INFANTILE HEMANGIOMA (IH)














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 / 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]


  • Reference [1]
High-risk IH features
Feature Associated risk
"Beard-area" segmental IH
  • "Beard-area" segmental IHs involving the lower face, anterior neck, oral, and/or pharyngeal mucosa are associated with a higher risk of obstructive airway hemangiomas
≥ 5 IHs
  • May be associated with hepatic hemangiomas which can lead to high-output cardiac failure in rare cases
  • Hepatic IHs have been associated with a rare form of hypothyroidism caused by inactivation of thyroid hormones by type 3 iodothyronine deiodinase
Periocular IH (>1 cm)
  • May affect vision and vision development
IH of lip or oral cavity
  • May affect feeding
Ulcerated IH
  • Ulceration occurs in 5 - 21% of IHs. Ulceration can lead to pain, bleeding, infection, and almost always, scarring.
  • Ulceration occurs most frequently in infants < 4 months of age. Features associated with a higher risk of ulceration include superficial and mixed IHs, segmental IHs, and those involving the scalp, neck, perioral, perineal, perianal, and intertriginous areas.
Disfigurement
  • IH features associated with a greater risk of disfigurement include:
    • Segmental IH (especially face and scalp)
    • Nasal tip or lip (any size)
    • Any facial IH ≥ 2 cm (> 1 cm if ≤ 3 months of age)
    • Scalp IH > 2 cm (more prone to bleeding; may leave permanent alopecia)
    • Neck, trunk, extremity IH > 2 cm or ≥ 2 mm thickness
    • Breast IH in females (may lead to asymmetry)
Face, scalp, and neck segmental IHs
  • Associated with a higher risk of PHACE syndrome
  • PHACE syndrome is present in 30% of infants with segmental IHs of the head and neck
    • P = Posterior fossa (abnormal structures in the cerebellum)
    • H = Hemangioma
    • A = Arterial brain anomalies
    • C = Cardiac anomalies, usually the great vessels
    • E = Eye abnormalities
Lumbosacral and/or perineal segmental IHs
  • Associated with a higher risk of LUMBAR syndrome
    • L = Lower body hemangioma and other cutaneous defects
    • U = Urogenital anomalies
    • M = Myelopathy
    • B = Bone deformities
    • A = Anorectal malformations, arterial anomalies
    • R = Renal anomalies

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


AAP Imaging Recommendations for IH
Diagnosing IH
  • Do not perform imaging unless the diagnosis of IH is uncertain
  • Ultrasonography (with Doppler imaging) is the preferred imaging modality for diagnosing IH. On US, most IHs appear as well-defined masses with high-flow vascular features.
Presence of ≥ 5 IHs
  • Perform liver doppler US to screen for hepatic hemangioma
IHs associated with higher risk of PHACE syndrome (face, scalp, and neck segmental IHs)
  • Perform MRI/MRA of head and neck including aortic arch
  • Perform Echocardiography
IHs associated with higher risk of LUMBAR syndrome (lumbosacral and/or perineal segmental IHs)
  • Spinal US (for those with a corrected age of < 6 months) and doppler US of the abdomen and pelvis may be used as an initial screening test
  • MRI is likely to be required, especially if there is high suspicion of underlying abnormalities [1]




  • Reference [1]
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

  • Data from the Hemangeol PI
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%
Precautions / Contraindications
  • 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 form and dosing
  • 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 form and dosing
  • 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.


Propranolol vs Placebo for Infantile Hemangioma, NEJM (2015) [PubMed abstract]
  • 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

  • † p<0.001 vs placebo
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%

Beta blocker associated adverse events
Side effect Pro 3 mg/kg for 6 mon Placebo
Hypotension 0% 2%
Bronchospasm 1% 2%
Bradycardia 0% 0%
Hypoglycemia 1% 0%
Other adverse events
Diarrhea 28% 7%
Sleep disorder 22% 13%
Bronchitis 17% 2%
Vomiting 13% 5%
Bronchiolitis 10% 5%
Cold hands and feet 10% 2%

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