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Year : 2020  |  Volume : 39  |  Issue : 3  |  Page : 536-539

Oral B-blockers versus intralesional corticosteroids in treatment of infantile cutaneous hemangiomas

1 Pediatric Surgery Department, Banha Children Hospital, Banha, Egypt
2 Pediatric Surgery, Menoufia, Egypt
3 Vascular Surgery, Menoufia, Egypt

Date of Submission12-Jan-2020
Date of Decision19-Jan-2020
Date of Acceptance23-Jan-2020
Date of Web Publication28-Aug-2020

Correspondence Address:
MBBCH, MRCS Ahmed O Mohamed
Flat 62, 6 Marquis Street, Leicester LE1 6RT, United Kingdom
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ejs.ejs_12_20

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Aim Infantile hemangioma (IH) is one of the most common benign tumors of childhood, with an incidence of between 4 and 10%. Multiple modalities for treatment for IH were proposed, most commonly B-blockers and corticosteroids. Our study objective was to compare between oral B-blockers and intralesional corticosteroids injections in treatment of IHs.
Patients and methods This was a prospective study that included 52 patients diagnosed with IH in two pediatric surgery tertiary centers in Egypt. Patients were divided into two groups: group A patients underwent intralesional injection of betamethasone at a dose of 10–40 mg/ml in three to six separate sessions at an interval of 1 month, whereas group B patients were given oral propranolol at a low dose of 0.5–1 mg/kg/day for 3–6 months. Changes in size and color of the hemangioma each month and the occurrence of any complications were recorded for 6 months. Regression of size was classified into excellent (75–100% decrease in size), good (50–75% decrease), poor (25–50% decrease), and no response.
Results ‘Good’ response to intralesional corticosteroids was achieved in nine patients, whereas most patients had either ‘poor’ or ‘no response’ (n=14). On the contrary, most patients in the propranolol group exhibited ‘excellent’ or ‘good’ response (n=21) with only four patients not responding to treatment. Ulceration occurred in two patients who underwent intralesional steroid injection, whereas hypotension occurred in one patient with B-blockers.
Conclusion Our study confirms the superiority of oral B-blockers in treatment of superficial IH when compared with intralesional injection of steroids.

Keywords: infantile hemangioma, intralesional corticosteroids, oral B-blockers

How to cite this article:
Mohamed AO, Abd El-Aziz TF, Zaid NA, Alkhateep YM, Loulah MA. Oral B-blockers versus intralesional corticosteroids in treatment of infantile cutaneous hemangiomas. Egypt J Surg 2020;39:536-9

How to cite this URL:
Mohamed AO, Abd El-Aziz TF, Zaid NA, Alkhateep YM, Loulah MA. Oral B-blockers versus intralesional corticosteroids in treatment of infantile cutaneous hemangiomas. Egypt J Surg [serial online] 2020 [cited 2020 Sep 21];39:536-9. Available from: http://www.ejs.eg.net/text.asp?2020/39/3/536/293655

  Introduction Top

Infantile hemangiomas (IH) are the most common benign vascular tumors of infancy, occurring in 1–4% of the white infants and are less common in the African and Asian races [1],[2].

IH natural course consists of a rapid proliferative phase in infancy which is followed by a gradual involutional phase over the next several years of life. Most cases of IH are treated by active nonintervention and observation. In cases of any function-threatening hemangiomas or airway lesions, active intervention is required. Psychological affection of the child or parents and the number of lesions are also associated factors to be considered [3],[4].

After being first reported by Léauté-Labrèze et al. [5], multiple studies have confirmed the therapeutic effect of propranolol on IH [6],[7]. Before propranolol, systemic corticosteroids have been the mainstay of treatment for several decades. However, owing to the systemic adverse effects of the drug, topical corticosteroids were used as an alternative. This was either by topical application or intralesional injections.

Our study aimed to compare between oral B-blockers and intralesional corticosteroids in treatment of infantile cutaneous hemangioma.

  Patients and methods Top

Two pediatric surgery tertiary centers participated in this study: Menoufia University and Benha Children Hospital. The study included 52 patients diagnosed with infantile cutaneous hemangioma. The study was registered and approved by the review board of the University of Menoufia. After obtaining consent, patients were randomized into two groups: group A patients underwent intralesional injection of corticosteroids (betamethasone) at a dose of 10–40 mg/ml in three to six separate sessions at an interval of 1 month, and group B patients were given oral B-blockers (propranolol) at a low dose of 0.5–1 mg/kg/day for 3–6 months.

All patients were subjected to the following: detailed history taking; thorough clinical examination to assess any associated congenital anomalies; cardiovascular workup, which was done with the help of pediatric cardiologists and involved baseline clinical observations (pulse, blood pressure, respiratory rate, weight and height); and echocardiogram. Routine laboratory investigations, including included complete blood picture, liver and kidney function tests, blood glucose level, were also done. Determination of the location and dimensions of hemangioma was based on direct measurement and photographic analysis. Radiological assessment was done using Doppler ultrasound to obtain baseline data with regards to site, size, depth, vascularity and flow.

In group A patients, local injection of betamethasone was done under local anesthesia using a 22-G needle until blanching of the hemangioma is observed. According to the initial size of the hemangioma and the response to treatment, the number of sessions was calculated.

In group B patients, parents were educated about the potential complications such as vomiting, hypoglycemia, and hypotension. Moreover, they were advised to keep a record of their child’s blood pressure and blood sugar at a regular interval of 2 weeks.

Patients were followed up monthly for changes in size and color of the hemangioma and the occurrence of any complications for 6 months. Regression size was classified into excellent (75–100% decrease in size), good (50–75% decrease in size), poor (25–50% decrease in size), and no response.

  Results Top

A total of 26 patients were included in each group, where most patients were females (15 in group A and 14 in group B), with a median age of 2 years in both groups. Patients’ demographics in each group are illustrated in [Table 1]. Most common sites were the face followed by abdomen and back.
Table 1 Demographics of patients included in the study

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In the intralesional corticosteroids group (group A), ‘good’ response to treatment was observed in nine patients, and 14 patients had either poor or no response. Only three patients exhibited more than 75% decrease in size after 6 months. On the contrary, most patients in the B-blockers group had either excellent or good response (n=21), and four patients did not respond to treatment, one of which had stopped treatment owing to development of hypotension and another was noncompliant. One patient had poor response to treatment. Apart from two patients, all patients in group B displayed an improvement or fading of the color of the lesion. This was better than patients in group A, where only 19 reported improvement of appearance. Ulceration occurred in two patients after steroids injection, whereas treatment with B-blockers had to be stopped in one patient after developing hypotension.

  Discussion Top

Multiple treatments for treating hemangiomas have been investigated including corticosteroids (systemic or intralesional), B-blockers, interferon alpha, laser, immunomodulators, embolization, and surgery [8].

Propranolol is a nonselective β-adrenergic receptor blocker that was found to have three different pharmacological effects on IH: early, intermediate and long-term effects. After initiation of therapy, the B2 inhibitory effect decreases the release of vasodilator transmitters such as nitric oxide causing vasoconstriction of feeding capillaries eventually leading to a visible change of color and softening of the lesion. The intermediate effects are owing to downregulation of pro-angiogenic factors such as vascular endothelial growth factors and basic fibroblast growth factors. Finally, propranolol causes apoptosis in the post-proliferative phase, resulting in regression of the hemangioma [9].

There is no consensus on the initiation age of propranolol in treatment of hemangiomas. A recent meta-analysis showed that oral propranolol was initiated at a mean age of 6.6 months (range, 3 days to 10 years) [10] In a single-center prospective study of 174 children, propranolol was administered at a mean age of 4.8 months (0.9–29 months) [11]. 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 to 12 months). In 11 cases, propranolol was started after 12 months of age [12].

In the recent consensus conference report on hemangioma, a target dose of 1–3 mg/kg has been recommended [4]. Few authors have also used a maximum dose of 4 mg/kg/day [13].

The duration of therapy depends on the morphological type of hemangioma, extent of involvement, and the treatment indications. In a recent randomized controlled trial by Hogeling et al. [14], treatment was for 6 months and can be increased up to 1 year in cases of deep and mixed IH. Marqueling et al. [10] 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).

Multiple studies agreed on the therapeutic efficacy of propranolol. Again, Marqueling’s et al. [10] meta-analysis shows that the overall response of IH to propranolol rate is 98% (range, 82–100%). The treatment response in most of the published studies is based on the visual changes in the color and volume and assessment of serial photographs. Only few studies categorized the response in terms of percentage reduction. In a study by Price and colleagues, response was categorized in terms of percentage reduction. They report more than 75% clearance in 81% of the cases over a mean period of 7.9 months. Similarly, Talaat et al. [7] reported 75% clearance in 75% and more than 50% clearance in 94% of their 80 cases with IH in 5–8 months (mean±SD, 6.53±0.75).

Moreover, propranolol was found to have the same therapeutic effect on life-threatening and complicated hemangiomas. Hermans et al. [11] reported improvement of respiratory symptoms in airway hemangioma within hours of treatment initiation with propranolol. 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) [15]. Our study confirmed the therapeutic effect of B-blockers, as 80% of our patients who underwent this treatment showed more than 50% regression in size of the hemangioma.

Further studies established additive value in the treatment of superficial periocular hemangioma from combining topical beta-blockers (timolol maleate) with systemic administration [16].

Documented adverse effects of propranolol include hypoglycemia, hypotension, pulmonary symptoms, sleep disturbances, somnolence, cold extremities, and gastrointestinal complaints. These adverse reactions are found to be reversible and dose dependent [4]. In 174 patients treated for IH from a single center, 62.1% had one or more adverse reactions. The two most common problems were cold extremities and nocturnal restlessness. Lower blood pressure was observed in six (3.4%) cases. Sixteen (3.2%) patients had pulmonary symptoms, of whom nine needed treatment. In 12 (6.9%) children, gastrointestinal complaints were recorded [12]. The other adverse effects reported in the literature include irritability, profuse sweating, and temporary hypotonia [10].

Systemic corticosteroids (prednisolone) have been the mainstay of treatment for IH for several decades. The mechanism of action of steroids is not entirely clear, though it is postulated to have an inhibitory effect on the production of vascular endothelial growth factor A by stem cells in hemangiomas [17],[18]. Steroids are most effective in the early proliferative phase. The usual recommended dose is 2–4 mg/kg/day, which should be continued until cessation of growth or shrinkage of hemangioma followed by gradual tapering [19].

However, long-term steroid use is associated with many adverse effects. Boon et al. [21] studied the complications of systemic steroids in treatment of hemangiomas, and they identified Cushingoid facies in 44 of 62 children, which began 1–2 months after starting a dose of 2–3 mg/kg/day. This was more common in patients who received therapy for more than 6 months [20]. Other adverse effects included faltering growth, weight gain, and personality changes such as mood changes, irritability, insomnia, and restlessness. Other adverse effects include gastric irritation, oral and/or perineal candidiasis, and steroid myopathy. Mazzola [22] first reported the use of intralesional corticosteroid injection for the treatment of hemangiomas in an attempt to overcome the steroidal systemic effects.

A systematic review by Prasetyono and Djoenaedi [23] found excellent results in 71% and good results in 23.4% in cases of head and neck hemangiomas treated by intralesional steroids, most commonly triamcinolone acetonide. Few cases exhibited systemic complications, with 42% of cases reporting no complications, either systemic or local. The most common local complication reported was ulceration (10 cases) followed by atrophy of skin (six cases). In a smaller study including six patients, all patients were reported to experience adrenal suppression [24]. In our study, 53% of our patients exhibited poor or no response to treatment, and ulceration occurred in two patients.

  Conclusion Top

Our study confirms the superiority of oral B-blockers in the treatment of superficial IH when compared with intralesional injection of steroids. B-blockers display more effective lesion clearance whether in size or color and are associated with fewer complications. Combining that with the easier administration orally when compared with intralesional injections, we believe oral B-blockers should be considered as the first-line agent in treatment of IH.

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Conflicts of interest

There are no conflicts of intererst.

  References Top

Li J, Chen X, Zhao S, Hu X, Chen C, Ouyang F et al. Demographic and clinical characteristics and risk factors for infantile hemangioma: a Chinese case-control study. Arch Dermatol 2011; 147:1049–1056.  Back to cited text no. 1
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Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics 2006; 118:882–887.  Back to cited text no. 3
Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics 2013; 131:128–140.  Back to cited text no. 4
Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008; 358:2649–2651.  Back to cited text no. 5
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Zakaria OM, Sadek FS, Sultan TA, Mousa A, EL Sayem K, Daoud MY et al. Management of infantile periorbital hemangiomas: a revisit. Egypt J Surg 2019; 38:478–484.  Back to cited text no. 8
Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol 2010; 163:269–274.  Back to cited text no. 9
Marqueling AL, Oza V, Frieden IJ, Puttgen KB. Propranolol and infantile hemangiomas four years later: a systematic review. Pediatr Dermatol 2013; 30:182–191.  Back to cited text no. 10
Hermans DJ, Bauland CG, Zweegers J, van Beynum IM, van der Vleuten CJ. Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions. Br J Dermatol 2013; 168:837–843.  Back to cited text no. 11
Menezes MD, McCarter R, Greene EA, Bauman NM. Status of propranolol for treatment of infantile hemangioma and description of a randomized clinical trial. Ann Otol Rhinol Laryngol 2011; 120:686–695.  Back to cited text no. 12
Kulungowski AM, Alomari AI, Chawla A, Christison-Lagay ER, Fishman SJ. Lessons from a liver hemangioma registry: Subtype classification. J Pediatr Surg 2012; 47:165–170.  Back to cited text no. 13
Hogeling M, Adams S, Wargon O. A randomized controlled trial of propranolol for infantile hemangiomas. Pediatrics 2011; 128:e259–e266.  Back to cited text no. 14
Price CJ, Lattouf C, Baum B, McLeod M, Schachner LA, Duarte AM et al. Propranolol vs corticosteroids for infantile hemangiomas: a multicenter retrospective analysis. Arch Dermatol 2011; 147:1371–1376.  Back to cited text no. 15
Hermans DJ, van Beynum IM, Schultze Kool LJ, van de Kerkhof PC, Wijnen MH, van der Vleuten CJ. Propranolol, a very promising treatment for ulceration in infantile hemangiomas: a study of 20 cases with matched historical controls. J Am Acad Dermatol 2011; 64:833–838.  Back to cited text no. 16
Marey HM, Elmazar HF, Mandour SS, Khairy HA. Combined oral and topical beta blockers for the treatment of early proliferative superficial periocular infantile capillary hemangioma. J Pediatr Ophthalmol Strabismus 2018; 55:37–42.  Back to cited text no. 17
Khan ZA, Boscolo E, Picard A, Psutka S, Melero-Martin JM, Bartch TC et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest 2008; 118:2592–2599.  Back to cited text no. 18
Greenberger S, Boscolo E, Adini I, Mulliken JB, Bischoff J. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med 2010; 362:1005–1013.  Back to cited text no. 19
Bennett ML, Fleischer AB Jr, Chamlin SL, Frieden IJ. Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation. Arch Dermatol 2001; 137:1208–1213.  Back to cited text no. 20
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Mazzola RF. Treatment of haemangiomas in children by intralesional injection of steroids. Chir Plast (Berl) 1978; 4:161–168.  Back to cited text no. 22
Prasetyono TO, Djoenaedi I. Efficacy of intralesional steroid injection in head and neck hemangioma. Ann Plast Surg 2011; 66:98–106.  Back to cited text no. 23
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