Propranolol
Propranolol is a non-selective -β adrenergic receptor blocker that recently has emerged as a good therapeutic option in IH. In 2008, Leaute-Labreze et al. reported regression of a facial IH in a child who was treated with propranolol for obstructive hypertrophic cardiomyopathy.[25] Ever since there has been a series of publications describing its therapeutic efficacy and side effects.[262728293031323334353637383940] Currently, it is widely used in IH, particularly for complicated and ulcerated IH, and appears to be the best therapeutic modality.[31]
Oral propranolol has three different pharmacological effects: Early, intermediate and long-term effects. The early effect of a visible change in colour and considerable softening of the lesion occurs within 1-3 days, after the initiation of therapy. This is related to the β2 inhibitory effect of propranolol that decreases the release of the vasodilator transmitters such as nitric oxide. The resulting vasoconstriction of the feeding capillaries is responsible for the early changes in haemangiomas. In view of its immediate clinical effect, propranolol is nowadays considered as the promising therapy in IH with ulceration or haemangiomas involving vital structures such as eyes, airways, genitalia etc.
In the proliferative phase of IH there is an increased expression of pro-angiogenic factors in particular the vascular endothelial growth factors (VEGF) and basic fibroblast growth factors (bFGF). The intermediate effects of propranolol are due to a downregulation of both VEGF and bFGF resulting in inhibition of proangiogenic cascade and angiogenesis. The long term effect of propranolol is due to apoptosis resulting in regression of haemangiomas.[41] This may be the reason for its use in the post proliferative phase.[41]
Ideally, propranolol should be initiated immediately once the decision is taken. Although there is no published evidence that early start of propranolol therapy results in less deforming residual skin changes, it is always better to start the treatment as early as possible before rapid proliferation of the tumour. A recent meta-analysis (including 1264 children in 41 studies) showed that oral propranolol was initiated at a mean age of 6.6 months (range from 3 days to 10 years).[27] In a single-centre prospective study of 174 children, propranolol was administered at a mean age of 4.8 months (0.9-29 months).[31] In an another recent review of 28 studies on IH, propranolol was initiated during infancy at a mean age of 4.5 months (range, 27 days-12 months). In 11 cases, propranolol was started after 12 months of age.[26]
In the recent consensus conference report on haemangioma, a target dose of 1-3 mg/kg has been recommended.[7] However, many researchers advocate a dose of 2 mg/kg/day. Hermans et al. in their large prospective study used a higher dose of 3 mg/kg/day in patients with haemangiomas causing airway obstruction or associated with repeated severe bleeding due to ulceration.[31] Few authors have also used a maximum dose of 4 mg/kg/day.[14] It is usually administered at a low starting dose of 0.5 to 1 mg/kg/day which is gradually escalated to the optimal dose over a period of days to weeks.[727]
The duration of therapy depends on the morphological type of haemangioma, extent of involvement and the treatment indications. Hogeling et al., based on their randomized controlled trial (RCT), suggest a treatment course of at least 6 months which could be modified according to the morphological subtypes, for example deep and mixed IH may continue to proliferate up to 1 year of age and hence, treatment may be extended up to this period.[35] The mean duration of treatment varies from 6 to 10 months. In a recent study on the propranolol treatment in complicated IH, the authors have used the drug for a mean duration of 10.7 months. In the deep and mixed type haemangiomas, they continued the treatment until the age of 12-16 months, in ulcerated lesions up to 9-12 months and in deep peri-orbital and airway lesions up to 15-18 months of age.[31] Marqueling et al. in their meta analysis of 1264 children in 41 studies found that the propranolol was administered for an average duration of 6.4 months (range, 1 weeks to 15 months).[27]
Oral propranolol is known to be effective during the rapid proliferative phase but there are several reports which have shown involution where propranolol was initiated at the end of growth phase or later.[27313236] Hogeling et al., in their trial of 40 children with IH, included a combination of growing, plateaued and involuting lesions. The authors noted a steady decrease in percentage volume for all weeks in the propranolol group compared to placebo.[35] This suggests that propranolol can be used at all stages of IH. Schupp et al.[32] and Zvulunov et al.[36] reported good clinical improvement with propranolol for IH beyond proliferative phase. However, Holmes et al. did not observe any improvement in children with IH in whom the propranolol was started after 9 months of age.[39] Hence, large prospective studies are needed to confirm the efficacy of propranolol in older age group of children.
A meta-analysis shows that the overall response rate is 98% (range, 82-100%).[27] Similar efficacy has also been observed in a large prospective study.[31] The treatment response in most of the published studies is based on the visual changes in the colour, volume and assessment of serial photographs. Only few studies categorized the response in terms of percentage reduction. Price et al. defined haemangioma clearance of 75% or more by correlating percentage of decrease in volume, cosmetically acceptable result by the physician and/or parent and a lack of need for further treatment. Based on these criteria they report >75% clearance in 81% (48/59) of the cases over a mean period of 7.9 months.[42] Talaat et al. reported 75% clearance in 75% and >50% clearance in 94% of their 80 cases with IH in 5-8 months (mean 6.53 ± 0.75).[40]
With propranolol therapy, the therapeutic efficacy is observed immediately. Sans et al. used propranolol at a dose of 2-3 mg/kg/day in 32 children with severe IH and noticed immediate changes in colour (within 24 hours) and softening in all the cases. Airway obstructive symptoms and haemodynamic compromise regressed within 48 hours.[29] Hermans et al. also reported improvement of respiratory symptoms in airway haemangioma within hours of treatment initiation with propranolol.[31] Propranolol also seems to be a promising drug for ulcerated haemangiomas. Painful ulceration in haemangioma has been reported to heal completely within 2 months. In a recent study of 20 children with ulcerated IH, oral propranolol significantly decreased the duration of ulceration compared with the control group (8.7 vs. 22.4 weeks, P < 0.01).[43] All these published observations suggest that oral propranolol can be considered as the best therapeutic option in cases with airway and other complicated IH. Figures 2 and 3 show near complete response to propranolol in two of our cases.
Figure 2  (a-d) Serial photographs of haemangioma on the right pectoral region responded to 30 months of propranolol. a: baseline; b: 1 month after treatment; c: 2 years of treatment; d: 2.5 years of treatment (Courtesy of Somesh Gupta)
Figure 3  (a and b) Photographs of haemangioma on the nose showing an excellent response to propranolol for 10 months. a: baseline; b: 10 months of treatment (courtesy of Somesh Gupta) Rebound or regrowth of haemangioma, defined as increase in size, change in colour or both, can occur after discontinuation of treatment. Studies showed that stopping propranolol before the age of 1 year increases the risk of rebound growth. In deeper haemangiomas, the proliferative phase could be longer and hence stopping the treatment early may be a risk factor for rebound growth.[42] In a recent retrospective analysis, the authors found that 2 of the 68 (3%) children in whom propranolol was started at 3 months and discontinued at 10 months, had relapsed.[42] In an another study, 2 of 32 cases had relapsed after stopping the drug before 1 year of age.[28] Menezes et al. in their meta-analysis found that 14 of 64 children who had treatment for a mean period of 5.1 months had a relapse.[26] Table 2 shows the summary of propranolol treatment in infantile hemangioma. In these cases, propranolol was stopped at a mean age of 7.2 months.[26] Relapse after cessation of propranolol after 1 year of age has also been reported.[42] In a recent meta-analysis, it has been reported in 17% of children who received propranolol for an average of 6.4 months.[27] Relapsed haemangiomas have been effectively re-treated with propranolol.[42] They can also be treated with adjunctive systemic steroids.[44]
Table 2  Summary of propranolol treatment in infantile hemangioma Propranolol-resistant IH have also been described as an absence of treatment response either in the proliferative phase or during the post-proliferative phase, after at least 4 weeks of oral propranolol at dosage of ≥2 mg/kg/day.[44] It is reported to occur at a frequency of 0.9% (10/1130). Of the 10 such cases reported from France, 8 had haemangioma on the face. Five children were in the proliferative phase (≤4.2 months) and showed continued growth. The remaining 5 (≥8 months) children, who did not show any decrease in the IH size, were in the post-proliferative phase.[44] This phenomenon needs to be investigated in a large scale studies in order to understand the different factors which influence the treatment outcome in children with IH.
Propranolol, being a beta blocker, has a negative inotropic and chronotropic effect on the heart. The effect on the pulse rate and BP can be seen around 2 hours after the oral dose. The most serious side effect is hypoglycaemia especially in infants < 3 months of age with poor feeding. The other possible side effects include pulmonary symptoms, sleep disturbances, somnolence, cold extremities and gastrointestinal (GI) complaints. These adverse reactions are not serious, reversible and dose-dependent.[7] In 174 patients treated for IH from a single centre, 108 children (62.1%) had 1 or more adverse reactions. The two most common problems were cold extremities (63, 36.2%) and nocturnal restlessness (39, 22.5%). Twenty-eight children (16.1%) were less active during the day. Lower blood pressure was observed in 6 cases (3.4%). Sixteen patients (3.2%) had pulmonary symptoms, out of which 9 needed treatment. In 12 children (6.9%), GI complaints were recorded.[31] In another meta-analysis of 39 studies in 1189 children, 371 cases had adverse reactions. The most common adverse event was sleep changes, which included insomnia, nightmares, night restlessness, fatigue and sleep disturbance in 136 cases followed by acrocyanosis in 61 children. There were 41 reports of GI problem like diarrhoea and gastroesophageal reflux. Respiratory adverse events were seen in 35 patients. Hypotension and bradycardia were seen in 39 and 8 cases, respectively. Hypoglycaemia was reported only in 4 cases.[27] The other side effects reported in the literature include irritability, profuse sweating and temporary hypotonia.[27]