2. METHODS
A systematic literature review from 1946 to March
of 2012 using the PubMed database of the National
Center for Biotechnology Information, National Li-
brary of Medicine (Bethesda, Md.), MEDLINE,
Google Scholar, and Cochrane database was com-
pleted for all relevant published studies describing
the use of propranolol or corticosteroids in the treat-
ment of infantile hemangiomas. Key words used
were “hemangioma,” “corticosteroid,” “proprano-
lol,” “beta-blockers,” “vascular malformations,” “cav-
ernous hemangioma,” “capillary hemangioma,” and
“cherry hemangioma.” All articles were reviewed for
reports of clinical cases, side effects, used doses, du-
ration of treatment, number of patients, and re-
sponse rate to treatment. Inclusion criteria included
studies with a clear indication of effect of propran-
olol or corticosteroids in the treatment of heman-
giomas in pediatric population. Studies without a
clear report of outcomes or those reporting the use
of steroids and propranolol for treatment of non-
cutaneous hemangiomas (visceral tissues, i.e., liver)
were excluded.
Data analysis was performed using R software
2.13.0, package META (function metaprop and
forest). Meta-analysis was carried out first by using
the Q statistic to test between-study homogeneity:
homogeneity was rejected when the Q statistic p
value was less than 0.10. Depending on whether
homogeneity was accepted or rejected, we used
the fixed or the random effect model to compute
the combined proportion of “success” and the 95
percent confidence interval. The I2 measure was
used to show the proportion of inconsistency be-
tween the studies that could not be explained by
chance alone. A value of p Ͻ 0.05 was considered
to be statistically significant.
Forest plot was graphed and contains individ-
ual studies representing the horizontal solid line
with their confidence intervals, and the surface of
the gray square proportional to the weight of the
study in the pooled estimate. Finally, meta-regres-
sion was performed to compare the two groups.
RESULTS
One thousand one hundred sixty-two studies
were identified (Fig. 1). Of those, only 56 articles
met our inclusion criteria after review by two in-
dependent reviewers (A.I. and J.K.) (Tables 1 and
2).3–62
Only 40 studies met final inclusion criteria
for meta-analysis (Fig. 1).
Efficacy and Complication Profile of
Corticosteroids
Nineteen studies comprising 2697 patients re-
ported use of oral or locally administered corti-
costeroids (Table 1). Of these, 2451 patients (90.8
percent) were treated for lesions located in the
head and neck, including airway hemangiomas.
The remaining 246 patients (9.2 percent) were
treated for lesions located on the trunk or
extremities.3
The most common dosage of corti-
costeroid was 2 to 3 mg/kg/day.3–5
Eight studies
investigated the effect of intralesional injection
of corticosteroid with a response rate of 66.4
percent.6–10
Duration of therapy was variable de-
Fig. 1. Flow chart of selection of articles for inclusion in systematic review.
Plastic and Reconstructive Surgery • March 2013
602
10. pending on the time period to improvement, most
commonly 4 to 8 weeks (Table 1).4
Sixteen studies
were included in the final meta-analysis, with an
overall efficacy of 69.1 percent (I2
ϭ 95 percent,
p Ͻ 0.0001) (Fig. 2). When intralesional studies
were omitted, the overall efficacy rate was seen to
be 71.0 percent compared with 97 percent for
propranolol (p Ͻ 0.0001) (Fig. 2).
The most common side effects reported were
altered growth (6 percent) and moon facies (5 per-
cent). Other reported side effects included osteo-
porosis, fungal infection, and hypertension (Table
2). Side effects were encountered in 475 of 2697
patients (17.6 percent), with a hemangioma resolu-
tion rate of 84.5 and 66.4 percent for systemic and
local administration, respectively (p Ͻ 0.0001).
Fig. 2. Meta-analysis comparing corticosteroids and propranolol in treatment of cutaneous infantile hemangiomas.
Plastic and Reconstructive Surgery • March 2013
610
11. Efficacy and Complications Profile of
Propranolol
Thirty-five studies comprising 799 patients
with an average reported age of 12.4 Ϯ 6.2 months
were identified and included initially for the effect
of propranolol, of which 600 patients had lesions
affecting the head and neck and the remaining
199 had lesions on the trunk or extremities (Table
2). The most commonly used dosage was 2 mg/
kg/d in divided doses of three or four times daily.11
Duration of therapy varied between 4 weeks and
12 months secondary to variable response rate.
All studies other than one reported a response
rate of greater than 90 percent. A single study
reported a 50 percent response rate following the
initial course of propranolol and a final 95 percent
response rate after additional courses.12
Overall,
98.9 percent of patients with infantile hemangio-
mas showed evidence of resolution of their lesions
following treatment with beta-blockers (Table 2).
Twenty-four studies finally met our inclusion cri-
teria for meta-analysis. Studies with fewer than 10
subjects were omitted. Meta-analysis demon-
strated an overall response rate of 97.3 percent
(I2
ϭ 68 percent, p Ͻ 0.0001) (Fig. 1).
Overall, 96 of 699 patients (13.7 percent) ex-
perienced side effects of propranolol therapy (Ta-
ble 2). There was no statistically significant differ-
ence observed between studies with fewer or
greater than 30 subjects. A comparison between
propranolol and corticosteroids in response rate
demonstrated statistical significance (71.0 percent
versus 97.3 percent; p Ͻ 0.0001).
DISCUSSION
Propranolol is a nonselective beta-blocker
commonly used to treat hypertension, congenital
cardiac abnormalities, and arrhythmias in the pe-
diatric population.13
It is an emerging therapy for
hemangioma associated with greater efficacy as
compared with steroids after either systemic or
local administration. In our systematic review, we
have demonstrated that propranolol was even
used in some refractory cases after initial cortico-
steroid therapy (Tables 1 and 2), with an overall
accumulative success rate of 91.0 percent for pa-
tients treated with only propranolol and an overall
rate of 98.9 percent.14,15
Performing meta-analysis
demonstrated a resolution rate of 97 percent com-
pared with 71 percent for propranolol versus sys-
temic corticosteroids.
Propranolol is thought to alter the course of
hemangioma growth by inducing vasoconstriction
and down regulation of angiogenic factors such as
vascular endothelial growth factor and basic fibro-
blast growth factor.2
Furthermore, it up-regulates
apoptosis of capillary endothelial cells. In addi-
tion, propranolol has been reported to be a se-
lective inhibitor of matrix metalloproteinase 9,
which further supports the antiangiogenic prop-
erties of propranolol.16
Liggett et al.17
describe a
certain protective genetic polymorphism in G pro-
tein–coupled receptor kinases, GRK5-Leu41, an
endogenous form of beta-blockade present in 40
percent of African Americans as a potential ex-
planation for the decreased incidence of heman-
giomas in the African American population.17,18
These observations and the success of propranolol
in treating hemangioma could suggest that beta-
adrenergic pathways have a critical role in angio-
genesis and progression of hemangioma. How-
ever, occasional regrowth of the lesion has been
reported on cessation of therapy, which can be
attributed to the effect of propranolol to maintain
hemangiomas in a regressed state rather than in-
ducing involution.19
After examining reported
complications, our review demonstrated that the
steroid therapy complication rate is more than
double when compared with propranolol (23 per-
cent versus 9.6 percent).
Boon et al.4
reported that the majority of chil-
dren who experienced growth retardation second-
ary to corticosteroid therapy returned to their pre-
treatment growth curve for height by 24 months
after cessation of a 2-week steroid course. How-
ever, numerous courses of steroid therapy can last
more than 2 weeks, leading to serious long-term
side effects.5
In contrast, propranolol side effects should be
monitored closely and dosage should be adjusted
in the event of developing side effects such as low
mean blood pressure of less than 50 mmHg, heart
rate less than 90 beats per minute, or glucose levels
less than 4 mM (72 mg/dl).20
Thus, many studies
recommend that, before initiation of therapy, pa-
tients should undergo a thorough cardiac workup
including an electrocardiogram and monitor for
any signs of bradycardia or hypoglycemia during
treatment initiation.7,20,21
Some studies suggest that most of the improve-
ment with propranolol treatment occurs in the
deep components of the lesion, whereas steroid
therapy usually results in improvement of super-
ficial components.12
Thus, propranolol could be
an effective adjunct to corticosteroid therapy. Un-
like local corticosteroids, use of local propranolol
was not shown to be as effective as systemically
administered propranolol.1,22
Volume 131, Number 3 • Treatment of Infantile Hemangioma
611
12. This study is not short of limitations. This re-
view includes only published data that could have
been affected by positive effect publication bias. In
addition, the effects of treatment on cutaneous
hemangiomas are subjective, which could also ad-
versely affect the outcomes. Another major draw-
back of this review is the absence of any random-
ized controlled trials comparing propranolol to
corticosteroid therapy. A randomized controlled
trial with a set dosage and duration of therapy with
appropriate follow-up is necessary to further val-
idate the observed therapeutic benefits of pro-
pranolol compared with corticosteroids.
CONCLUSIONS
Propranolol is an emerging, popular therapy
for treatment of hemangiomas, with promising
results and fewer side effects as compared with
corticosteroids. The discovery of propranolol’s
utility in treating hemangiomas has led to a better
understanding and treatment of the disease. The
present systematic review suggests that proprano-
lol therapy could be potentially superior to the
current standard first-line therapy with corticoste-
roids. However, further randomized controlled
studies are needed to evaluate and compare the
long-term effects of beta-blocker therapy for in-
fantile hemangiomas.
Ali Izadpanah, M.D., C.M., M.Sc.
Plastic and Reconstructive Surgery
McGill University Health Centre
760 Upper Lansdowne Avenue
Westmount, Quebec H3Y 1J8, Canada
ali.izadpanah@mail.mcgill.ca
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