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Nnenna Agim

An Update on Treatment of Infantile Hemangiomas

Nnenna Agim

Monday, September 01, 2014

Prevalence of infantile hemangiomas (IHs)

The most common benign tumor that may be found on the head or neck of a child is an IH. These vascular neoplasms are seen more often in female versus male infants, and prematurity or low birth weight (as a result of multiple gestation) are significant predisposing risk factors. Most IHs follow the course of neonatal proliferation, stabilization in late infancy and resolution over a period of years. However, a noteworthy percentage of hemangiomas occur in locations where proliferation is problematic, for example, eventuating in ulceration, structural deformity or other forms of significant morbidity.

Some IHs are associated with internal abnormalities which intensify their degree of severity. For example, the well-described PHACES syndrome features large segmental, usually telangiectatic/minimal change IHs, along with one or more systemic abnormalities: Disorders of cerebral or cervical vascular architecture, atypical cerebral configuration, cardiac structural or functional anomaly, ophthalmologic or endocrinologic dysfunction, and truncal skin or skeletal aberrations.

IHs involving facial segment 3, also known as the 'beard' area, may be accompanied by subglottic hemangiomas which threaten respiration. Periocular IHs have the potential to temporarily or permanently distort development of the visual axis, and the discomfort associated with a perioral or perineal ulcerated hemangiomas confers interminable distress to a growing infant. These complicated IHs require either medical or surgical intervention. Given that the latter option carries risk for permanent scarring, medical treatment is preferred where feasible.

 

Treatment of IH

Since the fortuitous discovery of oral propranolol for the treatment of IHs, there has been an explosion of literature describing the drug's efficacy, limitations, dosing recommendations, and alternatives. Seeing a formerly inconsolable infant with a large ulcerated IH cooing contentedly in their mother's arms 4 weeks after initiation of therapy is a blessing on both sides of the therapeutic relationship (see Figure 1 for a demonstration of propranolol's efficacy). There has been such great momentum behind this form of therapy that an FDA-approved medical indication for the drug was sought and approved in the spring of 2014.

 

Fig 1a pretreatment

Figure 1a. Female patient presenting with a large ulcerated IH pre-treatment

 

Fig 1b Posttreatment

Figure 1b. Marked improvement in IH following treatment with propranolol

 

Given the invested involvement of the group making the original discovery and a wealth of pediatric dermatology experts, the new medication, propranolol hydrochloride (4.28 mg/mL), is now available with laudable attributes. The medication does not carry the requirement for hospitalization in healthy infants, and is formulated in a vehicle which averts the noted side effects of dental caries and allergic sensitization to dyes and preservatives. It can also be readily obtained via a number routes that are convenient for the patient's parents/carer.

Given the sheer number of cases for which treatment is indicated, this formulation of the drug may allow physicians in the community to initiate treatment as early as possible, rather than waiting for a referral to a sub-specialist in a tertiary referral center, while the hemangiomas grows. We now know that proliferation begins as early as the second week of life and the major portion of growth may take place within 2-3 months. Reproducibly, in the absence of complication, IHs respond more quickly and completely to treatment initiated early in the proliferative phase, with lower risk of rebound. However, treatment for an entire year is still recommended as early withdrawal of the drug-induced growth suppression can result in the reappearance of IHs.

 

Adverse events

The side effects associated with propranolol include dental caries, hypotension, insomnia, agitation, aggravation of bronchitis/bronchospasm, gastrointestinal disturbance, dry skin, glucose abnormality, bradycardia, fatigue, and cold hands and feet. The medication is relatively contraindicated in patients with a history of asthma, PHACES, or decompensated cardiac failure. Blood pressure and heart rate monitoring are recommended upon initiation and with dose changes. In fact, a recent study of patients hospitalized for propranolol initiation showed that with frequent assessment following administration, the decreases in diastolic blood pressure and heart rate were not dramatic in most cases.

 

Alternative treatment options for IHs

Alternatives to systemic therapy with propranolol included topical administration of timolol (see Table 1 for a comparison). The 0.5% gel-forming solution may carry a lower risk of systemic absorption, and when administered as 1-2 drops twice daily, there is no requirement for systemic monitoring. Application of this beta blocker on ulcerated IHs and at mucosal sites, increases risk for access to the circulation, conferring the same risk profile as oral propranolol use. For thin or superficial IHs, the response can be quite significant, albeit at a slower rate than with oral propranolol. This medication is useful for patients in whom oral propranolol is contraindicated or cases where the IHs is less severe (see Table 2 for IH treatment indications [oral propranolol versus topical timolol]).

 

Table 1. Comparison between propranolol and timolol treatment for IHs

 

Propranolol

Timolol

How treatment is supplied

Oral solution or suspension

Solution or gel-forming solution

Frequency of administration

BID to TID

BID

Route of administration

Oral

Topical

Time to onset of action

2 weeks

12 weeks

Typical treatment duration

9-12 months

12 months+

Limitations

Monitoring at onset and dose changes

Not effective alone on exophytic or complicated IHs

Side effects

Endocrine, neurologic, cardiac and respiratory complications

On intact skin, limited to mild skin irritation

Contraindications

Severe asthma, significant cardiac abnormality, PHACES

Ulceration

BID=twice daily; IHs=infantile hemangiomas; TID=three times a day.

 

Table 2. Treatment indications for IHs

 

Oral propranolol (+/- systemic corticosteroid)

Topical timolol

Ulceration/erosion

+

-

Disfigurement (e.g. facial, diaper area/genital, female breast)

+

+

PHACES/LUMBAR

+/-

+

Rapid enlargement

+

-

Obstruction of vital structure (e.g. periocular, airway, spine)

+

-

Uncomplicated or minimally symptomatic mixed or deep IH

+

+/-

Uncomplicated or minimally symptomatic superficial IH

+

+

KEY: + (indicated); - (best avoided); +/- (applicable in select cases)

IHs=infantile hemangiomas.

 

Oral corticosteroids still have a role and are now mostly used as adjunctive therapy to quickly arrest growth or relieve compression of vital structures, such as the airway, visual axis or spinal cord. Systemic corticosteroids are also useful for IHs involving the parotid gland, as these frequently do not respond as quickly to propranolol monotherapy. A short exposure to this drug class limits the formerly frequent side effects of hyperglycemia, hypertension, susceptibility to infection, irritability, gastrointestinal discomfort and growth suppression.

Given the reported consistency of response in a majority of cases, oral and topical beta blockers are an important addition to the physician's armamentarium aimed at the treatment of IHs.

 

References

Bagazgoitia L, Torrelo A, Gutiérrez JCL, et al. Propranolol for infantile hemangiomas. Pediatr Dermatol 2011;28:108-14.

Bonifazi E, Acquafredda A, Milano A, et al. Severe hypoglycemia during successful treatment of diffuse hemangiomatosis with propranolol. Pediatr Dermatol 2010;27:195-6.

Bracken J, Robinson I, Snow A, et al. PHACE syndrome: MRI of intracerebral vascular anomalies and clinical findings in a series of 12 patients. Pediatr Radiol 2011;41:1129-38.

Breur JM, de Graaf M, Breugem CC, et al. Hypoglycemia as a result of propranolol during treatment of infantile hemangioma: A case report. Pediatr Dermatol 2011;28:169-71.

Chakkitakandiyil A, Phillips R, Frieden IJ, et al. Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangiomas: A retrospective, multicenter, cohort study. Pediatr Dermatol 2012;29:28-31.

Fabian ID, Ben-Zion I, Samuel C, et al. Reduction in astigmatism using propranolol as first-line therapy for periocular capillary hemangioma. Am J Ophthalmol 2011;151:53-8.

Frieden IJ, Drolet BA. Propranolol for infantile hemangiomas: Promise, peril, pathogenesis. Pediatr Dermatol 2009;26:642-4.

Hernandez-Martin A, Torrelo A. Cutaneous and paravertebral infantile hemangioma: Report of two cases. Pediatr Dermatol 2008;2;193-5.

Hogeling M, Adams S, Wargon O. A randomized controlled trial of propranolol for infantile hemangiomas. Pediatrics 2011;128:e259-66.

Léauté-Labrèze C. Hemangiomas of infancy: New approach to management. Presented at Society for Pediatric Dermatology Annual Meeting, 2011.

Liu LS, Sokoloff D, Antaya RJ. Twenty-four-hour hospitalization for patients initiating systemic propranolol therapy for infantile hemangiomas - is it indicated? Pediatr Dermatol 2013;30:554-60.

Moehrle M, Léauté-Labrèze C, Schmidt V, et al. Topical timolol for small hemangiomas of infancy. Pediatr Dermatol 2013;30:245-9.

Ni N, Langer P, Wagner R, et al. Topical timolol for periocular hemangioma: Report of further study. Arch Ophthalmol 2011;129:377-9.

Saint-Jean M, Léauté-Labrèze C, Mazereeuw-Hautier J; Groupe de Recherche Clinique en Dermatologie Pédiatrique. Propranolol for treatment of ulcerated infantile hemangiomas. J Am Acad Dermatol 2011;64:827-32.

Shehata N, Powell J, Dubois J. Late rebound of infantile hemangioma after cessation of oral propranolol. Pediatr Dermatol 2013;30:587-91.

Suh K-Y, Rosbe KW, Meyer AK, et al. Extensive airway hemangiomas in two patients without beard hemangiomas. Pediatr Dermatol 2011;28:347-8.

Theletsane T, Redfern A, Raynham O, et al. Life-threatening infantile hemangioma: A dramatic response to propranolol. J Eur Acad Dermatol Venerol 2009;23:1465-6.

Zvulunov A, McCuaig C, Frieden IJ, et al. Oral propranolol therapy for infantile hemangiomas beyond the proliferation phase: A multicenter retrospective study. Pediatr Dermatol 2011;28:94-8.

 

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