|Year : 2014 | Volume
| Issue : 2 | Page : 55-60
Beta blockers in infantile hemangiomas: A practical guide
Manish K Shah
Associate Honorary Consultant, Pediatric Dermatology Unit, B. J. Wadia Hospital for Children, Parel, Mumbai, Maharashtra, India
|Date of Web Publication||27-Aug-2014|
Manish K Shah
Pediatric Dermatology Unit, B. J. Wadia Hospital for Children, Parel, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
Beta blockers have now become first-line therapy for infantile hemangiomas (IH). Since the first report by Lιautι-Labrθze et al.,  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|| |
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. 
| Common complications of infantile hemangiomas|| |
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:
- 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. 
| Oral propranolol for infantile hemangiomas|| |
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 
- 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|| |
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. 
| Monitoring during propranolol therapy|| |
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.
| Response of infantile hemangiomas to oral propranolol|| |
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. ,, Progressive flattening and fading of color ensues with almost complete resolution in most cases by 4 months [Figure 2] and [Figure 3].
| Duration of propranolol therapy for infantile hemangiomas|| |
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. 
| Adverse effects of oral propranolol|| |
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.  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 
- Each patient receiving oral propranolol for IH in our institution is counseled thoroughly and given a set of written instructions [Table 1].
- 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
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).  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|| |
Absence of response after 4 weeks of oral propranolol was reported in 10 of 1130 cases in a retrospective study.  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.  Another laryngotracheal IH acquired resistance after propranolol interruption. 
| Propranolol dose revision|| |
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|| |
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.  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.  Another retrospective study comparing 20 propranolol-treated patients and 20 matched historical controls concluded that propranolol significantly reduced the duration of ulceration in IH. 
| Propranolol In Posterior Fossa Defects, Hemangioma, Arterial Anomalies, Cardiac Defects And Coarctation of The Aorta, And Eye Anomalies Syndrome|| |
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.  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. 
| Propranolol for eyelid hemangiomas|| |
Significant reduction of the IH with diminished incidence of astigmatism and prevention of ocular disfiguration was reported in a cohort of 30 cases.  The benefits of propranolol in periocular IH have been documented echographically. 
| Propranolol for hepatic hemangiomas|| |
Propranolol has been recommended as first-line therapy for hepatic IH. 
| How does oral propranolol work?|| |
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. 
Recently, serum VEGF levels were shown to decrease dramatically 1-month after oral propranolol with a less pronounced fall at 3 months.  Serum VEGF levels in IH patients were higher than controls.
| Propranolol versus corticosteroids|| |
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. 
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. 
| Oral atenolol for infantile hemangiomas|| |
Due to concerns with adverse effects of propranolol, more cardioselective beta-blockers like atenolol have been used for treating IH. , 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|| |
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.  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.  Topical timolol appears to be more effective for plaque than for nodular lesions, and for proliferating than for involuting lesions. 
| Intralesional propranolol|| |
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. 
| Management of residual lesions|| |
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.  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.  It seems reasonable to offer a trial of oral propranolol to shrink residual lesions before contemplating surgery to improve the appearance.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]