Journal of Pediatric Cardiology and Cardiac Surgery 8(2): 96‒102 (2024)

Case Report

Etilefrine for Chylothorax in Patients With Congenital Heart Disease
Hiroaki Sammori, MD1), Kazuhiro Shoya, MD2), Yu Matsumura, MD1),Naoki Wada, MD3), and Tadahiro Yoshikawa, MD1)
1) Department of Pediatric Cardiology, Sakakibara Heart Institute, Tokyo, Japan

2) Department of Critical Care Medicine, Sakakibara Heart Institute, Tokyo, Japan
3) Division of Pediatric Cardiac Surgery, Department of Cardiovascular Surgery,

Sakakibara Heart Institute, Tokyo, Japan

Chylothorax is accumulation of chyle in the pleural space and is one of the common postoperative complicationsof congenital cardiac surgery in children. It is challenging to manage chylothorax, and the complication is associated with increased postoperative mortality and morbidity. The definitive treatment for chylothorax has not yet
been established. Currently applied managements are mostly based on previous reports, including dietary adjustment, drug administration, and surgical procedures. Some reports showed that etilefrine, a sympathetic agent,
was a potential treatment option for chylothorax, although it remains unclear whether this drug is effective andsafe in treating chylothorax in patients with congenital heart disease. We administered etilefrine in four patientswith congenital heart disease who developed chylothorax in the perioperative period. All four patients did not
respond to dietary adjustments nor steroids, but required further treatment. Three patients seemed to have some
improvement in chylothorax with addition of etilefrine to conventional treatment, while one showed insufficient
treatment effect. Although some cardiovascular side effects, such as hypertension and arrhythmia, had beenreported, no side effects were noted in simultaneous administration of etilefrine and inotropes in our series. Thisis the first report on etilefrine infusion to manage chylothorax in patients with congenital heart disease. Use ofthis drug might be a potential option for treating chylothorax.

Keywords: chylothorax, congenital heart disease, etilefrine, pediatric cardiac surgery

Introduction
Chylothorax is a well-known and serious postoperative complication in children undergoing congenital
cardiac surgery, occurring with an incidence between
0.6 and 6.6%.1, 2) Possible causes of chylothorax are
injury to the thoracic lymph duct, increasing central
venous pressure, congenital lymphatic malformation,and chromosomal abnormality.1, 2) In some patientswith congenital heart disease, chylothorax happens evenduring the preoperative period due to increased central
venous pressure. Chylothorax increases both mortality
and morbidity. In particular, it can cause prolonged
intensive care unit (ICU) stay and need for mechanicalventilation. Those patients are susceptible to infection,

venous thrombosis, and malnutrition.2, 3) There is no
overall consensus regarding the optimal treatment ofchylothorax, while fat-free or low-fat diet, nil per os(NPO) with total parenteral nutrition (TPN), administration of steroids or octreotide, pleurodesis, and surgical procedures are generally adopted and widely used as
current treatments.1, 2, 4, 5)
Although our institution has not set a strict protocol for chylothorax treatment, the practical approach
adopted by us is summarized in Fig. 1. We initiallyattempted a low-fat diet once diagnosing the patientas chylothorax, and prednisolone was administered inthose not responding to a low-fat diet. Following this,octreotide was administered as the next step. NPOs
with TPN were usually introduced when patients had

Received: September 5, 2023; Accepted: February 26, 2024
J-STAGE Advance Published Online: July 5, 2024
Corresponding author: Hiroaki Sammori, MD, Department of Pediatric Cardiology, Sakakibara Heart Institute, 3-16-1, Asahicho,
Fuchu, Tokyo183-0003, Japan
E-mail: hiroaki_sanmori@tmhp.jp
doi: 10.24509/jpccs.23-014© 2024 Japanese Society of Pediatric Cardiology and Cardiac Surgery
This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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Fig. 1 Flow chart of treatment approach for chylothorax in our institution
We used octreotide previously and have used etilefrine instead of octreotide since April 2021. NPO, nil per os; TPN, total
parenteral nutrition.

not responded to other medical therapies. Pleurodesis
was considered necessary when dietary adjustments andmedical therapy were ineffective. Further intervention,such as ligation of the lymph duct or lymphangiography,
was considered when chylothorax did not improve after
the conservative treatments. The threshold for drain
removal was determined to be less than 10 mL/day(3‒5 mL/kg/day) in neonates and <3 mL/kg/day in older
children. When the amount of pleural effusion did notcome down below the criterion for drain removal, we
discussed additional treatments still further.
Octreotide is a somatostatin analog that is administered frequently off-label for several conditions, including chylothorax. Hypotension and necrotizing enterocolitis are known side effects,6) and this drug should be
used with caution, especially in neonates. Octreotide
was previously regarded as the next step at our institution when pleural effusion did not resolve after initiationof dietary adjustments and administration of steroids.

Though this drug is currently widely used for chylothorax, we have experienced some patients in whom octreotide was less than effective. In fact, some of those did
not tolerate continued administration of octreotide due
to hypotension as its side effect.
It has been reported that etilefrine is effective forchylothorax after esophageal surgery in children andadults,2, 7) and for idiopathic chylothorax.8) Etilefrine
infusion is also an off-label use for chylothorax, and it
has side effects such as hypertension, tachycardia, andarrhythmia.2, 7‒9)
On the other hand, there have been no reports ofetilefrine infusion in patients with congenital heart disease. This report describes four patients with refractorychylothorax who underwent congenital cardiac surgery
at our institution between April 2021 and March 2022;
safety and efficacy of etilefrine were evaluated in thesepatients. Another two patients with congenital heartdisease received etilefrine infusion during this period,© 2024 Japanese Society of Pediatric Cardiology and Cardiac Surgery

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but either of them was excluded because drainage
output through the chest tube could not be evaluatedprecisely due to intrathoracic lavage being performed
for open chest management after resuscitation. In thisreport, chylothorax was defined as refractory when notresponding to treatments by dietary adjustments anduse of steroids and, at the same time, when deemed torequire additional treatment. We administered etilefrine, instead of octreotide, in our four patients.

Patients
All patientsʼ information are provided in Table 1.
Case 1 (Fig. 2a)
A female child, born at 37 5/7 weeks gestational age(GA), delivered by cesarean section. She was transferredfrom another hospital on the second day of life (DOL)
with a postnatal diagnosis of supracardiac total anomalous pulmonary venous connection (TAPVC). The
patient underwent TAPVC repair on DOL 12. Following
surgery, she was hemodynamically unstable, and a large
pleural effusion was noted, which required a continuous
indwelling chest drain. She was diagnosed as having
chylothorax by fluid analysis, which revealed an elevatedlymphocyte fraction (96%) on the eighteenth postoperative day (POD). Enteral feeding was initiated with
low-fat milk on the same day. Prednisolone was subsequently started at 2 mg/kg/day for treating chylothorax.
Despite these treatments, right- and left-sided pleural
effusion remained around 80 and 35 mL/kg/day, respectively. On POD 31, etilefrine infusion was initiated at
0.7 µg/kg/h and titrated by 0.15 µg/kg/h every 24 h up
to 1.0 µg/kg/h, while circulatory parameters were continuously monitored in the ICU to detect side effects, ifany, such as hypertension, tachycardia, and arrhythmia.
There were no such signs of side effects, and right- andleft-sided pleural effusion decreased over 10 days and 2
weeks, respectively. The patient was extubated on POD
42. The right- and left-sided chest tubes were removed
on POD 40 and 43, respectively. Etilefrine infusion was
weaned off on POD 46.
Case 2 (Fig. 2b)
A male child, born at 37 4/7 weeks GA via vaginal
delivery at a previous hospital. Shortly after birth, thepatient developed cyanosis and was intubated because
of severe hypoxemia. His heart disease was postnatallydiagnosed as transposition of the great arteries (TGA)
with an intact ventricular septum. The patient was thentransferred to our hospital for surgery. On DOL 6, thepatient underwent the arterial switch operation. A large
pleural effusion accumulated on the left side of the chest,
requiring insertion of a chest tube into the left-sided
pleural space on POD 8. Breast milk feeding was initiated on POD 10. The following day, the appearanceof output through the chest tube changed to a milky
one. Although a lymphocyte fraction measured was
57%, we diagnosed his condition as chylothorax basedon elevated triglyceride levels (140 mg/dL) on the fluid
analysis. A low-fat diet was initiated on the same day,and prednisolone (2 mg/kg/day) was started on POD
12. However, the right- and left-sided pleural effusion remained at approximately 30 and 45 mL/kg/day,
respectively. Hence, etilefrine infusion was initiatedat 0.7 µg/kg/h on POD 19 and titrated by 0.3 µg/kg/h
every 24 h up to 1.0 µg/kg/h, on continuous monitoring
to detect side effects in the ICU. The pleural effusion
declined over 6 days. The patient was extubated on POD

Table 1 Patients characteristics and clinical courses
Case Sex
1 Female

Birth weight(gram)

Cardiac diagnosis

Underlying
diseaseOperation

Age at surgery(days old)

Duration of drain
placemant (days)

Duration of etilefrine
administration (days)

2097

Supracardiac TAPVC

None

TAPVC repair

12

43

15

6

24

14

2

Male

2892

TGA with intact ventricular septumNonearterial
switch(Lecompte)

3

Male

2660

incomplete AVSD,
common atrium, IVC
interruption

Leftisomerism

mPAB+PDA
ligation

12

12

33

4

Male

2014

complete AVSD

21 trisomy

mPAB+PDA
ligation

14

37

33

AVSD, atrioventricular septal defect; IVC, inferior vena cava; mPAB, main pulmonary arterial banding; PDA, patent ductus arteriosus;
TAPVC, total anomalous pulmonary venous connection; TGA, transposition of the great arteries

J Pediatr Cardiol Card Surg Vol. 8, No. 2 (2024)

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Fig. 2 Clinical course and the trends of chest drain output
LCD, left chest drain; NPO, nil per os; PE, pleural eﬀusion; POD, postoperative day; RCD, right chest drain; TPN, total
parenteral nutrition

22, and the chest tubes were removed on POD 24. Etilefrine was discontinued on POD 33. No side effects werenoted during infusion of the agent.
Case 3 (Fig. 2c)
A male child, born at 37 weeks GA via vaginal delivery, had prenatal diagnosis of left atrial isomerism,
incomplete atrioventricular septal defect (AVSD), common atrium, and inferior vena cava interruption. The
patient developed respiratory failure after delivery andrequired intubation in a neonatal ICU (DOL 0). Breast
milk feeding was initiated on DOL 3. Subsequently,
pleural effusion accumulated on both sides of the chest,
and breast milk feeding was discontinued on DOL 6. The
following day, prednisolone was administered at a doseof 2 mg/kg/day. On DOL 10, although low-fat milk had
been introduced, the patient respiratory complications
worsened due to a right-sided pleural effusion, requiring
insertion of a chest tube into the right pleural space.
Fluid analysis revealed chylothorax, as evidenced bya white blood cell (WBC) count of 3983 cells/µL (97%
lymphocytes). On DOL 12, main pulmonary arterial
banding (mPAB) and ligation of patent ductus arteriosus(PDA) were performed. A large pleural effusion accu-

mulated on the left side of the chest, requiring insertionof another chest tube into the left pleural space on POD
1. Subsequently, the right- and left-sided pleural effusion
remained around 10 and 5 mL/kg/day, respectively. The
chest tubes could not be removed during the early postoperative period. Thus, etilefrine infusion was initiatedat 0.3 µg/kg/h on POD 4 and titrated by 0.35 µg/kg/h
approximately every 12 h up to 1.0 µg/kg/h, on continuous monitoring to detect side effects in the ICU. Leftand right-sided pleural effusion ceased over 3 days and 6days, respectively. Hence, the left- and right-sided chest
tubes were removed on POD 6 and 9, respectively. The
patient was extubated on POD 13. Etilefrine was weaned
off on POD 37 without any side effects.
Case 4 (Fig. 2d)
A male child, born at 37 5/7 weeks GA by cesarean
section. The patient was postnatally diagnosed withcomplete AVSD in the setting of trisomy 21. On DOL
14, the patient underwent mPAB and PDA ligation. On
POD 2, a right-sided chest tube was inserted because of
pleural effusion. On POD 8, he was diagnosed with chylothorax following a fluid analysis revealing a WBC of1380 cells/µL (94% lymphocytes). Hence, enteral feeding© 2024 Japanese Society of Pediatric Cardiology and Cardiac Surgery

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was initiated with low-fat milk. Subsequently, a left-sided
chest tube was also inserted because of accumulation of
pleural effusion, and prednisolone (2 mg/kg/day) was
initiated on POD 11. The right- and left-sided pleural
effusion remained at over 30 and 50 mL/kg/day, respectively. Etilefrine infusion was initiated at 0.5 µg/kg/h on
POD 14 and titrated by 0.5 µg/kg/h approximately every
24 h up to 1.0 µg/kg/h, on continuous monitoring todetect side effects. The patient was extubated on POD
24. The pleural effusion from the right-sided pleural
effusion decreased over 10 days and was removed on
POD 28. In contrast, the amount of drainage fromthe left-sided pleural cavity remained high at over
45 mL/kg/day. Therefore, pleurodesis was performedon the left side of the chest on PODs 26 and 30. Subsequently, pleural effusion decreased over approximately
2 weeks, and the left-sided tube was removed on POD
37. Etilefrine was weaned off on POD 47 without side
effects. He was transferred back to the previous hospitalon POD 59.

Discussion
Chylothorax is one of the common causes of pleural
effusion, and may result in significant losses of bodily
fluids, lymphocytes, and proteins. Chylothorax is
responsible for high in-hospital mortality (odds ratio[OR], 2.13; 95% confidence interval [CI], 1.75‒2.61),10)
and prolongs the length of mechanical ventilation and
ICU stay. Additionally, it is associated with a higher
rate of reintubation; the event increases challenging
immunological issues such as sepsis and malnutrition.
Chylothorax is known to occur more frequently in theyounger age groups, particularly in neonates (OR, 7.03;
95% CI, 4.61‒10.7).10) Moreover, some particular surgeries have higher incidences of postoperative chylothorax:
the Fontan type operation (5.7%), the arterial switch
operation for TGA (4.3%), repair of congenital aorticarch anomalies (3.7%), and repair of TAPVC (3.7%).10)
Precise diagnosis is the key to early treatment. Thereare currently no established criteria for chylothorax, but
it is generally diagnosed based on the following featuresof pleural effusion described in previous reports: 1)
triglyceride levels >110 mg/dL, 2) absolute cell count>1000 cells/µL, and 3) lymphocytes >80%.4, 11) In
neonates, however, diagnosing chylothorax remains
challenging since definition of chyle triglyceride level isunclear at this stage of life.12) In addition, some medical
J Pediatr Cardiol Card Surg Vol. 8, No. 2 (2024)

reports state that the diagnosis of chylothorax requires
minimum fat intake.4, 11)
The current treatment strategy includes NPO, fat-freeor low-fat diet, NPO with TPN, medical therapy, pleurodesis, and surgical treatment, such as thoracic duct
ligation.4, 5) Generally, noninvasive treatment precedes
surgical treatment. Steroid therapy may cause infection,
hyperglycemia, hypertension, and delayed wound healing as side effects. As mentioned in the introduction, we
had no pre-defined treatment protocol for chylothorax,
and the timing of additional treatment varied from one
case to another. In this series, we initiated use of etilefrine following conventional therapy. Pleurodesis could
have been the next step after addition of etilefrine remedy. Surgical procedures to significant hemodynamic
impediments should also have been considered as far
as such residual lesions were causing increased venous
pressure.
Etilefrine is a sympathomimetic drug used to treat
postural hypotension and stimulates α and β adrenergic
receptors. It causes systemic smooth muscle contraction
and decreases chyle flow by constricting the thoracic
ducts.7, 8) We infused etilefrine via a central venous catheter, initially at 0.3‒0.7 µg/kg/h, and increased the doseby 0.15‒0.5 µg/kg/h approximately every 12‒24 h up to
1.0 µg/kg/h with careful monitoring in the ICU based on
previous reports.2, 9) There was no established regimen
for its dose; the plan for initiation, titration, and reduction was carefully determined in each case. Moreover,the use of etilefrine is also still off-label, and therefore
we obtained approval from the ethics committee of
our institution and obtained consent from the patient's
guardian.
To the best of our knowledge, this is the first report
to investigate efficacy and safety of etilefrine for chylothorax in patients with congenital heart disease. In
our study, etilefrine plus conventional therapy seemed
to be effective in Cases 1, 2, and 3. When etilefrine wasinitiated, their pleural effusion was not below the threshold for removal. The pleural effusion decreased over5‒14 days after the addition of etilefrine. In Case 4, in
contrast, adding etilefrine to conventional therapy was
insufficient, and the left-sided pleural effusion persisted
over 45 mL/kg/day. According to a previous report,
trisomy 21 can sometimes have thoracic duct malformation,13) which might influence the large amount ofpleural effusion in our case. There are some medical

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reports on the successful management of chylothorax
with a combination therapy of octreotide, pleurodesis,
and etilefrine.9, 14) We added the pleurodesis as the subsequent step in Case 4. After pleurodesis, the pleural
effusion on the left side resolved.
We recommend continuous monitoring during use of
etilefrine, though side effects of this drug are relatively
rare, such as hypertension (<5%), tachycardia, andarrhythmia. In our patients, there were no such episodes
when etilefrine was used concomitantly with inotropes.
As mentioned earlier, octreotide has demonstrated someevidence of efficacy in the management of chylothorax.
That is why octreotide is widely used for chylothorax. It
is noteworthy, however, that a previous report described
octreotide caused hypotension (12%) and necrotizing
enterocolitis (2%) in neonates.6) In particular, hypotension is a concern in patients hemodynamically unstableand on inotropic drugs; they require careful administration. Moreover, the elimination half-life of octreotide
is approximately 90‒120 min.15) For these reasons, wethink octreotide would be unsuitable for patients withhemodynamic instability. Therefore, octreotide should
be carefully administered especially in neonates, as wellas in those requiring infusion of inotropes, undergoing
surgery for congenital heart disease. When considering
the effect on blood pressure, hypertension may pose aless severe effect on the outcome than hypotension doesin patients with compromised hemodynamics. Thus, it
is possible that etilefrine is safer than octreotide whentreating chylothorax. Furthermore, etilefrine is significantly more cost-effective compared to octreotide. As
far as etilefrine proves to be effective, it can potentiallyreduce healthcare costs. If hemodynamic instability is
the main concern, it would be a good idea to start withetilefrine. In case one drug regimen turned out to be lesseffective, a combination therapy might be implemented
which can be advantageous as indicated by a previous
report.8)
Our report has some limitations because of the small
number of cases. Although the pleural effusion wasabove the removal threshold when etilefrine was initiated, there was a slight downward trend of the effusion
at that time. Additionally, it is difficult to propose a newtreatment protocol for chylothorax based on this report.

Conclusion
Our cases demonstrated that the administration of

etilefrine was safe and appeared effective for chylothorax. Therefore, etilefrine might be an alternative nonsurgical treatment for chylothorax. Further research isneeded to determine which treatment option is more
effective for chylothorax in patients with congenital
heart disease.
Acknowledgments
We thank Edward Neil for his assistance with editing themanuscript.
Conﬂicts of Interest
The authors have no conflicts of interest to declare.
Ethical Declarations
This case series and the use of etilefrine was approved by
the Ethics Committee of the Sakakibara Heart Institute. The
patients and their guardians were provided the opportunity
to opt out of this study, and the identity of the patients wasprotected. Etilefrine has not been approved for chylothorax,
and written consent to use of etilefrine was obtained fromthe patientʼs guardians in each case prior to initiation of
etilefrine infusion.
Author Contribution
Hiroaki Sammori drafted and prepared the initial manuscript and made the corresponding revisions. Kazuhiro
Shoya revised the manuscript and made scientific contributions. Yu Matsumura reviewed the manuscript and madescientific contributions. Naoki Wada and Tadahiro Yoshikawa reviewed the manuscript. All authors have approved
the final manuscript as submitted and agreed to be accountable for all aspects of the work.

References
1) Milonakis M, Chatzis AC, Giannopoulos NM, et al: Etiology and management of chylothorax following pediatricheart surgery. J Card Surg 2009; 24: 369‒3732) Muniz G, Hidalgo-Campos J, Valdivia-Tapia MDC, et al:
Successful management of chylothorax with etilefrine:
Case report in 2 pediatric patients. Pediatrics 2018; 141:e20163309
3) Ismail SR, Kabbani MS, Najm HK, et al: Impact of chylothorax on the early post operative outcome after pediatric cardiovascular surgery. J Saudi Heart Assoc 2014; 26:87‒924) Soto-Martinez M, Massie J: Chylothorax: Diagnosis andmanagement in children. Paediatr Respir Rev 2009; 10:199‒207© 2024 Japanese Society of Pediatric Cardiology and Cardiac Surgery

1025) Saad D, Makarem A, Fakhri G, et al: The use of steroids intreating chylothorax following cardiac surgery in children:
A unique perspective. Cardiol Young 2022; 1: 1‒66) Testoni D, Hornik CP, Neely ML, et al: Best Pharmaceuticals for Children Act̶Pediatric Trials Network
Administrative Core Committee: Safety of octreotide in
hospitalized infants. Early Hum Dev 2015; 91: 387‒392
7) Guillem P, Billeret V, Houcke ML, et al: Successful management of post-esophagectomy chylothorax/chyloperitoneum by etilefrine. Dis Esophagus 1999; 12: 155‒1568) Kinoshita S, Shoya K, Shimotakahara A, et al: Etilefrine
infusion for idiopathic chyle leakage in a critically ill child.
Pediatr Int 2022; 64: e14850
9) Tomobe Y, Mizuguchi U, Shimotakahara A, et al: Combination therapy with etilefrine and pleurodesis forrefractory congenital chylothorax. Biomed Hub 2020; 5:
907‒91110) Mery CM, Moffett BS, Khan MS, et al: Incidence andtreatment of chylothorax after cardiac surgery in children:
Analysis of a large multi-institution database. J Thorac

J Pediatr Cardiol Card Surg Vol. 8, No. 2 (2024)

Cardiovasc Surg 2014; 147: 678‒686.e1
11) Büttiker V, Fanconi S, Burger R: Chylothorax in children:
Guidelines for diagnosis and management. Chest 1999;
116: 682‒68712) Senarathne UD, Rodrigo R, Dayanath BKTP: Milky pleural effusion in a neonate and approach to investigating
chylothorax. BMJ Case Rep 2021; 14: e245576
13) Buchwald MA, Laasner U, Balmer C, et al: Comparisonof postoperative chylothorax in infants and children withtrisomy 21 and without dysmorphic syndrome: Is therea difference in clinical outcome? J Pediatr Surg 2019; 54:1298‒1302
14) Ohkura Y, Ueno M, Iizuka T, et al: New combined medical
treatment with etilefrine and octreotide for chylothorax
after esophagectomy: A case report and review of the literature. Medicine (Baltimore) 2015; 94: e2214
15) Basma H, Saras S, Khalid H: Somatostatin analogues forthe treatment of hyperinsulinaemic hypoglycemia. Ther
Adv Endocrinol Metab 2020; 11: 2042018820965068