initiation of non-surgical management options have decreased the mortality rate of congenital chylothorax from 50%, before the 1950’s, to 10–20% currently. Data regarding the use of octreotide treatment with surgery is limited. Surgery should be reserved for severe and refractory cases [16].

3 Conclusions

The low incidence but high mortality rates associated with chylothorax in neonatal patient populations has led to more studies on available treatment options for chylothorax. First-line management of chylothorax among neonates includes dietary modifications including aggressive fasting, formulas enriched with medium-chain triglycerides, as well as total parental nutrition. When first-line management fails to be effective in resolving chylothorax, octreotide is used as a pharmacological treatment option. However, the influence octreotide has on patient health outcomes is dependent on dose and the method of administration. (Table 1.2)

In conclusion, octreotide has proven to effectively resolve chylothorax in neonatal patients. As a therapy, octreotide has proven to effectively treat both acquired chylothorax and congenital chylothorax. However octreotide has been more effective in treating congenital chylothorax compared to acquired chylothorax. Furthermore there are inconsistencies pertaining to the optimal octreotide dose. Both low and high doses of octreotide treatment not only have effectively treated chylothorax, but they have been associated with no or less serious side effects. Somatostatin/octreotide treatment has also been shown to reduce pleural drainage, decreasing the need for respiratory support without any major side effects. Regardless of the advantages associated with octreotide administration, further studies should be conducted. Yin and colleagues posit that randomized controlled trials (RCTs) should involve more patients to better determine the inherent benefits of octreotide in neonatal patients with congenital chylothorax.

In summary, in our experience and based on the results from this literature review (Table 1, 2), we suggest that the dose of octreotide in neonatal chylothorax can be safely titrated to a maximum of 20μg/kg/h, resulting in encouraging outcomes and no notable increases in side effects. This is especially true for settings in which that low doses of octreotide (1 –10μg/kg/h) have been deemed ineffectual.