Pediatrics and Neonatology (2018) 59, 390e396

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Original Article

Effect of oral propranolol on periocular

Capillary Hemangiomas of Infancy*
Kirthi Koka a, Bipasha Mukherjee a,*, Sumita Agarkar b

a
Orbit, Oculoplasty, Reconstructive & Aesthetic Services, Sankara Nethralaya, Medical Research
Foundation, Chennai, India
b
Dept of Pediatric Ophthalmology & Strabismus, Sankara Nethralaya, Medical Research Foundation,
Chennai, India

Received Nov 26, 2016; received in revised form Sep 2, 2017; accepted Nov 30, 2017
Available online 6 December 2017

Key Words Background: To assess the safety and efficacy of oral propranolol in the management of perio-
capillary cular Capillary Hemangiomas of Infancy (CHI).
hemangioma; Methods: Medical records of 21 infants diagnosed with periocular capillary hemangioma during
ptosis; a period of 5 years from 2009 to 2014 were retrospectively reviewed. The data collected
propranolol; included demographic details, clinical features and details of imaging studies and response
periocular; to the therapy. All patients received oral propranolol under the supervision of a pediatrician.
proptosis The initial dose was 0.2e1 mg/kg body weight, which was increased to 2 mg/kg body weight (3
divided doses) in 48 h if there was no adverse reaction to the initial dose. The response to the
treatment was assessed clinically as well as by radiographic imaging. Photographic documen-
tation was done periodically.
Results: Out of 21 patients, 18 were females and remaining three were males. The median age
at the time of presentation was 4 months. The most common presenting feature was lid mass
(n Z 17, 80%) followed by proptosis (n Z 7, 33%). Reddish discoloration of face was seen in 2
(1%) patients. All patients showed reduction in the size of the lesion. None of the patients
included in this study had any adverse reaction to propranolol or recurrence following cessa-
tion of the therapy.
Conclusion: Oral propranolol is highly effective and safe in the treatment of periocular capil-
lary hemangiomas in infants.
Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

*
Presentations: Part of this study has been presented in 1. Tamil Nadu Ophthalmic Association Annual Meeting, 2014, Coimbatore, India.
2. All India Ophthalmology Conference, 2015, New Delhi.
* Corresponding author. Medical Research Foundation, 18, College Road, Chennai, 600 006, India. Fax: þ91 44 2825 4180.
E-mail address: beas003@yahoo.co.uk (B. Mukherjee).

https://doi.org/10.1016/j.pedneo.2017.11.021
1875-9572/Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Propranolol in Capillary Hemangiomas of Infancy
1. Introduction
Capillary Hemangioma of Infancy (CHI) is the most common
benign vascular tumor in children. Capillary hemangioma
involutes spontaneously by 7 years of age in up to 70% of the
patients.1,2 Hence historically management consisted of
close observation. However, CHI in the periocular region,
especially involving the upper eyelid, can be potentially
vision threatening specially in infants where it obscures the
visual axis. These infants require early intervention to
prevent stimulus deprivational amblyopia. Numerous ap-
proaches have been tried in such cases, such as oral or
intra-lesional corticosteroids.1,3 Oral propranolol, a non-
selective beta-blocker, is a recent addition in the arma-
mentarium against CHI.4 Propranolol causes endothelial cell
apoptosis, decreased blood flow along with inhibition of
angiogenesis thus causing a rapid decrease in size of the
lesion. Literature states a rapid onset of action as early as
within 1 week from onset of treatment. This rapid
onset along with low cost and side effect profile of the drug
makes it highly suitable for treatment. Most of the studies
on the efficacy of the drug include data from both peri-
ocular and systemic lesions. Data regarding use of pro-
pranolol for only periocular lesions are few and in the form
of case reports or small case series with very few reports
from India.1,2,5e7
We report a series of children with periocular capillary
hemangiomas who were treated with oral propranolol. To
the best of our knowledge, this is the largest series re-
ported from India.
2. Materials and methods
Records of 21 infants diagnosed with CHI during a period
of 5 years between 2009 and 2014 at a tertiary care
hospital in India were retrospectively reviewed. Institu-
tional review board and ethics committee approval was
taken and the study followed the tenets of declaration of
Helsinki.
Infants with periocular and orbital capillary hemangioma
causing severe mechanical ptosis with obscuration of visual
axis; progressive proptosis; significant anisometropia; or
gross cosmetic deformity were considered as indications for
treatment and were included in the study.
Demographic details including age, gender and gesta-
tional age at time of delivery were recorded for analysis. All
the infants underwent a comprehensive ophthalmic evalu-
ation including cycloplegic refraction and dilated fundus
evaluation using indirect ophthalmoscopy. Location and
size of the lesion were noted specially in reference to their
impact on the visual axis. Radio imaging was done to
establish the diagnosis if indicated. Most children under-
went magnetic resonance imaging (MRI) as it helps to
delineate the lesion better and decreases the risk of
exposure to radiation which occurs with Computed To-
mography (CT). Imaging was done in children under seda-
tion with clinically evident proptosis with no external lesion
or children with cutaneous lesions in whom an orbital
component was suspected. MRI was the preferred modality
of imaging. MRI was repeated, if, on follow up, no evidence
of regression of the lesion was detected, or when some
391
amount of residual lesion was suspected. The response to
treatment was measured clinically. Follow up was advised
after 1 week, 1 month, 3 months, 6 months and 1 year.
Photographic documentation was done periodically at each
follow up to assess decrease in the size of the lesion. For
the purpose of this study, improvement was defined as
either a decrease in the size of lesion based on serial
photographs or on imaging findings when present. Change in
the color or texture of the skin overlying the lesion was also
documented.
All patients underwent a detailed systemic and cardiac
evaluation prior to the therapy. The therapy was initiated
under the supervision of a pediatrician. Inpatient younger
than 6 months, the initial dose of propranolol was 0.2 mg/
kg body weight in three divided doses. Blood glucose level
and blood pressure were monitored for a period of at least
48 h. In the absence of any adverse reaction, the dose was
increased to 2 mg/kg body weight/day. In patients older
than 6 months; the initial dose of oral propranolol was
1 mg/kg body weight. It was increased to 2 mg/kg body
weight after 48 h of monitoring provided there were no
adverse events. Dose was adjusted as the infants gained
weight during the follow up. Each patient was initially
reviewed after 1 week and then at 1 month, 3 months, 6
months and 1 year, by both the ophthalmologist as well as
the pediatrician. All children received oral propranolol
throughout the duration of their proliferative phase. Chil-
dren showing significant decrease or complete resolution of
the lesion clinically or radiologically were advised to taper
oral propranolol over a period of 2 weeks and then stop the
medication.
All data were maintained using Microsoft Excel and
analyzed using SPSS software 14.0. A p value of <0.05 was
considered statistically significant.
3. Results
The median age at the time of presentation was 4 months
(interquartile range: 7.50 months). Out of 21 patients, 18
(85%) were female. All infants, barring two were full
term babies. The average duration of presenting symp-
toms was 4.11 months. The most common presenting
features were lid mass (n Z 17) followed by proptosis
(n Z 7). Reddish discoloration on the face was also seen
in 2 patients. Six infants (28.57%) had lid swelling that
obscured the visual axis (Fig. 1a & b). Magnetic Reso-
nance Imaging (MRI) was done in 15 patients, Computed
Tomography (CT) scan in two and ultrasonography (USG)
in one patient. Based on the imaging, the lesions were
found to involve the intra and extra-conal compartments
in 4 patients, preseptal and extraconal spaces in 3 pa-
tients, purely extraconal in 4 patients and intraconal in 1
patient (Fig. 2a, b, c & d).
Two out of the 21 patients were lost to follow up. All the
remaining patients showed improvement on clinical exam-
ination, as well as on imaging. Improvement was noticeable
as early as within 1 week of initiating therapy in 6 patients.
Nine patients showed significant improvement between 2
and 8 weeks and remaining 4 patients showed improvement
by the 20the24th week (Figs. 3 and 4). The average dura-
tion for first signs of clinical improvement was at around
392 K. Koka et al

complete resolution of the lesion. Remaining five patients

had significant reduction in the size of the lesion clinically
as well as radiologically to warrant tapering of the drug.
Oral propranolol was gradually tapered in all children and
stopped. Six patients remained under our care for further 3
years after the cessation of the therapy. None of them
showed any signs of recurrence.

4. Discussion

Capillary Hemangiomas of Infancy (CHI) constitute 8e10%

Figure 1 Children presenting with capillary hemangioma of
infancy. a) Right upper eyelid mass causing mechanical ptosis.
b) Right eye proptosis due to periocular as well as orbital
hemangioma.
7.47 weeks (range: 1e24 weeks). Duration of treatment
varied from 8 to 56 weeks.
Nine patients out of 21 continued to be under follow up
(range from 1 month to 12 months). Four of these showed
of the benign pediatric tumors with 80% of them occurring
in the head and neck region.3,4 These are vascular tumors
and consist of rapidly dividing endothelial cells.5 Predis-
posing factors include female gender, low birth weight and
pre-term birth.8 Even though prematurity is a known risk
factor only two patients in our series had history of pre-
maturity. They are not apparent at birth but are charac-
terised by rapid growth between 3 and 12 months of age
(proliferation phase) followed by spontaneous regression
between 3 and 7 years of age (involution phase).1,9 Most
cases are asymptomatic and do not require any interven-
tion. However, about 10% of hemangiomas are associated
with significant morbidity and functional impairment,

Figure 2 Imaging: a) Axial and b) Sagittal view MRI showing a well-circumscribed, lobulated mass containing flow voids, hypo-
intense/intermediate signal on T1W signal, and homogenous hyper intense signal with internal flow voids and septae in T2 W1
suggestive of capillary hemangioma in the intraconal space. c) Coronal and d) Axial CT scans showing homogeneously enhancing
lobulated mass lesion in the nasal preseptal as well as orbital space.

Figure 3 a) Child presenting with an ulcerated capillary hemangioma. b) Lesion after 1 week of oral propranolol showing healing
of ulcer. c) Lesion after 3 more weeks of treatment showing fading and decrease in size of lesion.
Propranolol in Capillary Hemangiomas of Infancy 393

Figure 4 a) Patient presenting with typical strawberry lesion. b) Lesion showing significant resolution after 3 months. c) After 12
months e minimal residual lesion with clear visual axis.

airway obstruction or ulceration, and require early inter-
vention to prevent scarring and cosmetic disfigurement.10
Ocular involvement can occur in the form of proptosis,
optic nerve compression, astigmatism and ptosis causing
obscuration of visual axis, leading to significant amblyopia.
All of these are potentially vision threatening in infants and
require prompt intervention.4,6,7 In our study six children
had eyelid swelling leading to mechanical ptosis and
obscuration of the visual axis. Seven children presented
with significant proptosis and the remaining eight had
periocular mass and skin discoloration causing cosmetic
deformity. We compared the median (spherical equivalent)

Table 1 Management protocol of periocular and orbital Capillary Hemangiomas of Infancy.

Treatment protocol for periocular CHI
Pretreatment evaluation
Comprehensive ophthalmic examination including cycloplegic refraction and fundus examination
Pediatrician evaluation to rule out any systemic problem, bronchospasm, cardiac abnormality (blood pressure, heart rate,
echocardiogram, electrocardiogram), blood sugar levels, PHACE Syndrome.
Documentation of size of lesion
Photographs
Clinical drawings
Measurement of ptosis/proptosis
Imaging (MRI without contrast)
Dosage
Oral suspension produced by dissolving 10 mg tablet in 5 ml of water
Children <6 months are started on 0.2 mg/kg/day
Children >6 months are started on 1 mg/kg/day
Monitor blood sugar and blood pressure in the first 48 h
If no adverse effects dose increased to 2 mg/kg/day in 1e2 weeks
(Total daily dose is administered in two-three divided doses)
Parent counseling
The risk of side effects may be minimized with proper education of parents or guardians about possible bradycardia,
hypoglycemia, hypotension, lethargy and diarrhea. Special care is needed in the first month of life as these infants are prone
to hypoglycemia due to non- regularization of feeding habit. Mothers need to be counseled about frequent and compulsory
feeding of the baby; to administering propranolol during or right after feeding and to stop treatment if the infant’s oral
intake is insufficient.
Adjunct management
Treat amblyopia with patching and glasses when and if required
Follow up
Assessment of ptosis/proptosis and photographic documentation of patients each visit
Cycloplegic refraction every 6 months
Follow up at 1 week initially; followed by follow up at 1 month, 3 months, 6 months and 1 year for adjustment of dose according
to weight
Evaluation by both Ophthalmologist and Pediatrician each visit
Stopping treatment
Continue treatment till there is significant regression or complete resolution of lesion
Preferably continue treatment till the age of 9e11 months (progressive phase of the lesion)
Stop oral propranolol over 2 weeks by tapering the dose (by serial halving)
Follow up the patients for signs of recurrence every 3 months for 1 year
Yearly follow up thereafter
394 K. Koka et al

pre and post treatment in the involved eye and found no
significant difference in the spherical equivalent. This is in
contrast to Snir et al. who in their series of 30 patients
found a statistically significant reduction in cylindrical
power (41%, p Z 0.02) and a non-significant reduction in
spherical power (31%, p Z 0.15) pre and post treatment
with oral propranolol in the affected eye.7 This could be
due to the lesser number of children in whom refractive
data was available in our study and a more meticulous
collection of refractive data by Snir at all. We also found
that one patient who did not have visually significant
refractive error at the time of presentation, however
developed astigmatism later. We believe that this just re-
flects a more reliable reading at an older age rather than
the effect of therapy.
Corticosteroids, either orally or through intra lesional
injection, have been the mainstay of treatment.1,3,11
However, steroids are only effective during the early pro-
liferative phase between 1 and 4 months of life, and do not
play a significant role in tumor regression.12 A majority of
children referred for therapy are older, hence the efficacy
of steroids is open to debate. In our study the mean age of
presentation was 4 months, which was during the prolifer-
ative phase of growth. However oral propranolol was cho-
sen as the modality of treatment. Propranolol though not
free of side effects, is safer if administered starting at a
lower dose with gradual increase in dose under careful
monitoring. Steroids in any form, especially in children, are
associated with systemic adverse effects such as weight
gain, cushingoid facies, hypertension and adrenal suppres-
sion. Local adverse effects such as hypopigmentation at the
injection site, central retinal vein occlusion and resultant
blindness have also been reported following intralesional
injections.3,12
Other pharmacological agents which have been used
include vincristine, cyclophosphamide, interferon alpha,
laser and surgical excision, all of which are associated with
significant adverse effects.1,2,12
Leaute-Labreze and colleagues first reported the inci-
dental regression of capillary hemangiomas in infants
treated with oral propranolol for cardiac and renal prob-
lems in 2008.13 Following their serendipitous discovery,
several reports on the efficacy of oral propranolol in sys-
temic capillary hemangiomas such as hepatic, sub glottis,
retroperitoneal, meditational and cutaneous hemangiomas
have been published.3,10,12
Propranolol is a non-selective beta-blocker, approved
for the treatment of arrhythmia, hypertension, thyrotoxi-
cosis and migraine prophylaxis. Regression of hemangioma
perhaps is a result of down regulation of growth factors
such as vascular endothelial growth factor (VEGF) and basic
fibroblast growth factor (FGF) which play a vital role in
tumor proliferation. Other postulated mechanisms include
decreased production of cyclic AMP in cell signaling

Table 2 Demographics, dosage and duration of treatment.

Pt. Age Sex Duration of Clinical features Location of lesion Dosage of oral First clinical 2nd Follow
No. (months) symptom Lid mass Proptosis on imaging propranolol improvement up (months)
(months) (weeks)
1 12 M 12 Yes No Preseptal þ extra conal 2 mg/kg 2 NA
2 4 F 4 Yes No NA 2 mg/kg 8 NA
3 7 F 3 Yes No Preseptal þ extra conal 2 mg/kg 4 9
4 1 F 1 Yes Yes Preseptal þ extra conal þ 0.2 mg/kg 1 9
intraconal
5 1 F 1 No Yes Intraconal þ extraconal 0.2 mg/kg 1 6
6 5 F 3 No Yes Intraconal 2 mg/kg 1 2
7 12 F 12 Yes No NA 2 mg/kg 22 NA
8 6 M 3 Yes No Extraconal 1 mg/kg 1 6
9 2 F 1 Yes No NA 0.2 mg/kg 1 NA
10 3 F 2.5 Yes No Preseptal 0.2 mg/kg 8 NA
11 10 F 9.5 Yes No NA 2 mg/kg 20 NA
12 4 F 4 Yes No NA LTF LTF NA
13 6 F 5 Yes No Preseptal þ post septal þ 2 mg/kg 4 2
extra conal þ intraconal
14 1 F 1 Yes Yes Preseptal þ extra conal 0.2 mg/kg 1 1
15 1 F 0.3 Yes No Extraconal þ intraconal 0.2 mg/kg 2 1
16 2 M 0.5 No Yes Intraconal þ extraconal 2 mg/kg 6 4
17 12 F 12 Yes No Preseptal 2 mg/kg 20 NA
18 96 F 0.5 No Yes Intra þ extra conal LTF LTF NA
19 9 F 4 Yes No Extraconal 1 mg/kg 8 NA
20 4 F 3 Yes No Extraconal 2 mg/kg 8 NA
21 4 F 4 Yes Yes Extraconal 1 mg/kg 24 NA
M e Male; F e Female.
NA e Not available.
LTF e Lost to follow up.
Propranolol in Capillary Hemangiomas of Infancy
pathways and induction of apoptosis (programmed cell
death).3,8,9,12,14
Reduction in the size of the lesion occurs as early as
few hours to within few days following administration.
Change in the color of the lesion and softening of the
mass is observed due to vasoconstriction.4,6,15 Nearly one
third of our patients had visible improvement within a
week.
Adverse effects of propranolol include hypotension,
bradycardia, hypoglycemia, bronchospasm, sleep distur-
bance, nightmares, diarrhea, and hyperkalemia. These ef-
fects are usually innocuous and can be prevented by close
monitoring.1e3,12,15 The recommended dose is 2 mg/kg/day
and dose can be adjusted as infant gains weight.13,16 In a
recently published multicentre, randomized, double-blind,
adaptive, phase 2e3 trial assessing the efficacy and safety
of oral propranolol in infants with proliferating infantile
hemangioma, propranolol, with the highest benefit-to-risk
ratio, was administered 3 mg per kilogram per day for 6
months.17
A systematic review of 100 cases by Cornish et al. found
adverse reactions in 26 patients. Only 5 of those patients
required discontinuation of the drug.4 None of the patients
in our study necessitated discontinuation of therapy. There
were no documented adverse events in our series. We
believe that relatively low incidence of adverse events
observed in our series could be attributed to initiating the
therapy with a lower dose and then following it up with the
recommended dose gradually.
Propranolol should be gradually tapered by reducing the
dose to 50% for duration of 1e2 weeks and then dis-
continued following the resolution of the lesion. This pre-
vents rebound increase in size and rebound
tachycardia.8,15,18 The duration of treatment in our study
ranged from 8 to 56 weeks. Bagazgoitia et al. in their study
found that 5 out of 21 patients developed rebound growth
following abrupt cessation of the therapy. Xiao et al.
recorded a recurrence rate of 6 %in their study group of 64
patients treated with oral propranolol for capillary hem-
angiomas.19 This recurrence has been attributed either to a
premature withdrawal of the drug or to the presence of a
deeper extra and intra conal component of the tumor.20 As
of now, there is no consensus on cessation of the therapy.
We believe that treatment should continue throughout the
duration of proliferative phase, i.e. up to 12 months to
prevent recurrence.10,18,21 In our study 11 patients
continued to be on oral propranolol throughout the prolif-
erative phase followed by gradual tapering. We did not
observe any recurrence in the patients even after with-
drawing the drug.
Propranolol is now considered the first line drug for the
treatment of Capillary Hemangiomas of Infancy. Based on
our experience with this large series of patients at our
institute, and review of available literature, we recom-
mend a treatment protocol of periocular and orbital CHIs
(Table 1).
5. Conclusion
Oral propranolol is safe and effective in treating selected
cases of periocular Capillary Hemangiomas of Infancy which
395
require early intervention. Proper dosage of the drug and
monitoring of the patients, especially infants less than 6
months, is extremely important and prevent untoward ef-
fects (see Table 2).
COI statement
The authors have no conflicts of interest relevant to this
article.
Acknowledgements
Dr. Shubhra Goel, Consultant Ophthalmologist, Apollo
Hospitals, Hyderabad. Dr. Lalitha, Consultant pediatrician,
Kanchi Kamakoti Childrens Trust Hospital, Chennai. Dr.
Olma Veena Noronha, Consultant Radiologist, VRR scans.
Dr. Sabyasachi Sengupta, Sengupta’s Research Academy,
Mumbai, India for assistance in manuscript editing.
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