eMedicine Specialties > Dermatology > Diseases of the Vessels

Infantile Hemangioma: Treatment & Medication

Author: Richard J Antaya, MD, Director of Pediatric Dermatology, Associate Professor, Departments of Dermatology and Pediatrics, Yale University
Contributor Information and Disclosures

Updated: Aug 18, 2009

Treatment

Medical Care

The vast majority of infantile hemangiomas do not require any medical or surgical intervention.33 Medical care of clinically significant hemangiomas has been limited to a few medications, including glucocorticosteroids (topical, intralesional, and oral), interferon alfa, and, rarely, vincristine and topical imiquimod.34   Beta-blockers, most specifically propranolol, have serendipitously been shown to induce involution of infantile hemangiomas and are beginning to be used in clinical practice at the time of this writing.35 36 The individual therapies are discussed in detail under Medication. Also see Further Reading for a partial listing of clinical trials that are currently recruiting.

Surgical Care

Laser surgery is beneficial in treating both proliferating and residual vessels from hemangiomas. The flashlamp-pumped pulsed-dye laser has become the most widely used laser for selective ablation of vascular tissue in childhood.  

  • Pulsed-dye laser surgery is effective for treating ulcerated hemangiomas and thin superficial hemangiomas, especially those on areas likely to result in significant functional or psychological impact (eg, fingers, eyes, lips, nasal tip, ears, face).37,38 Many ulcerated hemangiomas respond with decreased pain (sometimes as early as a few days after the initial treatment), rapid reepithelialization, and hastened involution.
    • Treatments generally are performed every 2-4 weeks until complete healing results. Occasionally, particularly with deep or combined superficial and deep lesions, ulceration may worsen with pulsed-dye laser treatment.39
    • The risk of scarring or residual skin changes associated with pulsed-dye laser surgery of hemangiomas may be greater than without early laser treatment or with the treatment of capillary malformations (port wine stains), but the benefits of early involution should be weighed against the risks of a passive approach or alternative therapies.40,41
  • Other lasers that appear to be efficacious in treating hemangiomas include the pulsed Nd:YAG, frequency-doubled Nd:YAG, and KTP lasers. Carbon dioxide lasers are occasionally used for airway hemangiomas.42 Each of these lasers has specific benefits and limitations regarding depth of penetration, absorption of skin chromophores, and caliber of the vessel treated. Complications also vary depending on the laser, settings, and site treated.43
  • See Laser Treatment of Acquired and Congenital Vascular Lesions for a detailed discussion.

Surgical excision of involuted hemangiomas is not uncommon because of the cutaneous defects resulting from them.44 Atrophic and hypertrophic scars, as well as anetodermic and tumoral fibro-fatty skin, may result in significant cosmetic or functional impairment. The benefits of excision during late involution include a reduced risk of hemorrhage and a potentially smaller lesion because of the natural course. In addition, because involuted hemangiomas are composed primarily of fibro-fatty tissue, complete removal of all tissue is unnecessary, while removing too much tissue could detract from proper contours.

Surgical excision of proliferating hemangiomas is potentially hazardous because of the risk of hemorrhage and damage to vital structures associated with them (ie, head, neck); therefore, only specially trained surgeons should perform this procedure. Certain benefits to early excision include saving a life or preserving vision and decreasing the negative psychosocial effects associated with a cosmetically disfiguring lesion during early childhood. Other benefits of early excision include the use of naturally expanded skin to aid in primary closure and the ability to use a relatively avascular tissue plane surrounding actively growing hemangiomas. New advancements in surgical instruments that cauterize while cutting lessen the risk of hemorrhage.

Consultations

  • An ophthalmologist or a pediatric ophthalmologist should evaluate children with periorbital hemangiomas, particularly with involvement of the upper eyelid. Refraction with retinoscopy is performed to evaluate for visual disturbances, particularly astigmatism, and to prevent visual deprivation amblyopia. Also see Hemangioma, Capillary in the eMedicine Ophthalmology section.
  • Infants with rapidly growing hemangiomas that are impinging on vital structures of the head and neck, particularly the airway or auditory canals, should be referred to an otolaryngologist or a pediatric otolaryngologist for evaluation and treatment. Infants with large V3 dermatomal hemangiomas (beard area hemangiomas) have a higher incidence of upper airway hemangiomas, and early consultation for mild signs or symptoms (noisy breathing or stridor) may prevent possible future complications.
  • Consultation with a plastic surgeon is indicated for symptomatic involuting or proliferating lesions that are unresponsive to medical therapy and for which surgical excision is being contemplated.
  • The presence of an infantile hemangioma over the midline lumbar back may be a cutaneous sign of an underlying occult spinal dysraphism, such as a tethered cord. MRI or ultrasonography if the infant is younger than 5 months is indicated for midline hemangiomas, especially if any other signs of spinal dysraphism (eg, deviated gluteal cleft, atypical sacral dimple, tuft of hair, tail) are present. MRI is the more sensitive study, even in infancy, and should be considered when clinical suspicion is high. Consultation with a pediatric neurosurgeon should be sought for any questionable or worrisome lesions.

Medication

The goals of pharmacotherapy for infantile hemangiomas are to reduce morbidity and mortality and to prevent complications. Note that none of the treatments is approved for treatment of infantile hemangiomas by the US Food and Drug Administration, and all therapies should be considered off-label usage.

Corticosteroids

Oral and intralesional corticosteroids are effective at slowing the growth and decreasing the size of proliferating infantile hemangiomas. The mechanism of action has not been elucidated completely; however, corticosteroids appear to act by potentiating vasoconstrictive effects of epinephrine and norepinephrine on vascular smooth muscle. Evidence indicates that corticosteroids block estradiol receptors in hemangiomas in vitro. Response vary widely, from less than 40% to greater than 90%, depending on dose, duration of treatment, and age at which corticosteroid therapy is initiated.45 Corticosteroid therapy should be administered during the proliferative phase because it has a negligible effect on involuting and otherwise stable infantile hemangiomas. The oral route generally is preferred over intralesional therapy; however, the location, size, patient age, and physician experience factor into the decision-making process.


Prednisolone (Prelone Syrup, Pediapred Oral Solution, Delta-Cortef, OraPred)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.

Adult

Pediatric

2-5 mg/kg/d PO initially; reassess at approximately 1-2 wk; if no response at sufficiently high dose, discontinue; if desired effect achieved, continue dose for 2-4 wk and taper slowly for 2-6 mo

Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects of corticosteroids; check antibody levels of routine immunizations given to infants during course of oral glucocorticosteroids (approximately 15% will have insufficient levels and require booster immunizations)

Documented hypersensitivity; viral, fungal, or tubercular skin lesions; infants with concurrent infection; underlying malignancy

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in hyperthyroidism, osteoporosis, cirrhosis, nonspecific ulcerative colitis, peptic ulcer, diabetes, and myasthenia gravis; adverse effects of systemic corticosteroids include behavioral disturbances (irritability, increased appetite, sleep disturbance), Cushing syndrome (from adrenal suppression with associated cutaneous features), growth retardation, gastroesophageal reflux, peptic irritation, possible ulceration, fluid, and electrolyte disturbances, hyperglycemia, hypertension, osteoporosis, and immune suppression; rare cases of Pneumocystis carinii pneumonia reported in infants being treated with oral glucocorticosteroids for infantile hemangiomas; most infants tolerate therapy well, but close monitoring is required and parental education regarding possible adverse effects is essential

Beta-adrenergic blocker

Beta-blockers, most specifically propranolol, have been in use since mid 2008 for infants with severe or disfiguring hemangiomas. Only a few reports are published in the literature.35,46 Most infants reported have been treated with propranolol at a dose of 2-3 mg/kg/d in 2-3 divided doses. Duration of therapy varies from 2-10 months. As early as 24 hours after the initiation of therapy, many infantile hemangiomas have begun to change from intense red to purple, with evidence of softening. Most continue to improve until nearly flat and with significantly diminished color.

The mechanism of action is unknown; however, some hypothesize that local vasoconstriction may be a factor, which is based on the early color change and softening of the lesion. One study has demonstrated that nonspecific and beta2-selective blockers (eg, propranolol) triggered apoptosis of capillary endothelial cells in adult rat lung tissue, suggesting a similar mechanism may be plausible for hemangioma endothelial cells.47
 
No protocol for initiating propranolol therapy in infants with hemangiomas is universally accepted. Therapy should be approached with extreme caution in neonates and infants who generally do not have preexisting venous hypertension or any other hemodynamic disorder. Of particular note, infants with hemangiomas associated with PHACES syndrome are at higher risk for cerebral vascular accidents secondary to cerebral vascular anomalies, and these infants should not receive beta-blockers.

Provisional guidelines for initiation may include the following:

  • Pretreatment
    • Exclude infants with evidence of the following:
      • Bronchospasm
      • Cardiac disease
      • CNS vascular anomalies (suspected PHACES syndrome, large cervicofacial hemangiomas [see Mortality/Morbidity for PHACES syndrome definition])
    • Baseline laboratory tests and evaluation include the following:
      • Blood glucose level
      • Blood pressure check
      • Electrocardiography
      • Echocardiogram (if considering PHACES syndrome or other clinical indications)
      • Pediatric cardiology consultation for evaluation and dosing recommendations
  • Dosing - See below
  • Monitoring
    • Initially in the hospital (whether in or out of intensive care unit, cardiac care unit, or monitored bed), monitor for 24-72 hours; practices vary considerably.
    • Monitoring 1 hour after administration (dosing) includes the following:
      • Blood pressure check
      • Heart rate check (hold dose for heart rate at <100 beats per min)
      • Blood glucose level
      • Temperature determination to evaluate for hypothermia
      • Observation for bronchospasm
    • At home, parents should observe for signs of lethargy, poor feeding, and/or bronchospasm.
    • Blood pressure and heart rate should be evaluated intermittently at the pediatrician's office.


Propranolol ( Inderal, InnoPran XL)

Propranolol hydrochloride is a synthetic nonselective beta-adrenergic receptor blocking agent. Generic is available as 10-, 20-, 40-, 60-, and 80-mg tab and as 60-, 80-, 120-, and 180-mg extended-release tab. Inderal is available as 10-, 20-, 40-, 60-, and 80-mg tab for PO administration. InnoPran XL is available as 80- and 120-mg extended-release tab. No commercially available liquid formulation is available for use in children and must be formulated by a qualified pharmacist. Indicated for hypertension and a variety of other cardiac conditions (angina) and migraine headache prophylaxis.

Adult

Not applicable

Pediatric

Initial dose: 0.5 mg/kg/d divided bid; increase to 2 mg/kg/d divided bid over 1 day to 3 weeks

Contraindicated to use with thioridazine
Avoid use with central alpha2 agonists, cimetidine, topical cocaine, COX-2 inhibitors, fenoldopam, hydrocodone/ibuprofen, ibuprofen/oxycodone, insulin, lansoprazole/naproxen, and NSAIDs
Caution with alpha2 agonists, amifostine, amiodarone, amitriptyline/perphenazine, aspirin/dipyridamole, aspirin/opiate combinations, atazanavir, other beta-blockers, bupropion, calcium channel blockers, chlorpheniramine/dextromethorphan/phenylephrine, chlorpromazine, cinacalcet, dexmedetomidine, diazoxide, digoxin, disopyramide, hydralazine, isosorbide dinitrate, hypoglycemics, imatinib, thiazolidinediones, warfarin, and zileuton

Contraindicated in infants who present with bronchospasm, cardiac disease, CNS vascular anomalies (eg PHACES syndrome), hypotension, bradycardia, significant congenital cardiac anomalies, and history of hypoglycemia

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adverse effects (as reported mainly in adults)
Cardiovascular: Bradycardia (occasionally severe and may be accompanied by hypotension, syncope, shock, or angina), hypotension
Endocrine: Hypoglycemia and/or masking signs and symptoms of hypoglycemia (one study in adults aged 45-64 y demonstrated an increased risk [about 28%] of developing type 2 diabetes mellitus
CNS: Usually after long-term treatment with high doses includes lightheadedness, ataxia, dizziness, irritability, sleepiness, hearing loss, visual disturbances, hallucinations, confusion, insomnia, weakness, fatigue, and mental depression
GI: nausea, vomiting, diarrhea, epigastric distress, abdominal cramping, constipation, and flatulence

Interferons

Initially used as an antiviral agent in HIV-infected patients, interferon alfa-2a was found to induce regression of Kaposi sarcoma. This led to its use in treating other vascular lesions (eg, hemangiomas). Interferon alfa inhibits endothelial cell migration and proliferation and specific growth factors (eg, endothelial growth factor, fibroblast growth factor). Numerous studies have demonstrated the efficacy of interferon alfa-2a and interferon alfa-2b in treating infantile hemangiomas.48,49

Because interferon alfa-2a works by a different mechanism, it can be used in lesions that are unresponsive to steroids.50 In fact, unlike steroids, it does not require that administration occur during the proliferation phase to be effective. The onset of action is slower than that of corticosteroids, usually requiring several weeks; this makes it less attractive for use in acute life- or sight-threatening situations. Interferon alfa-2a should be used only if steroid, beta-blocker, and other potentially toxic therapies fail.
 
The most significant adverse event limiting its use in hemangiomas is potentially irreversible spastic diplegia; while most infants have displayed significant recovery of spasticity of lower extremities, it appeared permanent in other infants.51,52 A meta-analysis of interferon use in children revealed all cases of neurological dysfunction occurred when interferon was used prior to the patient’s first birthday.53


Interferon alfa-2a (Roferon-A)

Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. May be given topically, systemically, and intralesionally.

Adult

Pediatric

3 million U/m2 SC qd for 6 mo or longer; if desired effect not observed after 1 mo, discontinue; if desired effect achieved, continue until proliferation phase has passed or drug is no longer indicated

Theophylline may increase toxicity of by reducing clearance; cimetidine may increase antitumor effects of interferon alfa; zidovudine and vinblastine may increase toxicity

Documented hypersensitivity; avoid in patients who have anaphylactic sensitivity to mouse immunoglobulin, egg protein, or neomycin; autoimmune hepatitis

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Etiology of spastic diplegia is currently unknown but infants <1 y appear to have an increased risk; infants should receive baseline, monthly, and post-therapy neurological and developmental evaluations when receiving interferon alfa-2a; all infants experience low-grade febrile reactions, especially at onset of therapy; some infants may develop transient neutropenia, anemia, elevated LFT results, or possibly thyroid dysfunction (hypothyroidism); baseline and monthly blood cell counts and LFTs recommended


Interferon alfa-2b (Intron A)

Protein product manufactured by recombinant DNA technology. Indications to treat adult hairy cell leukemia, malignant melanoma, condyloma acuminata, AIDS-related Kaposi sarcoma, and certain forms of chronic viral hepatitis. Has also used to treat children with these conditions and, most recently, infants with life-threatening hemangiomas.

Adult

Pediatric

Life-threatening infantile hemangiomas: 3 million U/m2 SC qd for 2.5-24 mo, if able; then decrease frequency to q48-72h after positive effect noted

Potential risk of renal failure when administered concurrently with interleukin 2; theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects of interferon alfa; zidovudine and vinblastine may increase toxicity

Documented hypersensitivity; patients who have anaphylactic sensitivity to mouse immunoglobulin, egg protein, or neomycin; autoimmune hepatitis

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Toxicity is common in infants; most adverse effects are mild and transient; flulike symptoms are most common, followed by mild anemia, neutropenia, elevation of liver enzyme levels, and mild-to-moderate neurologic toxicity; to date, only 1 of 60 infants reportedly developed permanent spastic diplegia when used for infantile hemangiomas; because this form of interferon is used less commonly, true incidence of spastic diplegia may be underestimated; etiology for this adverse effect is currently unknown; infants should receive baseline, monthly, and post-therapy neurological and developmental evaluations; baseline and monthly cell blood counts and LFTs recommended

Biologic immune response modifiers

Only a few case reports and one small open-label uncontrolled trial suggest efficacy for the treatment of infantile hemangiomas.54,55 This treatment should be considered experimental until placebo-controlled trials are performed and therapy is determined safe for infants. Imiquimod cream is the only medication in this new class. It purportedly works by stimulation of toll-like receptor 7 (TLR-7) and increases local interferon alpha and gamma, through which it may exert antiangiogenic effects. In a mouse model, imiquimod-treated vascular tumors showed decreased tumor cell proliferation, increased tumor apoptosis, and increased expression of tissue inhibitor of matrix metalloproteinase-1, with decreased activity of matrix metalloproteinase-9, both of which are observed in the natural involution of infantile hemangiomas.


Imiquimod 5% cream (Aldara cream)

Immune response modifier indicated for treatment of condyloma acuminata, actinic keratoses, and superficial basal cell carcinoma in adults. Not approved by FDA for use in children.

Adult

Apply small amount topically hs (thrice weekly), usually Monday, Wednesday, and Friday, to affected area

Pediatric

Administer as in adults

Documented hypersensitivity to imiquimod or any of its excipients; avoid lesions involving eyelids or mucous membranes

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Local skin reactions (eg, erythema, erosions, excoriation, flaking, edema) are common; ulceration has complicated its use in some reports when used to treat hemangiomas; because of this, use with extreme caution in infants


Becaplermin 0.01% gel (Regranex Gel)

A few reports in the literature (Metz, 2004) suggest this is helpful for ulcerated infantile hemangiomas, especially those in the diaper area. Data limited and no placebo-controlled trial published to date. Seven infants with refractory ulcerated infantile hemangiomas experienced healing 3-21 d after initiating therapy.

Adult

Pediatric

Not established; case series (Metz, 2004) reported application to ulcer qd to twice weekly

Documented hypersensitivity to drug or component of formulation; neoplasm at site of application; active infection at ulcer site

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

For external use only; caution if concurrently using corticosteroids, cancer chemotherapy, other immunosuppressive agents

More on Infantile Hemangioma

Overview: Infantile Hemangioma
Differential Diagnoses & Workup: Infantile Hemangioma
Treatment & Medication: Infantile Hemangioma
Follow-up: Infantile Hemangioma
Multimedia: Infantile Hemangioma
References
Further Reading
[ CLOSE WINDOW ]

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Keywords

infantile hemangiomas, hemangioma of infancy, hemangioma, superficial hemangioma, deep hemangioma, compound hemangioma, strawberry mark, angioma, cavernous hemangioma, capillary hemangioma

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Contributor Information and Disclosures

Author

Richard J Antaya, MD, Director of Pediatric Dermatology, Associate Professor, Departments of Dermatology and Pediatrics, Yale University
Richard J Antaya, MD is a member of the following medical societies: American Academy of Dermatology, American Academy of Pediatrics, and Society for Pediatric Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Jean Paul Ortonne, MD, Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France
Jean Paul Ortonne, MD is a member of the following medical societies: American Academy of Dermatology and American Dermatological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas Health Science Center
Van Perry, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Laser Medicine and Surgery
Disclosure: Nothing to disclose.

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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