|Year : 2017 | Volume
| Issue : 2 | Page : 77-80
Successful use of propranolol in infantile hemangiomas
Rajendra Saoji1, Manasi Shirolikar2
1 Consultant Paediatric Surgeon, Midas Heights, Ramdaspeth, Nagpur, Maharashtra, India
2 Department of Dermatology, NKP Salve Institute of Medical Sciences, Lata Mangeshkar Hospital, Nagpur, Maharashtra, India
|Date of Web Publication||28-Dec-2017|
Dr. Rajendra Saoji
Consultant Paediatric Surgeon, Midas Heights, Ramdaspeth, Nagpur, Maharashtra
Source of Support: None, Conflict of Interest: None
Infantile hemangioma (IH) is a benign vascular tumor of the capillary endothelium that exhibits a characteristic clinical course of early rapid growth followed by spontaneous slow involution by the first decade of life. Most IHs regress spontaneously by the end of the 1st year, but some may require urgent medical or surgical intervention if they encroach on vital organs affecting their function; or may cause significant cosmetic disfigurement on the resolution. We report three cases of large IHs over eyelid, vulva, and the tongue which were causing considerable impairment or were cosmetically disfiguring and in whom surgery was difficult due to their anatomic location. In these cases, oral propranolol therapy was initiated with successful outcomes. Propranolol was well tolerated in all these patients without significant side effects.
Keywords: Infancy, Infantile hemangioma, propranolol
|How to cite this article:|
Saoji R, Shirolikar M. Successful use of propranolol in infantile hemangiomas. Indian J Drugs Dermatol 2017;3:77-80
|How to cite this URL:|
Saoji R, Shirolikar M. Successful use of propranolol in infantile hemangiomas. Indian J Drugs Dermatol [serial online] 2017 [cited 2019 Jun 24];3:77-80. Available from: http://www.ijdd.in/text.asp?2017/3/2/77/221750
| Introduction|| |
Hemangiomas are benign tumors of the endothelium of blood vessels in infants. The incidence ranges from 1% in neonates to 12% at 1 year,,,, seen more often in premature newborns and infants who have had chorionic villus sampling. Hemangiomas undergo 3 phases, i.e., proliferative phase showing postnatal growth for 8–12 months; involuting phase over the next 1–5 years consisting of regression and phase of involution showing continuous improvement until 6–12 years. Complications such as ulceration, vital structure compression, and visceral involvement may be seen depending on size and location of hemangioma.,,, Facial hemangiomas may cause disfigurement and scarring.,,
Current medical therapeutic modalities for complicated hemangiomas include topical, intralesional and systemic steroids, recombinant interferons alpha-2a and 2b, vincristine, imiquimod, etc. Interventional therapies include cryotherapy, Argon, Nd-YAG, flashlamp-pumped pulse dye laser, embolization, sclerotherapy, surgery, and radiotherapy.,,,,,,,,, The mainstay of treatment continues to be “wait-and-watch.” Here, we describe 3 cases of hemangioma treated with propranolol.
| Case Reports|| |
A 2-year-old female child came with reddish lesion on the right side of face since birth [Figure 1]a. There was rapid increase in size to the current state where it had formed a large vascular nodule. The child had not received any treatment earlier. The lesion was not posttraumatic or associated with tenderness, discharge. General and systemic examination was normal. On cutaneous examination, there were soft compressible reddish nodules present over the right eyelid and eyebrow and extending onto the temporal area and lateral side of forehead, suggestive of hemangioma. There was associated narrowing of the right palpebral fissure because of the size of hemangioma leading to decreased vision. Due to the localization of the hemangioma over the right eyelid, there was imminent danger of amblyopia. As the site of hemangioma was difficult for surgical excision, we decided to start this patient on oral propranolol. The patient was treated over the course of 3 years intermittently with oral propranolol at the dose of 1 mg/kg/day for 3 days under supervision, with close monitoring of hypotension, bradycardia (by pulse oximeter), and hypoglycemia (by glucometer). Imaging was done in the form of two-dimensional (2D)-echo, which was normal. As there were no adverse effects noted, the dose was stepped up to 2 mg/kg/day. The patient tolerated the treatment well. There was rapid response within a week with regards to alteration in color and texture. At the end of 3 months [Figure 1]b, significant improvement was noted, which continued till next 6 months [Figure 1]c. There was near total clearance of hemangioma at the end of 5 years [Figure 1]d.
|Figure 1: (a) Hemangioma present on the right eyelid, extending to surrounding area. (b) Follow up after 3 months showing slight decrease in hemangioma. (c) Follow-up after 1 year showing marked decrease in size. (d) Follow-up after 3 years showing near-total clearance.|
Click here to view
A 3-month-old female child presented with lesions on genitals since first 2 weeks of life [Figure 2]a. The child had not received any treatment beforehand. The lesion was not posttraumatic or associated with tenderness, discharge. General and systemic examination was normal. On cutaneous examination, there was soft compressible vascular swelling over the right side of labia major an extending to right perianal region, suggestive of hemangioma. The site was not amenable to surgery due to its anatomical location. The patient was treated with oral propranolol at the dose of 1 mg/kg/day for 3 days under supervision, with close monitoring of hypotension, bradycardia (by pulse oximeter), and hypoglycemia (by glucometer). Imaging was done in the form of 2D-echo, which was normal. As there were no adverse effects noted, the dose was stepped up to 2 mg/kg/day and was given for 12 months. The patient tolerated the treatment well. Over the course of one year [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, the lesion completely regressed with almost no scarring, with response being noted as early as 7 days.
|Figure 2: (a) Vulval hemangioma on right side in a 3-month-old female child. (b) Slight decrease in size after 3 months. (c) After 6 months of treatment. (d) After 1 year of treatment.|
Click here to view
An 8-year-old female child came with lesions on dorsal and ventral surfaces of the tongue since first 2 weeks of life [Figure 3]a and [Figure 3]b. The lesions were associated with recurrent bleeding, not associated with pain or trauma. The general and systemic examination was normal. Cutaneous examination revealed multiple bluish-red vascular lesions on the tongue. As this site was difficult for surgical excision, we decided to start this patient on oral propranolol. The patient was given oral propranolol at 1 mg/kg/day for 3 days under supervision, with close monitoring of hypotension, bradycardia (by pulse oximeter), and hypoglycemia (by glucometer). Imaging was done in the form of 2D-echo, which was normal. As there were no adverse effects noted, the dose was stepped up to 2 mg/kg/day, for 6 months, with marked improvement in size [Figure 3]c and [Figure 3]d. The patient tolerated the treatment well, with response being noted within a week in the form of change in size and texture. There was no recurrence of hemangioma after discontinuation of propranolol.
|Figure 3: (a) Lesions on the dorsal surface of tongue in an 8-year-old female. (b) Lesions on the ventral surface of tongue in an 8-year-old female. (c) Lesions on the dorsal surface of tongue after 3 months of treatment. (d) Lesions on the ventral surface of the tongue after 6 months of treatment.|
Click here to view
| Discussion|| |
Propranolol, is a nonselective beta-blocker and if not contraindicated, stands as the first-line agent for hemangiomas that impair function or cause permanent disfigurement. In 2014, propranolol hydrochloride oral solution was approved by the US Food and Drug Administration for the treatment of proliferating infantile hemangioma (IH) requiring systemic therapy. Other modalities of treatment for IHs include oral steroids, vincristine, interferon alpha, surgery, and pulsed dye laser, but these are cumbersome and associated with variable side effects and complications. Surgical excision at times is not possible due to difficult anatomic sites and due to risk of cosmetic disfigurement.
The efficacy of propranolol in IHs was reported serendipitously by Léauté-Labrèze et al. in 2008 where the use of propranolol in their patient for hypertrophic myocardiopathy caused by corticosteroids lead to dramatic improvement in patient's hemangioma. Propranolol inhibits the growth and induces regression of IHs by its potential mechanisms of inducing vasoconstriction, decreased expression of vascular endothelial growth factor and matrix metalloproteinases, and/or triggering of apoptosis.,, The proposed mechanism of action of propranolol in hemangiomas included vasoconstriction, apoptosis of capillary endothelial cells, and decreased the production of vascular endothelial growth factor and fibroblastic growth factor. During the growth phase, these latter two major pro-angiogenic factors are involved. Propranolol leads to decreased expression of genes related to them and down-regulation of the rapidly accelerated fibrosarcoma mitogen-activated protein kinase pathway  and the triggering of apoptosis of capillary endothelial cells.
Since then, due to its effects on vascular endothelium, it has been used to treat hemangiomas by many others and was found to be safe  In rare instances, the drug has been reported to cause adverse effects such as hypoglycemia, bradycardia, hypotension, bronchospasm, and high output cardiac failure in infants with very large hemangiomas. All our patients, however, showed no adverse effects, with dramatic regression of hemangioma clinically.
One must be careful using propranolol in cases of posterior fossa malformations, hemangiomas, arterial abnormalities, cardiac defects, eye abnormalities, sternal cleft, and supraumbilical raphe syndrome (PHACES syndrome) since potentially hypoperfusion of the brain is a small possibility.
Contraindications to the use of propranolol are reported to be cardiogenic shock, documented chronic and significant sinus bradycardia, documented chronic and significant hypotension, greater than first-degree heart block, heart failure, history of bronchospasm or wheezing, hypersensitivity to propranolol, and preterm infants with corrected age <5 weeks (postnatal age in weeks − number of weeks preterm). Our patients did not have any of these conditions and hence was administrated oral propranolol for a long duration of time.
As per conventional literature, the pretreatment evaluation should include detail history to rule out cardiovascular and respiratory abnormalities (e.g., poor feeding, dyspnea, tachypnea, diaphoresis, wheezing, heart murmur, and family history of heart block or arrhythmia). The thorough physical examination should be performed for cardiac or pulmonary assessment and measurement of heart rate and blood pressure.
Imaging studies including cardiac ultrasound or cardiac magnetic resonance imaging should be obtained in children with large facial hemangiomas at risk for PHACES to rule out the possibility of severe aortic coarctation, which is a contraindication for propranolol use. In these patients, baseline head and neck MRI with angiography are also preferred before propranolol unless the clinical situation requires urgent treatment (e.g., severe visual obstruction due to an orbital hemangioma). In such cases, propranolol can be initiated at a lower dose and slowly titrated up to a maximum dose of 1 mg/kg/day. However, we could not perform these investigations due to lack of facilities.
| Conclusion|| |
Many treatment modalities are available to treat IHs. Of these, propranolol seems to be the most promising. However, more studies are needed to confirm the efficacy of propranolol before considering it as a possible first-line drug in the treatment of infantile hemangiomas.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics 1976;58:218-22.
Metry DW, Hebert AA. Benign cutaneous vascular tumors of infancy: When to worry, what to do. Arch Dermatol 2000;136:905-14.
Frieden IJ, Eichenfield LF, Esterly NB, Geronemus R, Mallory SB. Guidelines of care for hemangiomas of infancy. American Academy of Dermatology Guidelines/Outcomes Committee. J Am Acad Dermatol 1997;37:631-7.
Werner JA, Dünne AA, Lippert BM, Folz BJ. Optimal treatment of vascular birthmarks. Am J Clin Dermatol 2003;4:745-56.
Jadhav VM, Tolat SN. Dramatic response of propranolol in hemangioma: Report of two cases. Indian J Dermatol Venereol Leprol 2010;76:691-4.
] [Full text]
Garzon MC, Frieden IJ. Hemangiomas: When to worry. Pediatr Ann 2000;29:58-67.
Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med 1999;341:173-81.
Enjolras O, Gelbert F. Superficial hemangiomas: Associations and management. Pediatr Dermatol 1997;14:173-9.
Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol 1996;132:307-11.
Metry DW, Dowd CF, Barkovich AJ, Frieden IJ. The many faces of PHACE syndrome. J Pediatr 2001;139:117-23.
Enjolras O, Riche MC, Merland JJ, Escande JP. Management of alarming hemangiomas in infancy: A review of 25 cases. Pediatrics 1990;85:491-8.
Special symposium. Management of haemangiomas. Pediatr Dermatol 1997;14:57-83.
Poetke M, Philipp C, Berlin HP. Flashlamp-pumped pulse dye laser for haemangiomas in infancy. Arch Dermatol 2000;136:628-32.
Darrow DH, Greene AK, Mancini AJ, Nopper AJ; Section on Dermatology, Section on Otolaryngology – Head and Neck Surgery, and Section on Plastic Surgery. Diagnosis and management of infantile haemangioma. Pediatrics 2015;136:e1060-104.
Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A, et al.
Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649-51.
Ozeki M, Nozawa A, Hori T, Kanda K, Kimura T, Kawamoto N, et al.
Propranolol for infantile hemangioma: Effect on plasma vascular endothelial growth factor. Pediatr Int 2016;58:1130-5.
Kum JJ, Khan ZA. Mechanisms of propranolol action in infantile hemangioma. Dermatoendocrinol 2014;6:e979699.
Sommers Smith SK, Smith DM. Beta blockade induces apoptosis in cultured capillary endothelial cells.In Vitro
Cell Dev Biol Anim 2002;38:298-304.
D'Angelo G, Lee H, Weiner RI. CAMP-dependent protein kinase inhibits the mitogenic action of vascular endothelial growth factor and fibroblast growth factor in capillary endothelial cells by blocking Raf activation. J Cell Biochem 1997;67:353-66.
Chen TS, Eichenfield LF, Friedlander SF. Infantile hemangiomas: An update on pathogenesis and therapy. Pediatrics 2013;131:99-108.
Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med 2008;359:2846.
Shah MK, Vasani RJ. Use of propranolol in infantile haemangioma. Indian J Drugs Dermatol 2017;3:48-52. [Full text]
[Figure 1], [Figure 2], [Figure 3]