Propranolol Therapy for Congenital Chylothorax

Case series

To assess the efficacy of propranolol treatment for severe congenital chylothorax (CC)

4 neonates: 2 treated prenatally, 2 treated postnatally

Fetuses diagnosed with severe congenital chylothorax without significant genetic, infectious, or cardiac anomalies; underwent other prenatal interventions

Propranolol was administered orally to pregnant women at 20 mg QID, increased to 40 mg QID (Cases 1 and 2), or to infants at 0.3 mg/kg/d, increased to 1 to 2 mg/kg/d (Cases 3 and 4).

Resolved at 24w3d gestation, 38 d after 40 mg QID

Alive and well 5 years later; asymptomatic

Resolved at 30w4d gestation, 32 d after 40 mg QID

Alive and well 5 years later; asymptomatic

DOL108: 0.3 mg/kg/d
DOL109: 0.6 mg/kg/d
DOL110: 1 mg/kg/d
DOL121: 1.3 mg/kg/d
DOL129: 1.8 mg/kg/d
DOL130: 2 mg/kg/d

Second admission: DOL137: Significant improvement 7 d after 2 mg/kg

Third admission:
DOL232-246: intubation for respiratory distress, R chest tube placement
DOL249: discharged clinically asymptomatic persistent R pleural effusion

Asymptomatic, active, normal exercise tolerance at 8 years old

Stabilized 10 d after 0.7 mg/kg/d. 

Asymptomatic, pleural effusion resolved on DOL260 (206 d after 1 mg/kg/d)

No significant maternal or neonatal complications from prenatal or postnatal propranolol use

Propranolol may be efficacious in treating severe fetal congenital chylothorax, with prenatal treatment leading to resolution before delivery and postnatal treatment stabilizing pleural effusions.

Strengths include the novel use of propranolol for congenital chylothorax and detailed case descriptions. Limitations include a small sample size, lack of a control group, and unknown optimal dosing for prenatal treatment. No information was provided on the propranolol dose titrations.

Propranolol treatment for chylothorax after congenital cardiac surgery

Design

Retrospective and prospective, observational, single-center, retrospective-controlled study

N= 50

Objective

To evaluate the efficacy of propranolol in reducing morbidities and duration of chest tube requirement in pediatric patients with high-output chylous effusion after congenital cardiac surgery

Study Groups

Control (n= 25)

Propranolol (n= 25)

Inclusion Criteria

Pediatric patients (< 7 years) with cardiac disease and high-output chylous effusion, defined as drainage >10 mL/kg/day, not responding to diet and diuretics; underwent cardiac surgery

Exclusion Criteria

None stated

Methods

This study prospectively enrolled 10 patients to receive propranolol following cardiac surgery; the remaining 15 patients who received propranolol were from retrospective chart reviews. The control group was a retrospective cohort of patients with the same inclusion criteria who did not receive postoperative propranolol during the same time period.

Propranolol dosing started at 0.5 mg/kg/day and increased every 48 hours by 0.5 mg/kg/day to a maximum of 2 mg/kg/day. Titration was done if the prior 48 hours had not resulted in a 20% decrease in fluid. The retrospective part of the experimental group received propranolol 0.5-2 mg/kg/day for high-output chylous effusion or prolonged chylous drainage. Propranolol was tapered off 2 weeks after chest tube removal by reduction of 1 dose/day/week for all patients.

Duration

2015-2020

Outcome Measures

Primary: Reduction in drainage volume by 80% or more in 9 days or less (responders)

Secondary: Morbidities, length of hospitalization, duration of chest tube requirement

Baseline Characteristics

Results

Control (n= 25)

Mortality

Responder

Four patients from the propranolol group died, three of whom were nonresponders. No deaths were attributed to propranolol. Mortality causes among propranolol patients varied, including respiratory failure and sepsis. 

In the control group, four patients also died, all more than 100 days postoperatively, due to cardiac and septic causes.

No significant difference was found in initial drainage volumes (p= 0.55) between the propanolol vs control or between responders vs nonresponders (p= 0.12).

There was also no significant difference between chest tube requirement between the groups (p= 0.15). However, responders had significantly reduced days with a chest tube when compared with both controls and nonresponders (p< 0.01).

While there was no difference in hospital stay between the groups, a significant difference was seen when propranolol responders were compared to the control group (p< 0.05) and nonresponders (p< 0.05).

Nonresponders were more likely to receive albumin as fluid replacement.

Adverse Events

Malnutrition was prevalent in all patient groups

Propranolol responders had significantly fewer infections (p< 0.0002) and thrombus (p< 0.005) compared to controls and nonresponders.

Study Author Conclusions

Responders to propranolol had significantly less morbidity and duration of chest tube requirement when compared with control patients and nonresponders. Nonresponders did not have worse outcomes than control patients. We conclude that propranolol may be an effective treatment of patients with refractory chylothorax.

InpharmD Researcher Critique

Use of Propranolol in the Treatment of Chylous Effusions in Infants

Case series

A premature infant, a girl born at 33 weeks and 6 days gestational age, was diagnosed with nonimmune hydrops and required a chest tube for a left-sided pleural effusion. Initially, octreotide was started on the second day of life for persistent chylothorax but showed no improvement. 

Propranolol was subsequently introduced on the fourth day at a dose of 0.25 mg/kg q6h, which resulted in a significant improvement within 24 hours. The propranolol dose was increased to 0.75 mg/kg q6h after two weeks due to persistent small pleural effusions.
As the infant began enteral feeds with breast milk, the pleural effusions worsened, necessitating an increase in propranolol to 1.5 mg/kg q6h. 

The infant was eventually discharged on propranolol at a maintenance dose of 1 mg/kg every 6 hours, which was the lowest tolerable dose effective in preventing the recurrence of effusions.

Case 2

A premature female infant, born at 22 weeks and 4 days gestational age, underwent a patent ductus arteriosus (PDA) ligation at 29 weeks and 3 days postmenstrual age (PMA). On the second postoperative day, she developed ascites, which required ultrasound-guided paracentesis. Initially, she was treated with intravenous octreotide at a rate of 10 mcg/kg/h and needed multiple paracenteses and catheter placements. Additionally, she developed bilateral pleural effusions, necessitating chest tube placement.

After four weeks, propranolol was introduced at 0.25 mg/kg q6h and gradually increased to 1 mg/kg q6h in addition to octreotide. Before propranolol, the peritoneal drainage was significant at 15 mL/kg per day. However, two days after starting propranolol, the drainage ceased, and the catheter was removed. The chylothorax resolved over the next two weeks, allowing for the removal of the chest tube and advancement of feeds. The patient was eventually weaned off both medications before being discharged.

A preterm female infant, born at 23 weeks 3 days gestational age, underwent PDA ligation and developed abdominal distension at 30 weeks' PMA while advancing feeds. Imaging confirmed ascites and fluid analysis showed an elevated WBC count. 

Propranolol was started at 0.5 mg/kg q6h to manage persistent ascites, which showed some improvement. The dose was increased to 1 mg/kg q6h due to worsening ascites with feeds.

Over two weeks, the infant tolerated full feeds of breast milk and was gradually weaned off propranolol.

A male infant, born at 37 weeks and 5 days of gestation, underwent duodenal atresia repair on day of life (DOL) 3 and PDA stent placement on DOL 14 for tetralogy of Fallot. On DOL 38, he developed abdominal distension characterized by centrally located bowel gas and ultrasound-confirmed ascites.

Propranolol was started at 0.25 mg/kg q6h and increased to 0.5 mg/kg q6h alongside advancing feeds, which led to improvement in ascites.

However, ascites recurred on DOL 69 while on propranolol and was associated with Candida albicans sepsis. Chylous fluid was confirmed through laboratory analysis. With worsening ascites, propranolol dosage was increased to 1 mg/kg q6h but was decreased to 0.75 mg/kg q6h due to bradycardia. After one week, feeds were reintroduced, and propranolol was gradually weaned and discontinued.

Highest propranolol dose

Case 2

Case 3

Study Author Conclusions

Propranolol should be considered in the treatment of chylous effusions, either in conjunction with or after failure of conservative measures. The authors recommend starting at a low dose and escalating as needed, until improvement is noted. The starting dose in previous case studies ranged from 0.5 to 2 mg/kg per day, with lower doses used in preterm infants. Notably, oral doses were used for these patients.

The novel use of propranolol in treatment of chylous effusions in infants appears to be safe. It could potentially decrease the duration of NPO status and, thereby, alleviate complications associated with long-term parenteral nutrition as well as reduce the duration and hence cost of hospitalization.

Propranolol for the Treatment of Lymphatic Malformations in a Neonate – A Case Report and Review of Literature

Design

Case presentation

A female born at 34 + 4/7 weeks’ gestation presented with bilateral pleural effusions and a large pericardial effusion that worsened with enteral nutrition despite conservative management with total parenteral nutrition and medium-chain triglyceride-enriched formulas. Given clinical deterioration, oral propranolol was started on day of life 16 at 0.3 mg/kg/day, divided every 8 hours.

Four days after the initiation of therapy, radiographic improvements showed significant reductions in pleural effusions, but they were still persistent. Propranolol was increased to 0.5 mg/kg, divided q8h, since the patient was tolerating the medication well.

The neonate was successfully extubated on day of life 23 (8 days after propranolol initiation), and full-volume breast milk feeds were introduced without recurrence of effusions. Repeat imaging showed complete radiographic resolution of her bilateral pleural effusions after 10 days of propranolol. Propranolol was discontinued after 20 days of treatment, and follow-up imaging over two months demonstrated no reaccumulation of fluid.

Study Author Conclusions

This report describes the case of a premature neonate with bilateral pleural effusions and a pericardial effusion unresponsive to treatment with TPN and MCT-enriched formulas who had successful treatment with oral propranolol.

Octreotide, while supported by a larger body of evidence, was not selected due to its limited efficacy in similar cases and potential for severe complications such as necrotizing enterocolitis and cholelithiasis. Sirolimus and sildenafil were also considered; however, sirolimus posed a significant risk of immunosuppression and hematologic toxicity, while concerns about exacerbation of retinopathy of prematurity in preterm neonates precluded the use of sildenafil.

Propranolol was ultimately chosen for its anti-lymphangiogenic action through VEGF inhibition and its favorable safety profile, as demonstrated in its widespread use for infantile hemangiomas. This report is unique in documenting a successful therapeutic response at a lower dose (0.5 mg/kg/day) than previously described, underscoring propranolol as a viable and well-tolerated option in refractory neonatal chylothorax.

Propranolol treatment for chylothorax due to diffuse lymphangiomatosis

Design

Case presentation

An 8-year-old boy presented severe respiratory distress. Laboratory evaluations revealed pleural fluid characteristics consistent with chylothorax, while imaging studies demonstrated intense bilateral pleural effusion and atelectasis without parenchymal involvement. After all the clinical and laboratory findings, he was diagnosed with lymphangiomatosis

After one month, due to the ineffectiveness of conventional therapies (bowel rest, total parenteral nutrition, octreotide infusion, and chest tube drainage), propranolol was initiated at a dose of 2 mg/kg/day. Over the course of treatment, the patient demonstrated significant clinical and radiologic improvement.

Within 15 days of propranolol initiation, chylous effusion markedly decreased, allowing for chest tube removal. Follow-up over 18 months revealed sustained respiratory recovery, improved exercise capacity, and resolving pleural effusions, as confirmed by chest radiographs. No adverse effects associated with propranolol were observed during the treatment period.

Study Author Conclusions

The report highlighted the potential efficacy of propranolol in managing lymphangiomatosis-related chylothorax, hypothesizing that its mechanism may involve the suppression of proangiogenic and lymphangiogenic factors such as VEGF, bFGF, and MMP-2, as well as the induction of endothelial cell apoptosis. Notably, this report emphasized that therapeutic benefits may be achievable at lower propranolol doses, potentially minimizing drug-related toxicities. However, optimal dosing strategies and treatment durations remain undefined.

Successful management of extremely high-output refractory congenital chylothorax with chemical pleurodesis using 4% povidone–iodine and propranolol: a case report

Design

Case report

Case presentation

A neonate, delivered at 33 weeks of gestation (APGAR scores 4, 6, and 7), presented with severe hydrops fetalis and respiratory distress, requiring immediate interventions, including high-frequency oscillatory ventilation and bilateral chest drainage. Chylothorax was diagnosed upon pleural fluid analysis. Traditional first-line therapies such as octreotide, total parenteral nutrition, and a medium-chain triglyceride-enriched enteral diet proved ineffective in reducing the remarkable chest tube output (as high as 306.5 mL/kg/day).

Due to deterioration in the child’s clinical condition, bilateral chemical pleurodesis with povidone-iodine was performed. On day 30 of life, 6 mL of 4% povidone-iodine were instilled into each pleural cavity for a duration of five hours, resulting in complete cessation of pleural fluid drainage. Follow-up assessments revealed no adverse effects on renal or thyroid function.

In addition to pleurodesis, propranolol was introduced on day 40 of life due to continued edema, starting at 0.5 mg/kg/day (divided q8h) and titrated to a maximum dose of 2 mg/kg/day (divided q8h) over 9 days. Propranolol administration led to significant diuresis, stabilization of weight, and substantial improvement in respiratory function, enabling extubation (transitioned to CPAP) by day of life 50.

The neonate was discharged on day of life 64 with supplemental oxygen and a propranolol regimen (dose, frequency, and formulations unspecified), which was later weaned after one year without recurrence of pleural effusions. Follow-up at 12 months indicated normal growth and development for corrected age.

Study Author Conclusions

This case underscores the efficacy of povidone-iodine pleurodesis in refractory congenital chylothorax while highlighting propranolol as a potential adjunct therapy for suspected lymphatic involvement.