- ACRONYMS AND DEFINITIONS
- AAP - American Academy of Pediatrics
- IH - Infantile hemangioma
- RCT - Randomized controlled trial
- US - Ultrasound
- EPIDEMIOLOGY
- Infantile hemangiomas occur in about 4 - 5% of infants. They are the most common benign tumor in children.
- Preterm and low birth weight infants have a higher risk with up to 30% of infants weighing < 1 kg being affected [1]
- RISK FACTORS
- Female sex
- Twins
- White race
- Preterm
- Low birth weight [1]
- PATHOLOGY
- IHs are benign vascular tumors thought to arise from circulating endothelial progenitor cells that migrate to the skin
- Characteristics that distinguish IHs from other vascular tumors include development during the first weeks to months of life, history of rapid growth followed by involution, and histological findings of markers unique to IHs (e.g. erythrocyte-type glucose transporter protein) [1]
- IH TYPES
- Overview
- IHs are categorized according to their tissue depth, size and location, and whether or not they have high-risk features
- High-risk features are hemangioma features that are sometimes associated with other underlying pathology and/or disfigurement and ulceration
- Tissue depth
- Superficial - bright red with little or no evidence of deeper skin involvement; often called "strawberry hemangioma"
- Deep - hemangioma that runs deeper into the skin and often has a blue hue; formerly called "cavernous hemangioma"
- Combined (mixed) - hemangioma that has both superficial and deep features
- Size and location
- Localized - well-circumscribed lesion arising from a central point
- Segmental - larger lesions (often > 5 cm) that are elongated and fill a large area of the region where they are found
- Indeterminate - not clearly localized or segmental
- Multifocal - multiple discrete lesions at different anatomical sites [1]
High-risk IH features | |
---|---|
Feature | Associated risk |
"Beard-area" segmental IH |
|
≥ 5 IHs |
|
Periocular IH (>1 cm) |
|
IH of lip or oral cavity |
|
Ulcerated IH |
|
Disfigurement |
|
Face, scalp, and neck segmental IHs |
|
Lumbosacral and/or perineal segmental IHs |
|
- NATURAL COURSE
- IH Growth
- The most rapid growth occurs between 1 and 3 months of age
- There appears to be a period of accelerated growth between 5 and 7 weeks of age
- IHs reach 80% of their full size by 3 months of age
- By 5 months of age, the majority of IHs have reached their full size [1]
- IH Involution
- Between 5 - 12 months of age, most IHs have stopped growing and started to involute
- Lesions flatten and shrink from the center outward
- By 4 years of age, 90% of IH involution is complete
- After involution is complete, telangiectasias and scarring may persist [1]
- See hemangioma education website for information and pictures of involuting IHs
- IMAGING RECOMMENDATIONS
AAP Imaging Recommendations for IH |
---|
Diagnosing IH
|
Presence of ≥ 5 IHs
|
IHs associated with higher risk of PHACE syndrome (face, scalp, and neck segmental IHs)
|
IHs associated with higher risk of LUMBAR syndrome (lumbosacral and/or perineal segmental IHs)
|
- AAP TREATMENT RECOMMENDATIONS
- Oral propranolol is the first-line agent for IHs requiring systemic treatment
- May prescribe oral prednisolone or prednisone to treat IHs if there are contraindications or an inadequate response to oral propranolol
- May recommend intralesional injection of triamcinolone and/or betamethasone to treat focal, bulky IHs during proliferation or in certain critical anatomic locations (eg, the lip)
- May prescribe topical timolol maleate as a therapy for thin and/or superficial IHs
- May recommend surgery and laser therapy as treatment options in managing selected IHs [1]
- MEDICATIONS
Estimated efficacy of medications for IH | ||
---|---|---|
Drug | Average expected clearance | 95% Bayesian credible interval |
Propranolol | 95% | 88 - 99% |
Topical timolol | 62% | 39 - 83% |
Intralesional triamcinolone | 58% | 21 - 93% |
Oral steroids | 43% | 21 - 66% |
Control | 6% | 1 - 11% |
Propranolol
Dosage forms
- Propranolol is available as a generic solution that comes in 4 mg/ml and 8 mg/ml concentrations
- Hemangeol® is a propranolol solution (4.28 mg/ml) that has been FDA-approved to treat IH. It does not have a generic and is very expensive.
Dosing
- AAP recommendation: Propranolol 2 - 3 mg/kg/day
- In the propranolol trial, patients assigned to 3 mg/kg/day were started on 1 mg/kg/day for 1 week, then titrated to 2 mg/kg/day for 1 week, then 3 mg/kg/day. The dose was divided in two and given in the morning and late afternoon, immediately before, during, or immediately after feeding. Patients were treated for 6 months.
- Hemangeol label: starting dose of 0.6 mg/kg twice daily, taken at least 9 hours apart. After 1 week, increase the daily dose to 1.1 mg/kg twice daily. After 2 weeks of treatment, increase the dose to 1.7 mg/kg twice daily and maintain this for 6 months.
Efficacy
Mechanism of action
- The exact mechanism by which propranolol treats IH is unclear. Proposed mechanisms include vasoconstriction, angiogenesis inhibition, induction of apoptosis, inhibition of nitric oxide production, and regulation of the renin-angiotensin system. [1]
Side effects
Side effect | Placebo (N=236) |
Propranolol 3.4 mg/kg/day (N=224) |
---|---|---|
Sleep disorder | 5.9% | 16.1% |
Bronchitis | 4.7% | 13.4% |
Peripheral coldness | 0.4% | 6.7% |
Agitation | 2.1% | 4.5% |
Diarrhea | 1.3% | 6.3% |
Somnolence | 0.4% | 0.9% |
Nightmare | 1.7% | 6.3% |
Irritability | 1.3% | 1.3% |
Decreased appetite | 0.4% | 3.6% |
Abdominal pain | 0.4% | 0.4% |
Contraindications / Precautions
- Premature infants with corrected age < 5 weeks - DO NOT GIVE
- Infants weighing less than 2 kg - DO NOT GIVE
- Known hypersensitivity to propranolol or any of the excipients - DO NOT GIVE
- Asthma or history of bronchospasm - DO NOT GIVE
- Heart rate <80 beats per minute, greater than first degree heart block, or decompensated heart failure - DO NOT GIVE
- Blood pressure <50/30 mmHg - DO NOT GIVE
- Pheochromocytoma - DO NOT GIVE
- Hypoglycemia - Propranolol may inhibit the response of endogenous catecholamines to correct hypoglycemia, and it may mask the adrenergic warning signs of hypoglycemia which include tachycardia, palpitations and sweating. Propranolol can cause hypoglycemia in children, especially when they are not feeding regularly or are vomiting. Propranolol should be administered with or immediately after feeds and withheld during times of reduced oral intake. Hypoglycemia becomes more likely after ≥ 8 hours of fasting and may present in the form of seizures, lethargy, or coma.
- Bradycardia and Hypotension - Propranolol may cause or worsen bradycardia or hypotension. In IH studies, the mean decrease in heart rate was about 7 bpm with little effect on blood pressure. Monitor heart rate and blood pressure in-office for 2 hours after treatment initiation or increases in dose. Routine pretreatment ECG is not recommended, but may be useful in infants with a baseline heart rate below normal for age, infants with a family history of congenital heart conditions or arrhythmias, infants with a maternal history of connective tissue disease, and/or infants with a history of arrhythmia or when one is auscultated during examination. Discontinue treatment if severe (<80 bpm) or symptomatic bradycardia or hypotension (systolic blood pressure <50 mmHg) occurs.
- Bronchospasm - propranolol can cause bronchospasm. Do not use in patients with asthma or a history of bronchospasm. Interrupt treatment in the event of a lower respiratory tract infection associated with dyspnea and wheezing.
- Cardiac Failure - beta blockers may worsen heart failure
- Increased Risk of Stroke in PHACE Syndrome - by dropping blood pressure, propranolol may increase the risk of stroke in PHACE syndrome patients with severe cerebrovascular anomalies. Investigate infants with large facial infantile hemangioma for potential arteriopathy associated with PHACE syndrome prior to propranolol therapy.
- Hypersensitivity - beta-blockers will interfere with epinephrine used to treat serious anaphylaxis [1,3]
Timolol
Dosage forms
- Timolol comes in an ophthalmic solution and gel-forming solution. In a large retrospective cohort study that reviewed IHs treated with timolol (N=731), most infants were treated with the 0.5% gel-forming solution with instructions to apply one drop twice daily to the IH surface. Average treatment duration was 9.47 months. [2]
Efficacy
- Timolol appears to be most effective on superficial, localized IHs that are < 1 mm thick. Early timolol treatment (≤ 3 months age) may inhibit IH growth. The average expected clearance with timolol is around 62%. [1,2]
Side effects / Precautions
- Side effects are rare with topical timolol. In a large retrospective cohort study that reviewed IHs treated with timolol (N=731), 3.4% of patients reported side effects with local irritation accounting for almost half of complaints. No adverse cardiovascular events were reported and 3 patients experienced bronchospasm. No adverse events led to drug discontinuation.
- Caution should be used when treating ulcerated lesions because systemic absorption may be increased. [1,2]
Corticosteroids
Dosage forms
- Steroids may be given orally or as intralesional injections
- Prednisone and prednisolone are typically used for oral treatment with doses in the medical literature ranging from 2 - 5 mg/kg/day. Treatment regimens that have been used include treating with full dose steroids for 4 to 12 weeks followed by a gradual taper and completion of therapy by 9 to 12 months of age.
- Triamcinolone and/or betamethasone have been used for intralesional injections. Injections are typically given an average of every 4 - 6 weeks with the number of injections ranging from 1 to 7. [1]
Efficacy
- Oral steroids have an average estimated IH clearance of 43%
- Intralesional steroids have an average estimated IH clearance of 58%. The AAP recommends using intralesional steroids to treat focal, bulky IHs during proliferation or in certain critical anatomic locations (eg, the lip). Injection of larger or more extensive lesions is not recommended. [1]
Side effects / Precautions
- Side effects reported with both oral and intralesional steroids include Cushingoid appearance, infection, growth retardation, hypertension, and mood changes
- The most common side effects reported with intralesional injections include transient Cushingoid features, failure to thrive, and local skin complications (fat and/or dermal atrophy and pigmentary changes). Adrenal suppression is rare with injections, but has been reported when large doses (> 4 mg/kg)) of steroids have been administered.
- STUDIES
- A trial in the NEJM enrolled 460 infants with hemangiomas
Main inclusion criteria
- 35 - 150 days old
- Proliferating hemangioma with a minimal diameter of 1.5 cm
Main Exclusion criteria
- Life-threatening, function-threatening, or severely ulcerated hemangiomas
Baseline characteristics
- Average age 104 days
- Hemangioma location: Facial - 70% | Nonfacial - 30%
- Morphologic classification - 90% localized
Randomized treatment groups
- Group 1 (99 patients) - Propranolol 1 mg/kg/day given in 2 divided doses for 3 months
- Group 2 (103 patients) - Propranolol 1 mg/kg/day given in 2 divided doses for 6 months
- Group 3 (101 patients) - Propranolol 3 mg/kg/day given in 2 divided doses for 3 months
- Group 4 (102 patients) - Propranolol 3 mg/kg/day given in 2 divided doses for 6 months
- Group 5 (55 patients) - Placebo
- Propranolol was administered immediately before, during, or after feedings
Primary outcome: Success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment
at week 24 versus baseline according to centralized evaluation
Results
Primary outcome at 24 weeks | ||||
---|---|---|---|---|
Pro 1 mg/kg for 3 mon | Pro 1 mg/kg for 6 mon | Pro 3 mg/kg for 3 mon | Pro 3 mg/kg for 6 mon | Placebo |
8% | 49% ✝ | 12% | 60% ✝ | 4% |
Adverse events | ||
---|---|---|
Side effect | Pro 3 mg/kg for 6 mon | Placebo |
Diarrhea | 28% | 7% |
Sleep disorder | 22% | 13% |
Bronchitis | 17% | 2% |
Vomiting | 13% | 5% |
Bronchiolitis | 10% | 5% |
Cold hands and feet | 10% | 2% |
Bronchospasm | 1% | 2% |
Hypoglycemia | 1% | 0% |
Hypotension | 0% | 2% |
Bradycardia | 0% | 0% |
Findings: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma
StraightHealthcare analysis
- In this study, propranolol at a dose of 1 - 3 mg/kg/day for 6 months was clearly effective in facilitating resolution of infantile hemangiomas
- Surprisingly, propranolol did not increase the risk of significant cardiovascular events. Another study measured the effects of propranolol 2 mg/kg/day on blood pressure in infants aged 1 - 5 months (average age 2.8 months). That study also found that propranolol did not adversely affect blood pressure. [PMID 26391729]
- Propranolol did increase the risk of other adverse events including diarrhea, sleep disorder, bronchitis, and vomiting
- BIBLIOGRAPHY
- 1 - PMID 30485062 - Clinical Practice Guideline for the Management of Infantile Hemangiomas, Pediatrics (2019)
- 2 - PMID 27527799 - Topical Timolol Maleate Treatment of Infantile Hemangiomas, Pediatrics (2016)
- 3 - Hemangeol PI