Topical propranolol cream in treatment of superficial infantile hemangiomas: a literature review and 4 years of clinical experience.
Infantile hemangiomas (IHs), the most common soft-tissue tumors in children with occurrence rates of 8.7 to 12.7%, present in up to 60% of cases on the head and neck region (1). Lesions occur more frequently in premature infants, females, multiple births, with advanced maternal age, and in Caucasians (2, 3). Classification of hemangiomas is based on the layer of skin they affect: superficial or capillary type, deep or cavernous type, and mixed type. Superficial hemangiomas involve the superficial dermis and present as red vascular plaques or nodules. Clinical findings of deep hemangiomas include partially compressible, bluish vascular swellings that involve the deep dermis and subcutis (4). Superficial and deep components are present in mixed hemangiomas. Based on their skin distribution, IHs can also be classified into localized, segmental, indeterminate, and multifocal (5). Localized hemangiomas are restricted to one area, whereas segmental hemangiomas include clusters of lesions that cover a large anatomical area. Multifocal hemangiomas include five or more noncontiguous lesions, often associated with systemic involvement, especially the liver (4).
Infantile hemangiomas appear promptly after birth and pass through two consecutive phases: a proliferative phase, which is most intense in the first 4 to 6 months of life and may last up to 18 months, and an involutional phase (6). Although approximately 90% of lesions involute by age 9, incomplete regression is seen in most cases with telangiectatic cutaneous vessels, fibrous fatty tissue, and scar formations (7-10). The rationale for therapy lies in the fact that the prognostic factors for infantile hemangiomas have not yet been elucidated. Development of complications such as visual axis occlusion, airway involvement, ulceration, or permanent disfigurement is related to the anatomical localization of lesions (5). Consequences of uncomplicated infantile hemangiomas include scarring, disfigurement, or minor functional impairment, which could all have psychosocial consequences on children's lives (11).
For more than 40 years, various forms of corticosteroids, including topical, intralesional, and systemic administration, have been the first-line treatment for IHs (12, 13). Pharmacotherapy (corticosteroids, IFN-a, vincristine), cryotherapy, surgery, and laser treatment were standard therapeutic approaches in treating infantile hemangiomas until 2008, when Leaute-Labreze et al. reported on the clinical efficacy of systemic propranolol in the treatment of infantile capillary hemangiomas (14). After this incidental discovery, the efficacy and safety of nonselective p-blockers as a therapeutic option for IHs became subjects of numerous studies worldwide, and within the last few years perorally administered propranolol became the gold standard in treatment of IH of all localizations (11, 15, 16). Advantages of systemic propranolol therapy are rapid onset of action, with good drug tolerability regardless of sex and age at onset of treatment, type of involvement, ulceration, or depth (17-20). Although the complete mechanism of the action of propranolol is not completely understood, explanations lie in possible mechanisms of influence on target endothelial cells: vasoconstriction, inhibition of angiogenesis or vasculogenesis, and induction of apoptosis (21). Vasoconstriction, a consequence of reduction in nitrogen oxide (NO) release, causes the tumor color to fade and the lesion to soften. Propranolol inhibits angiogenesis by down-regulating the RAF mitotic original for activating the protein kinase pathway that leads to decreased expression of VEGF and bFGF, responsible for halting tumor growth. Beta blockers reduce tumor growth by inducing apoptosis in endothelial cells and also by decreasing migration of endothelial progenitor cells (22, 23). Itinteang et al. suggested that blockade of p-receptors may affect tumor involution through regulation of the renin-angiotensin pathway (24). Nevertheless, systemic use of propranolol may have side effects such as hypotension, bronchospasm, bradycardia, hypoglycemia, acrocyanosis, gastrointestinal and sleep disturbances, and respiratory infections (25). Because of the possible side effects of systemic propranolol treatment as therapy for IHs, and the intention to adjust this "miracle" therapeutic option for strictly dermatological use, the idea arose to use topical p-blockers for IHs therapy, especially superficial capillary type IHs (26). The idea for topical treatment of superficial hemangiomas is based on the need to deliver high concentrations of drugs directly to target skin tissues and avoid undesirable systemic effects. Guo and Ni first applied 0.5% topical timolol solution as a treatment for superficial capillary hemangioma of the eyelid in a 4-month-old infant with very successful results (26). After this report, various studies reported high efficacy of topical timolol gel and solution in treatment of superficial infantile hemangiomas on various anatomical localizations (27-36). Topical propranolol therapy for superficial IHs in concentrations of 1% to 3% has recently been suggested (8, 17, 21, 37). Xu et al. applied 1% propranolol ointment three times a day on 28 lesions in children up to 10 months old; good or partial response was observed in 90% of IHs without side effects (8). Kunzi-Rapp treated 45 children (from preterm infants to 33 months old) with 65 IH with 1% propranolol ointment twice daily (17). The best outcome was observed when topical propranolol was administered in the first 6 months of life, with regression in 59% and growth cessation in 26% of the hemangiomas. Good therapeutic response was also observed in patients 7 to 33 months old with improvement in all cases. No side effects were noticed regardless of age and lesion size (17). Wang et al. applied 3% propranolol gel three times a day in 28 patients 28 days to 12 months old with superficial IHs. Reduction in size from 50% to more than 75% was observed in 20 patients (21). Niu et al. treated 49 children 1 to 10 months old with 58 superficial IHs with 1% propranolol ointment; 53.1% showed good response and 34.7% partial response (37). Mouhari-Toure et al. reported successful treatment of two superficial IHs in an 11-week-old infant with 2% propranolol ointment; rapid regression was observed on the 45th day of treatment with 75% reduction of the lesions (38). These excellent results encouraged us to estimate the clinical efficacy and safety of 1% propranolol cream in treatment of superficial infantile hemangiomas in our study group.
Patients and methods
Diagnosis of the superficial type of hemangioma was made using Waner and Suen's 1999 classification (39). The locations, sizes, and colors of the lesions were documented with clinical photographs. The thickness of the lesions was measured by ultrasound examination. Possible contraindications for applying topical propranolol were excluded by monitoring the heart rate, blood pressure, and blood glucose. Patients 3 to 12 months old without previous treatment interventions were included in this study. Eight patients (five males, three females) with eight superficial hemangiomas were treated with 1% propranolol cream at our outpatient clinic from 2011 to 2014. Propranolol cream was manufactured in collaborative pharmacy practice at a 1% concentration of propranolol-hydrochloride in a hydrophilic cream. Parents received instructions for applying the cream: twice daily in a thin layer on the surface of the hemangioma. Localization of hemangiomas included the forehead, posterior side of the neck, forearm, abdomen, and posterior side of the trunk. Size, texture, and color changes of the IHs were regularly monitored and photographed at intervals of 1 to 2 months. The therapeutic efficacy was evaluated using the Archauer system: Grade I (bad) reduction in size < 25%; Grade II (medium) reduction between 26% and 50%; Grade III (good) reduction between 51% and 75%; Grade IV (excellent) reduction > 75% (40).
Duration of treatment was 10 months. A clinical evaluation and photographic documentation were performed every 1 to 2 months. The outcome of the therapy was evaluated using the Archauer system (40) (Table 1).
Of the eight patients with eight IHs, five treated hemangiomas (62.5%) achieved a Grade IV success rate with a reduction in the size of the lesion of > 75% after 7 to 10 months of therapy (Figures 1-5). Improvement between 51 and 75% (Grade III) was observed in one patient with an IH lesion on the posterior side of the neck after 10 months of treatment. Lesions on the abdomen showed a reduction in size between 26 and 50% (Grade II).
Topical propranolol 1% cream was well tolerated, without noticeable side effects (hypotension, bronchospasm, bradycardia, hypoglycemia, acrocyanosis, gastrointestinal and sleep disturbances, or respiratory infections) in any patient.
Topical potent corticosteroids and topical imiquimod as part of treatment of IHs have been in use for several years with variable efficacy and several side effects (41-46). Atrophy of the epidermis and hyper-pigmentation are common side effects in corticosteroid therapy, whereas undesirable effects of topical imiquimod treatment usually present as ulceration and crusting (41-46). Side effects of effective treatment for IHs with perorally administered propranolol occur in high incidence due to its variable absorption profiles (17). Topical [beta]-blockers accumulate in the skin in concentrations between 10.4% and 36.6% with minimal systemic penetration (4.1-16.1%) and consequently obtain high efficacy in treatment of IHs without side effects of systemic administration of the drug (47). Our preliminary study suggests that 1% topical propranolol appears to be safe and effective for treatment of superficial IHs. Further studies are needed to determine the exact concentration of propranolol in the formulation, optimal duration of treatment, and possible inclusion of other [beta]-adrenergic receptor antagonists in the treatment of superficial IHs.
Received: 13 October 2014 | Returned for modification: 28 October 2014 | Accepted: 10 November 2014
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Maja Kovacevic  ([mail]), Vesna Lukinovic Skudar , Goran Maricic , Gordana Krnjevic-Pezic , Andrija Stanimirovic 
 Croatian Vitiligo Association, Zagreb, Croatia.  School of Medicine, University of Zagreb, Zagreb, Croatia.  Naftalan Special Hospital for Medical Rehabilitation, Ivanic Grad, Croatia.  Department of Clinical Medicine, University of Applied Health Sciences, Zagreb, Croatia. ([mail]) Corresponding author: firstname.lastname@example.org
Table 1 | Efficacy of 1% propranolol cream in different anatomical localizations of superficial infantile hemangiomas. Grade I: Grade II: Localization of Number improvement improvement superficial IHs of IHs < 25% (%) 26-50% (%) Forehead 1 -- -- Posterior side of the neck 2 -- -- Forearm 1 -- -- Abdomen 2 -- 2 (25%) Posterior side of trunk 2 -- -- TOTAL 8 0 2 (25%) Grade III: Grade IV: Localization of Number improvement improvement superficial IHs of IHs 51-75% (%) > 75% (%) Forehead 1 -- 1 (12.5%) Posterior side of the neck 2 1 (12.5%) 1 (12.5%) Forearm 1 -- 1 (12.5%) Abdomen 2 -- -- Posterior side of trunk 2 -- 2 (25%) TOTAL 8 1 (12.5%) 5 (62.5%)
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|Author:||Kovacevic, Maja; Skudar, Vesna Lukinovic; Maricic, Goran; Krnjevic-Pezic, Gordana; Stanimirovic, And|
|Publication:||Acta Dermatovenerologica Alpina, Pannonica et Adriatica|
|Date:||Oct 1, 2014|
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