Many studies had established the efficacy of propranolol in treating complicated or problematic IH, but till now there is no consensus regarding the optimal duration of treatment with scarcity of research emphasizing the effect of age on the expected rate of regression. In this study, we used oral propranolol therapy as the first line of treatment for cases of IH starting at early ages as we can as possible and continued for variable periods with analysis of our data to decide the best age of starting treatment and the recommended duration of therapy
There is a general agreement that propranolol is effective in lightening up and reducing the size of IH when given early in the proliferative phase of development [12, 13]. According to Fuchsmann et al. [14] and Smithson et al. [15], these changes continued thereafter. Theories suggest that propranolol impedes the growth of hemangiomas by its antiangiogenic activity and induction of apoptosis when given early. Nevertheless, several case studies have further provided evidence of the dramatic response of massive, proliferating, life-threatening, and involuting lesions to propranolol therapy [16,17,18]. In the present paper, we noticed that the earlier initiation of propranolol therapy within the proliferative phase, the more reduction in the different percentage of surface area with a significant inverse correlation (R2 linear = 0.482 at 0.01 level, P = 0.0001) (Table 2, Figs. 2 and 5). A previous Turkish study showed that there is no statistically significant relation between the age of initiation of propranolol therapy and the response rate, but there was a significant increase in the response rate in association with the duration of therapy [19].
The mean difference percentage of the surface area of IH at 6 months of treatment was 51%, while it was 75% at the end of completed treatment with a statistically significant P value of 0.0001 (Table 3). A considerable number of patients continue to exhibit a significant reduction in the difference percentage of surface area when treatment extended for more than 6 months (as shown in Fig. 3) and those patients who did not show any difference in the percentage of surface area for two consecutive months of propranolol therapy were actually stopped exhibit regression of the lesion and considered for termination of treatment.
Chang et al. described that treatment duration depends on patient’s response rather than the age at which therapy was initiated [20]; they noted that a longer duration of treatment is usually required for those patients who experience partial regression of the lesion and those in which the recurrence rate is frequently high and the best time to stop treatment is when complete regression achieved [20]. Analysis of our data showed that there was a significant inverse correlation between the age of the patients at the initiation of therapy and duration of treatment (R2 linear = 0.234 at 0.01 level, with statistically significant Pearson correlation P = 0.009) (Fig. 4), the younger ages at starting treatment required longer duration of treatment. Patients who were treated earlier were probably in the earlier period of the proliferative phase and therefore they required longer treatment. This is also could be attributed to the fact that, starting to treat large size hemangiomas in a young infant showed a dramatic response which encourages the parents to continue the therapy until nearly complete disappearance of the lesion (as in Figs. 6 and 7). In contrast, when treatment starts late, the reduction in the surface area is not remarkable which discourages the parent to continue treatment.
Rebound growth in IH after stopping propranolol therapy occurs in 6–25% of cases [21]. Shah et al. noted that in addition to hemangioma size, depth, gender, and location, the risk of rebound growth was linked to the duration of treatment and the age of discontinuation of therapy [22]. In this series, two patients (7.14%) developed rebound growth following cessation of treatment (Table 1). In one case, the patient was female with right labial hemangioma which start treatment at the age of 6 months and then the parents stopped the treatment abruptly at the age of 14 months without gradual tapering of the dose, which required resuming propranolol therapy for 4 weeks followed by gradual tapering for another two weeks. In the other case, the patient developed mild rebound growth of perianal hemangioma at age of 12 months in spite of 8 months duration of treatment and gradual tapering of propranolol therapy it was just mild regrowth and did not require repeating the propranolol treatment. Our finding of the recurrence rate is consistent with the study of Chang et al. who stated that rapid rebound growth occurs with sudden termination of therapy and that those patients with complete regression need 2 weeks of gradual tapering of treatment [20].
The most common reported adverse effects of propranolol are transient bradycardia and hypotension. Other reported adverse effects include ECG changes (prolong PQ duration), sleep disturbance, hypoglycemia, bronchospasm, diarrhea, hyperkalemia, and gastroesophageal reflux [23,24,25,26]. We encountered simple adverse effect of propranolol in two cases. One case was a female patient aged 7 months experienced sleep disturbances after 3 months from initiation of therapy, and it was temporary for 3 days only and disappeared without any intervention or modification of the propranolol dose. The second patient was an 8-month-old male who developed exacerbation of a wheezy chest following chest infection for which we temporarily stopped the treatment for 5 days only according to the report of consensus conference in 2013 by Drolet et al. [24].