What is the role of propranolol (beta blocker) in treating hemangiomas in pediatric patients?

Propranolol is the First-Line Treatment for Infantile Hemangiomas Requiring Systemic Therapy

Oral propranolol should be used as the first-line agent for all infantile hemangiomas (IH) requiring systemic treatment, with a target maintenance dose of 2-3 mg/kg/day divided into 2-3 doses, achieving 95% expected clearance compared to only 6% with observation alone. 1

Evidence Supporting Propranolol as First-Line Therapy

The superiority of propranolol is unequivocal based on high-quality randomized controlled trial data:

• Network meta-analysis demonstrates propranolol achieves 95% expected clearance (95% Bayesian Credible Interval: 88-99%), vastly superior to oral steroids at 43% clearance, intralesional triamcinolone at 58%, and control at 6%. 1
• In a pivotal RCT of 460 infants, 60% achieved complete or nearly complete resolution at 3 mg/kg/day for 6 months versus only 4% with placebo. 1
• Overall efficacy (excellent, good, or medium response) reaches 98.97% with propranolol versus 31.25% with observation (P < 0.05). 1
• Treatment failure rate is remarkably low at only 1.6% across comprehensive literature reviews. 1

Propranolol received FDA approval in March 2014 (as Hemangeol) specifically for proliferating IHs requiring systemic therapy, replacing systemic corticosteroids as the previous gold standard. 1

Standard Dosing Protocol

Initial Dosing

• Start at 1 mg/kg/day divided into 2-3 doses for the first 24 hours, then escalate to maintenance dosing. 2, 3
• After 24 hours, increase to 2 mg/kg/day as the standard maintenance dose. 2, 3
• For non-responders, titrate up to a maximum of 3 mg/kg/day. 1, 2, 3

The 6-month duration at 3 mg/kg/day is superior to 3-month regimens or lower doses based on RCT data. 1

Modified Dosing for High-Risk Populations

Start at 0.5 mg/kg/day for the following patient groups: 2, 3

• Preterm infants
• Low birthweight infants
• Infants with faltering growth
• Conditions predisposing to hypoglycemia
• Patients with PHACE syndrome (after appropriate cardiac workup)

For PHACE syndrome specifically, obtain brain MRI/MRA, echocardiogram, and ECG before initiating full-dose propranolol due to risks of coarctation of the aorta and cerebrovascular anomalies. 1, 2, 3

Critical Administration Guidelines

Feeding Requirements

Propranolol must always be administered with or immediately after feeding to prevent hypoglycemia. 2, 3

Hold doses during any period of:

• Reduced oral intake
• Vomiting or diarrhea
• Acute illness interfering with normal feeding

Administer doses at intervals not exceeding 8 hours (or 6 hours in younger infants) to reduce hypoglycemia risk. 1, 2

Treatment Duration

Continue propranolol until at least 12 months of age to minimize rebound growth risk. 2, 3

Most patients do not require treatment beyond 17 months of age. 2 The 6-month treatment duration is superior to 3 months based on RCT evidence showing 60% complete resolution versus lower response rates with shorter courses. 1, 3

Pre-Treatment Assessment

Mandatory Cardiovascular Evaluation

Perform a thorough history and physical examination focusing on: 1, 2

• Cardiac auscultation for murmurs or abnormal sounds
• Peripheral pulse assessment
• Abdominal examination for hepatomegaly
• Lung auscultation for wheezing or obstructive airway disease

Electrocardiography is recommended, particularly in: 1

• Younger infants (especially <8 weeks)
• Infants with low heart rate
• Those with abnormal cardiac examination findings
• Family history of congenital heart disease

However, pretreatment cardiac screening appears of limited value in patients with unremarkable cardiac history and examination. 1

Special Imaging Requirements

For segmental head/neck hemangiomas, obtain brain MRI/MRA before or shortly after therapy initiation to evaluate for PHACE syndrome. 2

Echocardiography is required for suspected PHACE syndrome to assess for coarctation of the aorta and other cardiac anomalies. 2

Monitoring During Treatment

Initial Monitoring

Measure heart rate and blood pressure: 2

• At baseline
• 1 hour after first dose
• 2 hours after first dose
• Repeat 1 and 2 hours after each dose increase ≥0.5 mg/kg/day

Ongoing Monitoring

Routine follow-up every 2-3 months for stable patients without complications. 2, 3

Blood pressure and heart rate monitoring is not required between appointments if the infant is well and stable. 2

Adjust dose for weight gain at each clinic visit. 3

Absolute Contraindications

Do not use propranolol in patients with: 1, 2

• Cardiogenic shock
• Sinus bradycardia
• Hypotension
• Heart block greater than first-degree
• Decompensated heart failure
• Bronchial asthma or obstructive airway disease
• Known hypersensitivity to propranolol

Clinical Response and Efficacy

Rapid Onset of Action

Lightening of color and softening of the tumor occurs within hours to days of the initial dose in most children. 1

Progressive improvement continues for at least 3 months in most patients. 1

Specific Clinical Scenarios

Vision-threatening periocular hemangiomas: Early treatment with propranolol is critical, as failure to treat can lead to amblyopia, significant refractive errors, and strabismus in up to 80% of untreated patients. 2 Co-management with ophthalmology is essential. 2

Airway hemangiomas: Require co-management with otolaryngology. 2, 3 Suspect airway involvement in any infant with hoarseness and stridor, particularly with segmental hemangiomas in mandibular, cervicofacial, or "beard" distribution. 2

Ulcerated hemangiomas: Propranolol is superior to ibuprofen and paracetamol for treating ulcerated IHs. 1 Complete healing of ulceration typically occurs in less than 2 months. 4

Adverse Effects and Safety Profile

Common Mild Effects

Side effects are generally limited and mild: 1

• Sinus bradycardia
• Hypotension
• Diarrhea
• Cool extremities
• Sleep disturbance

Serious Adverse Effects (Rare)

• Hypoglycemia/seizures (prevented by proper feeding protocols)
• Bronchospasm (discontinue if wheezing requires treatment)

In large case series, adverse effects were uncommon and mild, with no severe adverse events reported in many studies. 5, 6, 7, 8

Discontinuation Protocol

Never abruptly discontinue propranolol. Plan for gradual taper over 1-3 weeks when discontinuation is necessary to prevent rebound growth. 2

After discontinuation, moderate-to-severe regrowth occurs in 9.3% of cases and mild regrowth in 22.5%, which typically responds to retreatment. 8

Mechanism of Action

While the precise mechanism remains unclear, proposed actions include: 1

• Vasoconstriction
• Inhibition of angiogenesis via suppression of VEGF-A
• Downregulation of matrix metalloproteinases and interleukin-6
• Regulation of the renin-angiotensin system
• Inhibition of nitric oxide production
• Prevention of IH stem cell differentiation into endothelial cells or pericytes

β2-adrenergic receptors are present on capillary endothelial cells in proliferating IH, and vascular endothelial growth factors are suppressed in the presence of β-adrenergic receptor blockade. 1

Key Clinical Pearls

• Propranolol is effective even after the proliferative phase has ended, not just during active growth. 1
• Earlier treatment may yield superior results, with some evidence suggesting preterm patients and those treated precociously show better responses. 5
• Propranolol allows discontinuation of systemic corticosteroids within a few weeks when transitioning therapy. 4
• The treatment is highly effective across age groups, with responses seen in 97% of patients under one year and 74% over one year. 6