Since the serendipitous discovery of their efficacy in the 1960s, systemic corticosteroids have been the mainstay of therapy for treatment of hemangioma9
. The regimen consists of administration of 2 to 4 mg/kg/day of prednisolone in a single morning dose, depending on the clinical situation. Corticosteroid treatments are most likely to be effective if given during the proliferative phase, typically during the first 1 to 4 months of life. Although steroids were effective, adverse effects of steroids are commonly observed. Side effects include gastrointestinal upset, irritability, weight gain, cushingoid appearance, hypertension, delayed growth, adrenal suppression, and immunosuppression11)
Propranolol is an attractive therapeutic alternative because its use can avoid the common adverse effects of prolonged high-dose steroid use and have dramatic and rapid response. Treatment with propranolol causes rapid halt of proliferation and promotes regression of problematic hemangioma with an apparent good safety profile, even after the growth phase is completed6)
. Propranolol is a non-selective beta adrenergic blocker, and has been used for several decades in treatment of hypertension, ischemic heart disease, arrhythmias, endocrine and neurologic disorders, and eye disorders. The mechanism of action of propranolol in hemangioma is not known; however, the proposed mechanism is that it induces vasoconstriction and capillary endothelial cell apoptosis. It also interferes with proangiogenic mechanisms involved in the growth phase12)
. The side effects of propranolol are well known and include transient bradycardia, hypotension, hypoglycemia, hyperkalemia, diarrhea and bronchospasm in patients with underlying reactive airways6
As experience with propranolol becomes more extensive across multiple institutions, it may become the first line standard of therapy. However, so far, there has been no generally accepted agreement on the ideal treatment regimen with propranolol.
Doses of propranolol have generally been in the range of 1 to 3 mg/kg/day. Some cases have suggested that a good treatment response could be related to dose and made using the maximum safe dose (3 mg/kg/day)13)
. However, successful results from administration of doses ranging from 1 to 2 mg/kg/day have been reported8)
. Some studies have recommended utilizing gradual dose escalation and close monitoring during the first several days of treatment in order to minimize the risk of adverse effects14)
. For outpatients or infants younger than 3 months of age, slower increases in dosaging could be used. And infants younger than 6 months of age might need to be fed every 3 to 4 hours in order to avoid drug-induced hypoglycemia. We also treated with propranolol at the final dosage of 2 mg/kg/day with a gradually increasing dose and we found that this regimen was effective and safe.
The ideal duration of propranolol treatment has not yet been confirmed; however, one study appeared to demonstrate that treatment should be continued until the lesion is fully involuted or the child is 12 months of age and dose should be altered to account for the growth and weight gain of the child15)
. Another study suggested that propranolol should be gradually tapered over a period of 4 weeks17)
. The potential for more frequent relapse resulting from relatively shorter courses of treatment and rapid tail-off therapy has been demonstrated17)
. That is, re-growth occurred in a patient who received treatment for the shortest duration (2 months). In our study, mean or range of treatment duration has not yet been confirmed because most of the children are still taking propranolol for hemangioma; however, we will probably continue to treat at least until the age of spontaneous regression of the hemanigoma, depending on the clinical response.
Our patients tolerated propranolol well without significant side effects and recurrence. Some studies have reported that propranolol induced several adverse effects, including bradycardia, hypotension, and hypoglycemia16)
. However, they showed rapid recovery and no other serious toxic effects or complications have occurred. For patients with objective and continuous change in vital signs, a dose reduction or discontinuation of propranolol might be required. In addition, sweats, cold extremities, and diarrhea have been reported with propranolol in hemangioma18)
. These side effects might be associated with liquid formulations of oral propranolol, which contain various amounts of maltitol, propylene glycol, sorbitol, ethanol, and benzyl alcohol14)
We have not observed any relapse in our cases; however, several cases involving relapse of the hemangioma after early interruption of treatment or rapid process of tapering off have been reported17
. These patients restarted propranolol treatment until the age of spontaneous regression of the hemangioma and showed good response to a second treatment course.
A few case studies have reported on the use of initial combined therapy of systemic corticosteroids and propranolol, which resulted in rapid resolution and allowed for quicker weaning of corticosteroids16)
. However, in many other cases, propranolol in management of hemangioma was found to be useful as the initial and single-agent therapy. According to one report, the effect of propranolol did not appear to be affected by previous medical treatments or history of surgery19)
. Further studies are needed in order to determine whether there is a benefit of propranolol treatment with combined therapy of corticosteroids or others.
Other beta-blockers, such as acebutolol, which has a differing beta-adrenoceptor affinity, have also been shown to be effective in treatment of hemangioma13)
. One study observed that a patient presenting with severe asthma as a noticeable side effect of propranolol was successfully treated with acebutolol as a substitute without relapse of the severe bronchoconstriction19)
. However, currently, because of a very good safety profile in children, propranolol has been the most widely reported beta-blocker agent used in treatment of hemangioma.
In conclusion, we observed that the use of propranolol was very effective in treatment of hemangioma without obvious adverse effects or relapse. However, due to the possible side effects of propranolol, a full cardiovascular and respiratory review prior to initiation of therapy and close monitoring during treatment with propranolol are needed. More clinical studies are required in order to determine the mechanisms of action and ideal treatment regimen.