Editorials Propranolol treatment for periocular capillary hemangiomas Oscar A. Cruz, MD,a,b and Elaine C. Siegfried, MDb,c
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n this issue of the Journal of AAPOS, Haider and colleagues1 reviewed the records of 17 patients administered oral propranolol for the treatment of amblyogenic capillary hemangiomas of the eyelid. Reports of first-line treatment of hemangiomas of infancy have multiplied since the initial report of a small case series of infants who demonstrated a dramatic improvement after treatment with oral propranolol.2 Ironically, propranolol therapy was discovered in that case series because the corticosteroids used to treat large hemangiomas led to cardiac disease, which then created the need for propranolol therapy, which in turn led to regression of the otherwise nonresponsive hemangiomas. As the authors note, a standard of care has not been established for treatment of vision-threatening hemangiomas. A variety of corticosteroid preparations, administered by a variety of routes (topical, injected, or parenteral), have all been considered first-line options. Although corticosteroids can be effective, the optimal molecule, formulation, and dosage has not been defined. Responses are variable, corticosteroids are not well tolerated, and side effects are common. Other medications that have been used to treat hemangiomas—including interferon alpha, cyclophosphamide, and vincristine—carry an even greater risk of adverse effects. When considering any medical treatment, an important confounding variable is timing. Early initiation of treatment may be much more effective to prevent growth than delayed treatment to promote shrinking. Pediatric ophthalmologists who do not participate with or have access to a multidisciplinary, subspecialty service (such as a ‘‘vascular anomalies team’’) should be familiar with initiating treatment, to avoid delay and risk hemangioma growth, even if the long-term plan is to refer these patients to another provider for medical management. The treatment regimen prescribed by Haider and colleagues appears appropriately conservative, slowly inSee accompanying report on pages 251-6. Author affiliations: aDepartment of Ophthalmology; bDepartment of Pediatrics; and Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, Missouri Submitted May 18, 2010. Revision accepted May 19, 2010. Reprint requests: Oscar A Cruz, MD, Department of Ophthalmology, Saint Louis University School of Medicine, 1755 South Grand, Saint Louis, MO 63104 (email:
[email protected]). J AAPOS 2010;14:199-200. Copyright Ó 2010 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2010/$36.00 1 0 doi:10.1016/j.jaapos.2010.05.003 c
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creasing steroid dosing to minimize potential complications. Nonetheless, nearly one-fourth of the patients had problems with medication adherence. Although compliance with recommended treatment by patients is a common, pervasive problem,3 the potential for serious adverse effects mandates better education and vigilance on the part of the prescribing physician. The most common serious adverse effects of propranolol are bradycardia, hypertension, and hypoglycemia. An important confounding safety issue is that propranolol may blunt the early clinical symptoms of these potentially serious side effects. Because hypoglycemia tends to occur in the first few hours after the administration of propranolol, feeding immediately after dosing and regularly every 4 to 6 hours may minimize the risk. Although the pharmacologically optimal dosing interval for propranolol is every 6 hours, compliance is improved if the medication is given every 8 to 12 hours.4 The authors make no attempt to elucidate a possible mechanism for propranolol’s effects in shrinking hemangiomas of infancy. The effect of propranolol on placenta has been demonstrated when used to treat preeclampsia.5 Perhaps beta-blockers induce apoptosis by antagonizing Glut-1 receptors or act through other pathways to inhibit growth of the hemangiomas. Topical propranolol has also been shown to reduce oxygen-induced retinopathy in a newborn rat, perhaps through down-regulation of vascular endothelial growth factor.6 The results described in this article, although laudable, merit additional scrutiny. Any reduction in the size of a hemangioma greater than 50% was classified as an ‘‘excellent result,’’ which makes it impossible to discern how many of those patients had complete or near complete resolution. In addition, the article does not attempt to define care standards, and so clinicians must carefully consider when to initiate therapy, assess efficacy, adjust dosage, and taper or discontinue the medication on an individual basis until such a standard is defined.4,7 The treatment protocol described by Haider and colleagues may not be the best approach for all patients. Eyelid hemangiomas may be equally responsive to topical, rather than systemic, beta-blocker therapy. This theoretically safer route of administration has recently been reported with the use of timolol, a selective beta-blocker formulated as an eyedrop for the treatment of glaucoma. Several studies have now documented the efficacy of topical timolol for superficial and eyelid hemangiomas.8-10 We are also aware of an international, multicenter, prospective, randomized, double-masked trial currently underway that
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will compare a combined regimen of oral propranolol and corticosteroids with corticosteroids alone.11 The authors are commended for proposing a uniform outpatient beta-blocker treatment regimen that maximizes the therapeutic outcome while addressing the common known side-effects of therapy in children. As this therapy continues to evolve, we anticipate that it will provide us with a solution to the clinical imperative of a visionthreatening periocular hemangioma. References 1. Haider KM, Plager DA, Neely DE, Eikenberry J, Haggstrom A. Outpatient treatment of periocular capillary hemangiomas with propranolol. J AAPOS 2010;251-6. 2. Leaute-Labreze C, Dumas de la Roque E, Hubiche F, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649-51. 3. Cutler DM, Everett W. Thinking outside the pillbox—medication adherence as a priority for health care reform. N Engl J Med 2010; 362:1553-5.
Volume 14 Number 3 / June 2010 4. Lawley LP, Siegfried E, Todd JL. Propranolol treatment for hemangioma of infancy: Risks and recommendations. Pediatr Dermatol 2009;26:610-14. 5. Rouget C, Barthez O, Goirand F, et al. Stimulation of the ADRB3 Adrenergic receptor induces relaxation of human placental arteries: Influence of pre-eclampsia. Biol Reprod 2006;74:209-16. 6. Ricci B, Ricci F, Maggiano N. Oxygen-induced retinopathy in the newborn rat: Morphological and immunohistological findings in animals treated with topical timolol maleate. Ophthalmologica 2000;214:136-9. 7. Frieden IJ, Drolet BA. Propranolol for infantile hemangiomas: Promise, peril, pathogenesis. Pediatr Dermatol 2009;26:642-4. 8. Chakkittakandiyil A, Pope E. Topical timolol gel for infantile hemangiomas—a pilot study. Arch Dermatol 2010;146:564-5. 9. Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol 2010;128:225. 10. Frieden IJ. Early laser treatment of periorbital infantile hemangiomas may work, but is it really the best treatment option? Dermatol Surg 2010;36:598-601. 11. Corticosteroids With Placebo Versus Corticosteroids With Propranolol Treatment of Infantile Hemangiomas (IH). Available at: http:// clinicaltrials.gov/ct2/show/NCT01074437?term5propranolol &rank54. Accessed May 16, 2010.
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