Infantil Hemangioma and Optimum Dose of Propranolol Treatment: A Retrospective Tertiary-Center Study

Background/Objectives: Propranolol is the mainstay treatment of infantile hemangioma, and the optimal dose is unclear. Few studies are comparing the ecacy of propranolol dose of 2 vs.3 mg/kg/day. We compared the ecacy between these two doses and propranolol groups with no treatment group. Methods: One hundred eight patients with infantile hemangioma (15 days-27 months of age) were examined. The patients with high-risk features and/or a score of >6 points are given propranolol with a nal dose of 2 or 3 mg/kg/day according to tolerance for 6-12 months. The resolutions rates for propranolol vs. placebo and propranolol 2 mg/kg/day vs. 3 mg/kg/day are compared. Results: The demographic and clinical features of the groups ( the non-treatment, propranolol 2 mg/kg/day group, propranolol 3 mg/kg/day group) are similar. Propranolol is signicantly ecent in infantil hemangioma treatment (p<0.001). The resolution rates are not statistically different between 2 mg/kg/day propranolol group vs 3 mg/kg/day propranolol group at the sixth (68,59 ± 28,95 vs 73,44 ± 32,54)(p=0,673) and twelfth month (p=0,673) (89,08 ± 46,58 vs 91,13 ± 37,46 respectively )of follow up. A milld (n=3)(4%) adverse event was reported with no need for cessation. Conclusions: Propranolol is a safe drug for treating infantile hemangioma with an ideal dose of 2 mg/kg/day rather than 3 mg/kg/day.


Introduction:
Infantil hemangioma is the most frequent benign tumor in infants (4%-5%). Half of the lesions spontaneously resolve in one year. Clear treatment indications are ulceration, functional impairment, dis gurement, life-threatening lesions (1). A score above six points on the infantile hemangioma severity scale is considered for treatment (2). Propranolol is used for treatment, and the dose range is 2-4 mg/kg/day, twice a day. The dose is escalated to 2 or 3 mg/kg/day in one-week intervals. However, the optimum dose of propranolol is not speci c (3). This treatment duration is generally six months.
Treatment is prolonged to one year in case of incomplete resolution (4). This study compares the resolution rates at the sixth and twelfth months of follow-up in the propranolol and non-propranolol groups. We also compare the resolution rates at the sixth and twelfth months between groups with two doses (2 mg/kg/day vs. 3 mg/kg/day).

Material-method:
One hundred eight patients (15 days, 27 months of age) with infantile hemangioma were included in this retrospective study. All of them are followed up for at least six months. In addition, the data between December 15, 2019, and December 15, 2019, was examined. This study is performed following the Declaration of Helsinki and Good Clinical Practice guidelines. In addition, the local ethics committee (both Ministry of Health, Osmangazi University Ethics comittee) approved this study. The study did not include patients with bronchospasm, asthma, hypoglycemia, hyperkalemia, bradycardia, congenital hemangioma, Kasabach-Merritt, or PHACE (posterior fossa malformations, hemangiomas, arterial abnormalities, cardiac abnormalities, eye abnormalities, sternal cleft) syndrome.
Propranolol hydrochloride was administered for the patients with high-risk criteria. High-risk criteria were life-threatening lesions, ulceration, and risk of functional impairment. In addition, lesions in the periorbital, nasal, labial, laryngotracheal, and limb joints had a functional impact (4). Hemangioma severity scale was performed for all of the patients. A score above six points was considered for treatment regardless of high-risk features (5). Propranolol hydrochloride (oral solution or tablet) was started with a dose of 1 mg/kg/day and increased 1 mg/kg/day every one-week intervals up to 3 mg/kg/day. Electrocardiogram, echocardiogram, full blood count, serum glucose, ALT, AST, creatinine, urea, bilirubin were studied at the rst week. The electrocardiogram, full blood count, serum glucose, ALT, AST, creatinine, urea, and bilirubin were repeated every visit, and the adverse events were documented. The drug was stopped in the cases with complete remissions after six months. To avoid rebound relapses, propranolol is escalated to half dose for one month before cessation. The treatment continued up to twelve months in case of incomplete Results: The patients (n=108) with infantile hemangioma were divided into three groups. These groups were the non-treatment group (n=33) and treatment groups (propranolol hydrochloride) receiving a recent total dose of 2 mg/kg/day (n=39) or 3 mg/kg/day (n=36 Only 21 (19,4%) of 108 patients had complete resolution at 6 months of follow-up. In the treatment groups (2 mg/kg/d, 3 mg/kg/d) and the non-treatment group, the resolution rates at sixth and twelft months of follow-up signi cantly differed ( Table 2). Duration of propranolol treatment was 8,26 ± 12,33 months in the in the propranolol group (2 mg/kg/day) and 6,56 ± 10,53 months in the propranolol group (3 mg/kg/day) (p=0,773). The resolution rates were similar between these groups with two different doses of propranolol (2 mg/kg/day vs. 3 mg/kg/day) at the sixth and twelft month of follow-up (Table 3).  Sleep disorder (n=2) (2.6%), and bronchiolitis (n=1)(1.3%) were documented side effects of propranolol and supportive treatment was given. These side effects were transient, treatment is not delayed or stopped in these patients.

Discussion:
Infantil hemangioma has tendancy for spontanous resolution. However, the patients with ulceration, impairment of vital function, dis gurement should be treated (7). Additionally, we added the hemangioma severity scale in decision making (1) With a score of 6 points is. The rst line treatment is propranolol. A target dose of 2-3 mg/kg/gün is recommended. Infants (corrrected age>8 weeks, without comorbidity and with signi cant social support can be managed outpatient (7). According to a consensus statement, recommendation of propranolol dose is 1 or 2 mg/kg/day, bid (8). Begining with 1 mg/kg/day and escalating up to 3 mg/kg/day is possible. However; FDA approved a nal dose of 3.4 mg/kg/day of propranolol hydrochlorur oral solution. However, optimal dose is not clear.Generally, treatment duration is 3-12 months (9). Generally 2 or 3 mg/kg/day nal dose is used for the treatment of infantil hemangioma. The most common side effects (%10) are diarrhea and sleep disorders (10).We did not exceed the dose of 3 mg/kg/day. We report few transient adverse events, sleep order in two, bronchiolitis is one.
In a prospective randomised trial, of 456 patients, placebo (n=268) group was compared with propranolol group (3 mg/kg/day)(n=188). In six months, complete remission rate was signi cantly higher in the propranolol group than the plasebo (60% vs. %4 respectively)(p<0.001). The rates of side effects did not differ between the groups (11). We similarly report that comparing with no drug group, the resolution rates are statistically higher in the propranolol groups.
In another trail, forty patients (age of 9 weeks-5 years) received a nal dose of 2 mg/kg/day propranolol. In the third trial fourteen patients aged <16 weeks received prooranlol 3 mg/kg/day fteen days and 4 mg/kg/day fteen days. The data of these three trials revealed that, the risk of total remission of the lesionafter oral propranolol 1 mg/kg/day was 13 There is no con ict of interest between the authors.3