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REVIEW
Year : 2014  |  Volume : 15  |  Issue : 2  |  Page : 55-60

Beta blockers in infantile hemangiomas: A practical guide


Associate Honorary Consultant, Pediatric Dermatology Unit, B. J. Wadia Hospital for Children, Parel, Mumbai, Maharashtra, India

Date of Web Publication27-Aug-2014

Correspondence Address:
Manish K Shah
Pediatric Dermatology Unit, B. J. Wadia Hospital for Children, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2319-7250.139498

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  Abstract 

The use of oral and topical beta blockers has revolutionized the management of infantile hemangiomas. Oral propranolol at 2 mg/kg/d in divided doses not only prevents further proliferation, but actually shrinks IH. Propranolol should be administered for at least 6 months or until the baby reaches one year of age. Side effects to be watched out for include hypoglycaemia, bradycardia and hypotension. Oral propranolol should be prescribed only in those IH where clearly indicated. More cardioselective beta blockers like atenolol are also being explored for treating IH. Topical timolol has been prescribed for smaller and superficial IH or when propranolol is contraindicated.

Keywords: Beta blockers, infant, hemangiomas


How to cite this article:
Shah MK. Beta blockers in infantile hemangiomas: A practical guide. Indian J Paediatr Dermatol 2014;15:55-60

How to cite this URL:
Shah MK. Beta blockers in infantile hemangiomas: A practical guide. Indian J Paediatr Dermatol [serial online] 2014 [cited 2020 Feb 18];15:55-60. Available from: http://www.ijpd.in/text.asp?2014/15/2/55/139498


  Introduction Top


Beta blockers have now become first-line therapy for infantile hemangiomas (IH). Since the first report by Lιautι-Labrθze et al., [1] many large series of oral propranolol for the treatment of IH have been published. There have been a lot of modifications like varied dosage schedules of oral propranolol, oral atenolol instead of propranolol, topical timolol and intralesional propranolol. This article is not a meta-analysis. The aim is to crystallize available information and practical experience to enable clinicians to use beta blockers in their practice.


  Diagnosis of infantile hemangiomas Top


Infantile hemangiomas have distinctive clinical characteristics. They usually appear few days or weeks after birth. They progressively grow for 6-9 months, followed by a phase of stabilization and gradual involution. It is unusual for IH to grow beyond 1-year of age. In contrast, vascular malformations and congenital hemangiomas are present since birth, and do not regress, except for rapidly involuting congenital hemangiomas. If the diagnosis is in doubt, magnetic resonance imaging with contrast can help. IH has a typical solid appearance with intermediate intensity on a T1-weighted spin-echo image, which is more intense compared with venous or lymphatic malformations. Skin biopsy can make the definitive diagnosis of IH with special staining for glucose transporter-1. [2]


  Common complications of infantile hemangiomas Top


Depending on the size of the IH and the location, certain complications can occur in the course of IH, that can be preempted if treatment is started early in the course. Common complications include:

  • Ulceration
  • Visual compromise
  • Auditory canal obstruction
  • Cardiac compromise.


Larger hemangiomas are more prone to complications and Haggstrom et al. have estimated that 10 cm 2 increase in size of the IH is associated with 5% increase in risk of complications. [3]


  Oral propranolol for infantile hemangiomas Top


Since the natural course is one of spontaneous regression, not all IH require medical intervention. But certain IH warrant early and decisive institution of treatment. These are:

  • Face (risk of scarring, ulceration)
  • Near the eyes (various complications like astigmatism, amblyopia, tear duct obstruction, proptosis, ptosis, strabismus and myopia)
  • Lips (suckling problems, little tendency to spontaneous regression, ulceration and extensive involvement of lower lip and adjoining skin can be associated with the presence of subglottic hemangioma)
  • Tip of the nose (high risk of deformity)
  • Fingers (tactile problems)
  • Breast and cleavage area in women
  • Anogenital (risk of ulceration)
  • Segmental IH has an approximately 11 times greater risk of ulceration [3]
  • Extensive, highly proliferating hemangiomas
  • IH showing complications, especially early ulceration
  • Presence of multiple IH (>5 IH associated with a risk of visceral hemangiomas).


Larger IH in any location is preferably treated, since even after regression, the residual fibrofatty issue can be cosmetically unacceptable.


  Administering oral propranolol to infants Top


Oral propranolol is usually given at a dose of 2 mg/kg/day. The author starts propranolol at 0.33 mg/kg/dose given 8 hourly for 1-week. After the 1-week follow-up visit, the dose is doubled to 0.67 mg/kg/dose to get the recommended 2 mg/kg/day dose. Small packets of each dose are prepared by the pharmacist and parents are asked to dissolve these in rose syrup or honey and administer to the baby.

Alternatively, a pharmacist can compound propranolol syrup as per dispensing formulations from resources available on the internet. [4]


  Monitoring during propranolol therapy Top


The author usually prescribes propranolol on an outpatient basis. Patients are admitted only in complicated IH like posterior fossa defects, hemangioma, arterial anomalies, cardiac defects and coarctation of the aorta, and eye anomalies (PHACE) syndrome. Patients are asked to follow-up once a week for the first 2 weeks, and then every fortnightly for the next 2 months and once a month thereafter. Each follow-up visit entails history of any untoward effects [Figure 1], examination of the pulse and evaluation of the IH. Parents are instructed to consult their pediatrician or get the infant to the emergency in case of coldness, shakiness, sweating, excess drowsiness. The parents are advised to see their pediatrician every 2 weeks for monitoring, especially of the blood pressure.
Figure 1: Case of segmental IH - Before treatment

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  Response of infantile hemangiomas to oral propranolol Top


Typically the IH becomes softer and the color becomes lighter within 48 h of starting the propranolol. IH growth stops within 24 h to 2 weeks for 97-100% of the lesions treated with propranolol. [5],[6],[7] Progressive flattening and fading of color ensues with almost complete resolution in most cases by 4 months [Figure 2] and [Figure 3].
Figure 2: Case of segmental IH - after 1-week of oral propranolol

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Figure 3: Case of segmental IH- After 16 weeks of oral propranolol

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  Duration of propranolol therapy for infantile hemangiomas Top


Infantile hemangiomas need to be treated for a minimum period of 6 months. It is logical to administer oral propranolol until the end of the proliferative phase between the 9 th month and 12 th months of life [Figure 4]. A recent article suggests that giving oral propranolol for 12 months diminishes the likelihood of relapse. [8]
Figure 4: Case of segmental IH- After 6 months of oral propranolol

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  Adverse effects of oral propranolol Top


In a series of 31 IH patients, the author has not encountered any significant adverse events. However, since they can be potentially very severe, it is advisable to be conversant with them.

  • Hypoglycemia is the most frequent and insidious side-effect observed with oral propranolol. Propranolol inhibits the protective physiological responses to hypoglycemia (lowering of insulin, glucagon release) and hepatic and muscle glycogenolysis. [9] Propranolol also masks some of the clinical manifestations of IH. Propranolol-induced hypoglycemia has been reported as late as 6 months after initiation of therapy [10]
  • Each patient receiving oral propranolol for IH in our institution is counseled thoroughly and given a set of written instructions [Table 1].
  • Hypotension
  • Bradycardia. It is prudent to discontinue propranolol if the blood pressure drops below 50/30 or the pulse is below 60 beats/min
  • Sleep disruption
  • Acrocyanosis
  • Diarrhea.
Table 1: Propranolol safety instructions for parents[11]


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In a meta-analysis of 39 studies involving 1,189 patients, the commonest adverse events were changes in sleep (n = 136) and acrocyanosis (n = 61). [12] Hypotension was reported in 39, bradycardia in 8 and hypoglycemia in 4 patients. Of these, symptomatic hypotension occurred in 5 patients, symptomatic bradycardia (irritability and seizures) and hypoglycemic seizures in one patient each.


  Propranolol-Resistant Infantile Hemangiomas Top


Absence of response after 4 weeks of oral propranolol was reported in 10 of 1130 cases in a retrospective study. [13] Cases of proliferating and postproliferative IH were chosen (range: 1.3-33.8 months). It can be argued that some IH may respond late and that propranolol should be given for a longer duration before being deemed ineffective. In the author's series of 31 cases no resistance or late response was noted.

Hemangiomas in the neck region may have to be watched closely. A subglottic IH that occurred while on propranolol and necessitated surgical intervention has been described. [14] Another laryngotracheal IH acquired resistance after propranolol interruption. [15]


  Propranolol dose revision Top


As the weight of the child increases, one may have to revise the dose of propranolol to maintain the 2 mg/kg/day dose. If this is not done, there is the possibility of suboptimal dosing and diminished efficacy.


  Propranolol for ulcerated hemangiomas Top


Ulceration is the most common complication of IH that has been treated with a host of measures including local barrier creams or dressings, oral antibiotics, pulsed dye laser, topical morphine 0.1% in hydrogel and topical becaplermin. [16] It seems logical to use propranolol in combination with these therapies in order to diminish the size of the IH. Propranolol was used successfully used in a retrospective evaluation of 33 ulcerated IH patients with an average healing time of 4.3 weeks and complete pain control achieved in average time of 14.5 days. [17] Another retrospective study comparing 20 propranolol-treated patients and 20 matched historical controls concluded that propranolol significantly reduced the duration of ulceration in IH. [18]


  Propranolol In Posterior Fossa Defects, Hemangioma, Arterial Anomalies, Cardiac Defects And Coarctation of The Aorta, And Eye Anomalies Syndrome Top


There is anxiety that using propranolol in PHACE syndrome can potentially increase the risk of stroke. In a collaborative study of 32 case with PHACE syndrome from seven centers, propranolol was used successfully, but the authors recommend lowest possible dosage, slow dose titration, 3 times/day dosing and close neurologic follow-up. [19] The authors have used propranolol in two cases of PHACE syndrome with good outcome. In a series of seven cases, propranolol treatment did not produce changes in brain perfusion as documented by SPECT. [20]


  Propranolol for eyelid hemangiomas Top


Significant reduction of the IH with diminished incidence of astigmatism and prevention of ocular disfiguration was reported in a cohort of 30 cases. [21] The benefits of propranolol in periocular IH have been documented echographically. [22]


  Propranolol for hepatic hemangiomas Top


Propranolol has been recommended as first-line therapy for hepatic IH. [23]


  How does oral propranolol work? Top


The exact mechanism by which propranolol shrinks IH is not known. Various explanations have been proposed, including vasoconstriction, decreased expression of vascular endothelial growth factor (VEGF) and beta fibroblast growth factor genes, apoptosis of capillary endothelial cells, blockage of the G protein-coupled receptor kinases Leu41, reduced matrix metalloproteinase-9 and effect on differentiation of mesenchymal stem cells. [24]

Recently, serum VEGF levels were shown to decrease dramatically 1-month after oral propranolol with a less pronounced fall at 3 months. [25] Serum VEGF levels in IH patients were higher than controls.


  Propranolol versus corticosteroids Top


Oral corticosteroids were hitherto the treatment of choice for IH. Most pediatric dermatologists now prefer to treat IH with propranolol rather than oral prednisolone due to greater efficacy and a better safety profile.

A prospective study of 30 patients treated with either propranolol alone, prednisolone or propranolol with prednisolone concluded that propranolol had a more consistent and rapid therapeutic response compared to oral prednisolone. Combined propranolol and prednisolone were comparable but not more efficacious than propranolol alone. [26]

In another retrospective study of 12 age-matched infants with similar type, location and size of IH, oral propranolol 2 mg/kg/day was significantly superior to prednisone. [27]


  Oral atenolol for infantile hemangiomas Top


Due to concerns with adverse effects of propranolol, more cardioselective beta-blockers like atenolol have been used for treating IH. [28],[29] Although atenolol was found to be as efficacious as propranolol with fewer side effects, more studies in a larger number of patients are required.


  Topical timolol for infantile hemangiomas Top


In practice, there are some cases of IH that seem to require treatment, yet not warrant oral propranolol. There have recently been reports of topical timolol gel for small or superficial IH. A randomized controlled study of 41 infants with IH found topical timolol maleate 0.5% gel to be safe and more effective than placebo. [30] Small superficial IH that had not ulcerated and that were not on mucosal surfaces were chosen.

Timolol containing gel manufactured from an ophthalmic formulation of timolol 0.5% eye drops applied under occlusion (Finn Chambers) for a dose of 0.25 mg timolol was used safely and to good effect in 9 children, including six preterm babies. [31] Topical timolol appears to be more effective for plaque than for nodular lesions, and for proliferating than for involuting lesions. [32]


  Intralesional propranolol Top


Interestingly, intralesional 1 mg/ml propranolol solution at a dose of 0.2 ml/cm 2 was ineffective in shrinking IH, though no adverse events occurred. [33]


  Management of residual lesions Top


After proliferation ceases, and regression occurs, the IH may not have completely involuted. Lesions remaining after further reduction in size and fading of color cease to occur termed residual lesions. [34] These residual lesions can be cosmetically disfiguring. In a retrospective study of 42 children above 1-year age, oral propranolol diminished the size of those IH that were well beyond the proliferative phase. [35] It seems reasonable to offer a trial of oral propranolol to shrink residual lesions before contemplating surgery to improve the appearance.

 
  References Top

1.Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008 12;358:2649-51.  Back to cited text no. 1
    
2.North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: A newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000;31:11-22.  Back to cited text no. 2
    
3.Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, et al. Prospective study of infantile hemangiomas: Clinical characteristics predicting complications and treatment. Pediatrics 2006;118:882-7.  Back to cited text no. 3
    
4.Available from: http://www.eahp.eu/sites/default/files/tch-023.pdf. [Last Accessed on 2014 Aug 2].  Back to cited text no. 4
    
5.Holmes WJ, Mishra A, Gorst C, Liew SH. Propranolol as first-line treatment for rapidly proliferating infantile haemangiomas. J Plast Reconstr Aesthet Surg 2011;64:445-51.  Back to cited text no. 5
    
6.Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, Mazereeuw-Hautier J, et al. Propranolol for severe infantile hemangiomas: Follow-up report. Pediatrics 2009;124:e423-31.  Back to cited text no. 6
    
7.Fuchsmann C, Quintal MC, Giguere C, Ayari-Khalfallah S, Guibaud L, Powell J, et al. Propranolol as first-line treatment of head and neck hemangiomas. Arch Otolaryngol Head Neck Surg 2011;137:471-8.  Back to cited text no. 7
    
8.Giachetti A, Garcia-Monaco R, Sojo M, Scacchi MF, Cernadas C, Guerchicoff Lemcke M, et al. Long-term treatment with oral propranolol reduces relapses of infantile hemangiomas. Pediatr Dermatol 2014;31:14-20.  Back to cited text no. 8
    
9.Lawrence AM, Hagen TC. Propranolol-associated hypoglycemia. N Engl J Med 1983;309:1327-8.  Back to cited text no. 9
    
10.Bonifazi E, Acquafredda A, Milano A, Montagna O, Laforgia N. Severe hypoglycemia during successful treatment of diffuse hemangiomatosis with propranolol. Pediatr Dermatol 2010;27:195-6.  Back to cited text no. 10
    
11.Martin K, Blei F, Chamlin SL, Chiu YE, Frieden IJ, Frommelt PC, et al. Propranolol treatment of infantile hemangiomas: Anticipatory guidance for parents and caretakers. Pediatr Dermatol 2013;30:155-9.  Back to cited text no. 11
    
12.Marqueling AL, Oza V, Frieden IJ, Puttgen KB. Propranolol and infantile hemangiomas four years later: A systematic review. Pediatr Dermatol 2013;30:182-91.  Back to cited text no. 12
    
13.Caussé S, Aubert H, Saint-Jean M, Puzenat E, Bursztejn AC, Eschard C, et al. Propranolol-resistant infantile haemangiomas. Br J Dermatol 2013;169:125-9.  Back to cited text no. 13
    
14.Goswamy J, Rothera MP, Bruce IA. Failure of propranolol in the treatment of childhood haemangiomas of the head and neck. J Laryngol Otol 2011;125:1164-72.  Back to cited text no. 14
    
15.Leboulanger N, Fayoux P, Teissier N, Cox A, Van Den Abbeele T, Carrabin L, et al. Propranolol in the therapeutic strategy of infantile laryngotracheal hemangioma: A preliminary retrospective study of French experience. Int J Pediatr Otorhinolaryngol 2010;74:1254-7.  Back to cited text no. 15
    
16.McCuaig CC, Cohen L, Powell J, Hatami A, Marcoux D, Maari C, et al. Therapy of ulcerated hemangiomas. J Cutan Med Surg 2013;17:233-42.  Back to cited text no. 16
    
17.Saint-Jean M, Léauté-Labrèze C, Mazereeuw-Hautier J, Bodak N, Hamel-Teillac D, Kupfer-Bessaguet I, et al. Propranolol for treatment of ulcerated infantile hemangiomas. J Am Acad Dermatol 2011;64:827-32.  Back to cited text no. 17
    
18.Hermans DJ, van Beynum IM, Schultze Kool LJ, van de Kerkhof PC, Wijnen MH, van der Vleuten CJ. Propranolol, a very promising treatment for ulceration in infantile hemangiomas: A study of 20 cases with matched historical controls. J Am Acad Dermatol 2011;64:833-8.  Back to cited text no. 18
    
19.Metry D, Frieden IJ, Hess C, Siegel D, Maheshwari M, Baselga E, et al. Propranolol use in PHACE syndrome with cervical and intracranial arterial anomalies: Collective experience in 32 infants. Pediatr Dermatol 2013;30:71-89.  Back to cited text no. 19
    
20.Hernandez-Martin S, Lopez-Gutierrez JC, Lopez-Fernandez S, Ramírez M, Miguel M, Coya J, et al. Brain perfusion SPECT in patients with PHACES syndrome under propranolol treatment. Eur J Pediatr Surg 2012;22:54-9.  Back to cited text no. 20
    
21.Snir M, Reich U, Siegel R, Zvulunov A, Friling R, Goldenberg-Cohen N, et al. Refractive and structural changes in infantile periocular capillary haemangioma treated with propranolol. Eye (Lond) 2011;25:1627-34.  Back to cited text no. 21
    
22.Wester ST, Johnson TE. Echographic evidence of regression of a periocular infantile capillary hemangioma treated with systemic propranolol. Ophthalmic Surg Lasers Imaging 2011;42 Online: e18-21.  Back to cited text no. 22
    
23.Cavalli R, Novotna V, Buffon RB, Gelmetti C. Multiple cutaneous and hepatic infantile hemangiomas having a successful response to propranolol as monotherapy at neonatal period. G Ital Dermatol Venereol 2013;148:525-30.  Back to cited text no. 23
    
24.Frieden IJ, Drolet BA. Propranolol for infantile hemangiomas: Promise, peril, pathogenesis. Pediatr Dermatol 2009;26:642-4.  Back to cited text no. 24
    
25.Chen XD, Ma G, Huang JL, Chen H, Jin YB, Ye XX, et al. Serum-level changes of vascular endothelial growth factor in children with infantile hemangioma after oral propranolol therapy. Pediatr Dermatol 2013;30:549-53.  Back to cited text no. 25
    
26.Malik MA, Menon P, Rao KL, Samujh R. Effect of propranolol vs prednisolone vs propranolol with prednisolone in the management of infantile hemangioma: A randomized controlled study. J Pediatr Surg 2013;48:2453-9.  Back to cited text no. 26
    
27.Bertrand J, McCuaig C, Dubois J, Hatami A, Ondrejchak S, Powell J. Propranolol versus prednisone in the treatment of infantile hemangiomas: A retrospective comparative study. Pediatr Dermatol 2011;28:649-54.  Back to cited text no. 27
    
28.de Graaf M, Raphael MF, Breugem CC, Knol MJ, Bruijnzeel-Koomen CA, Kon M, et al. Treatment of infantile haemangiomas with atenolol: Comparison with a historical propranolol group. J Plast Reconstr Aesthet Surg 2013;66:1732-40.  Back to cited text no. 28
    
29.Raphaël MF, de Graaf M, Breugem CC, Pasmans SG, Breur JM. Atenolol: A promising alternative to propranolol for the treatment of hemangiomas. J Am Acad Dermatol 2011;65:420-1.  Back to cited text no. 29
    
30.Chan H, McKay C, Adams S, Wargon O. RCT of timolol maleate gel for superficial infantile hemangiomas in 5- to 24-week-olds. Pediatrics 2013;131:e1739-47.  Back to cited text no. 30
    
31.Moehrle M, Léauté-Labrèze C, Schmidt V, Röcken M, Poets CF, Goelz R. Topical timolol for small hemangiomas of infancy. Pediatr Dermatol 2013;30:245-9.  Back to cited text no. 31
    
32.Semkova K, Kazandjieva J. Topical timolol maleate for treatment of infantile haemangiomas: Preliminary results of a prospective study. Clin Exp Dermatol 2013;38:143-6.  Back to cited text no. 32
    
33.Torres-Pradilla M, Baselga E. Failure of intralesional propranolol in infantile hemangiomas. Pediatr Dermatol 2014;31:156-8.  Back to cited text no. 33
    
34.Couto RA, Maclellan RA, Zurakowski D, Greene AK. Infantile hemangioma: Clinical assessment of the involuting phase and implications for management. Plast Reconstr Surg 2012;130:619-24.  Back to cited text no. 34
    
35.Zvulunov A, McCuaig C, Frieden IJ, Mancini AJ, Puttgen KB, Dohil M, et al. Oral propranolol therapy for infantile hemangiomas beyond the proliferation phase: A multicenter retrospective study. Pediatr Dermatol 2011;28:94-8.  Back to cited text no. 35
    


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  In this article
Abstract
Introduction
Diagnosis of inf...
Common complicat...
Oral propranolol...
Administering or...
Monitoring durin...
Response of infa...
Duration of prop...
Adverse effects ...
Propranolol dose...
Propranolol for ...
Propranolol for ...
Propranolol for ...
Propranolol vers...
Oral atenolol fo...
Topical timolol ...
Intralesional pr...
Management of re...
Propranolol-Resi...
Propranolol In P...
How does oral pr...
References
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