J Huazhong Univ Sci TechnolMed Sci

DOI
10.1007/s11596-012-1059-6
32(6):923-926,2012
J Huazhong
Univ Sci TechnolMed Sci 32(6):2012

923

Topical Propranolol Hydrochloride Gel for Superficial Infantile

Hemangiomas
Lie WANG ( )1, Yin XIA ( )1, Yanan ZHAI ()1, Chengjin LI ()1#, Yiqing LI ()2#
1
Department of General Surgery, Fuzhou General Hospital of Nanjing Military Commands, Fuzhou 350025, China
2
Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
430030, China
Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2012

Summary: The clinical efficacy and safety of topical propranolol hydrochloride gel in the treatment of
superficial infantile hemangiomas (IHs) were assessed. Fifty-one cases of IHs from Oct. 2010 to Sept.
2011 were subjected to the topical propranolol hydrochloride gel intervention in Fuzhou General Hospital of Nanjing Military Commands, China. Changes in size, texture, color, peak systolic velocity of the
hemangiomas, resistance index and adverse effects were observed. The results were evaluated by using
Achauer system, and responses of IHs to pranpronolol were considered scale(poor) in 4 patients
(17.24%), scale(moderate) in 18 patients (24.14%), scale (good) in 22 patients (44.83%) and
scale (excellent) in 7 patients (13.79%). The response of superficial hemangiomas was significantly
better than other hemangiomas (P<0.05), and no differences in response were found among different
primary sites (P>0.05). Our study indicates that topical application of 3% propranolol hydrochloride gel
is effective and safe in treating IHs.
Key words: propranolol; hydrochloride gel; infantile hemangiomas

Infantile hemangioma (IH) is the most common

tumor in children, and its pathophysiology is still unclear.
Management of IH includes pharmacotherapy, surgery,
laser treatment and cryotherapy. In 2008, Laut-Labrze
noted that propranolol was effective in treating IH[1].
Then, propranolol was reported in more and more clinical researches and suggested the first-line agent[2].
We report the treatment of superficial IHs with
topical propranolol hydrochloride (3% gel) in 51 patients
admitted from Oct. 2010 to Sept. 2011.
1 MATERIALS AND METHODS
1.1 General Data
Fifty-one IHs children (22 males and 29 females)
meeting the inclusion criteria were accepted in our
out-patient clinic. Their ages varied from 28 days to 12
months (mean 3.8 months). The size of the tumor varied
from 5 mm5 mm to 78 mm18 mm. According to the
classification by Waner and Suen, of all the cases 28
were classified into superficial IH, 6 deep IH and 17
mixed IH. Considering the involved sites, there were 32
cases located in head and neck region, 10 cases in trunk
and 9 in extremities.
1.2 Inclusion Criteria
(1) Age<12 months, and definite diagnosis of hemangioma; (2) without propranolol contraindications
Lie WANG, E-mail: fzptwk@126.com
#
Corresponding authors, Chengjin LI, E-mail: licheng_jin@
yahoo.com.cn; Yiqing LI, E-mail: qzg599@126.com

such as sinus bradycardia, atrioventricular block, tracheal

bronchial asthma, bronchitis and pneumonitis etc.; (3)
without congenital heart disease or other systemic diseases; (4) without previous intervention; (5) signing informed consent by their parents or guardians.
1.3 Drugs and Administration
Propranolol hydrochloride gel was manufactured by
the Department of Pharmacy, Fuzhou General Hospital
of Nanjing Military Command, and its specifications
were 20 g:600 mg (3%). The formulation was as follows:
propranolol hydrochloride 3 g, chitosan 2 g, glycerol 10
g, azone 2 g.
All parents were instructed to gently spread 3%
propranolol hydrochloride gel topically onto the surface
of the hemangioma using their fingertip three times
daily.
During the initial two days of treatment in hospital,
we measured the vital signs of the children, fasting blood
sugar 2 h before and after the drug use. Changes in tumor
volume, and color were recorded at each follow-up time
point.
Drug was withdrawn under the following conditions:
(1) Hemangiomas fade away without recurrence after
withdrawing the gel; (2) Adverse response or other situations requiring ceasing this therapy happened.
All children were followed-up at 1s, 2nd, 3rd, 5th,
7th, 9th, and 12th month after starting this therapy.
1.4 Data Collection
Data collected before the therapy and within the
follow-up period included: (1) digital photographs of the
IHs taken by specially-assigned person; (2) changes in

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J Huazhong Univ Sci TechnolMed Sci 32(6):2012

the size, thickness as well as peak systolic velocity (PSV)

and resistance index (RI) measured by color Doppler in
all IHs; (3) electrocardiogram examination, changes in
blood pressure and heart rate; (4) routine blood test, biochemical test.
1.5 Outcome Evaluation
Achauer system was used to assess the clinical efficacy[3]: grade, bad, the reduction of the size<25%;
grade, medium, the reduction of the size between 26%
and 50%; grade , good, the reduction of the size between 51% and 75%; grade , excellent, the reduction
of the size>75%.
1.6 Statistical Analysis
Data of curative effect of different types, sites and
measurements were analyzed using Ridit. Measurement
data were described with s. The difference of measurement data was compared with t test between the two
groups. Count data and the measurement data of multiple
groups were compared by analysis of variance. P<0.05
was considered statistically significant.
Type of IHs
Superficial
Deep
Mixed
Total

Duration of the follow-up was 110 months. One

patient with deep hemangiomas in the forehead received
additional oral propranolol one month after topical application of 3% propranolol hydrochloride gel due to the
enlargement of IH. Three children took oral propranolol
instead 2 months later due to poor response. Other 47
children finished the propranolol gel treatment course.
All the 47 IHs experienced a gradual reduction in size
and hardness. Twenty-four of these cases were found an
increase in PSV and reduction in RI measured with color
Doppler.
Of the 51 cases, 4 (7.84%) were considered grade
, 18 (35.29%) grade , 22 (43.14%) grade and 7
(13.73%) grade .
Response of superficial hemangiomas was better
than that of deep or mixed type ones using Ridit analysis
(table 1, P<0.05).

Table 1 Effects of propranolol gel in different types of hemangiomas (%)

n
(%)
(%)
(%)
28
1 (3.57%)
7 (25.00%)
15 (53.57%)
6
2 (33.33%)
3 (50.00%)
1 (16.67%)
17
1 (5.88%)
8 (47.06%)
6 (35.29%)
51
4 (7.84%)
18 (35.29%)
22 (43.14%)

No significant differences in the response of IHs

between different lesion sites were found using Ridit
Location
Head and neck
Trunk
Extremities
Total

2 RESULTS

analysis (table 2, P>0.05).

Table 2 Effects of propranolol gel in different parts of hemangiomas (%)

n
(%
(%)
(%)
32
1 (3.13%
12 (37.50%)
15 (46.88%)
10
2 (20.00%
4 (40.00%)
3 (30.00%)
9
1 (11.11%
2 (22.22%)
4 (44.44%)
51
4 (7.84%
18 (35.29%)
22 (43.14%)

As compared with pretreatment, PSV was markedly

reduced, and RI was significantly increased after treat-

(%)
5 (17.86%)
0 (0)
2 (11.76%)
7 (13.73%)

(%)
4 (12.50%)
1 (10.00%)
2 (22.22%)
7 (13.73%)

ment (table 3, P<0.05).

Table 3 Changes in PSV and RI before and after treatment ( s, n=24)

Treatment duration (months)
0
1
3
5
7
PSV (cm/s)
69.3314.11
54.6213.74*
40.1913.62*
29.769.71*
23.3011.26*
RI
0.560.12
0.710.13*
0.780.14*
0.810.16*
0.840.11*
*
P<0.05 vs. pretreatment

9
21.229.32*
0.880.15*

Typical cases included: Male, 4 months old, with

superficial hemangioma located in extremities, receiving
treatment for two months, grade (fig. 1); Male, 7
months old, mixed hemangioma located on head, receiving treatment for 5 months, grade(fig. 2); Female, 5
months old, with mixed hemangioma located on head,
receiving treatment for 7 months, grade(fig. 3); Male,
12 months old, mixed type hemangioma located on head,
receiving treatment for 9 months, grade(fig. 4).
Of the 51 cases, 2 developed skin redness in the application area, and 1 developed red rash around the lesion. These symptoms disappeared spontaneously without any intervention. During the follow-up period, the
general conditions of the children were stable. No notable fluctuations in the heart rate, the blood pressure and
the fast blood-glucose level were observed. The electro-

cardiogram didnt show any abnormalities. Tiny but still

within normal range fluctuation in the blood routine and
the blood biochemistry indexes were observed during the
treatment course.

Fig. 1 A: Pre-treatment, PSV: 64 cm/s, RI: 0.54; B Two months

after treatment, color was faded. PSV: 41 cm/s, RI: 0.75

J Huazhong Univ Sci TechnolMed Sci 32(6):2012

925

Fig. 2 A: Pre-treatment, PSV: 77 cm/s, RI: 0.56; B: One month after treatment, the size of the hemangioma was reduced by 10%.
PSV: 64 cm/s, RI: 0.56; C: Three months after treatment, the size of the hemangioma was reduced by 40%. PSV: 48 cm/s, RI:
0.64; D: Five months after treatment, the size of the hemangioma was reduced by 95%. PSV: 21 cm/s, RI: 0.79

Fig. 3 A: Pre-treatment, PSV: 79 cm/s, RI: 0.59; B: One month after treatment, the size of the hemangioma was reduced by 25%.
PSV: 62 cm/s, RI: 0.70; C: One month after treatment, the size of the hemangioma was reduced by 90%. PSV: 25 cm/s, RI:
0.79

Fig. 4 A: Before the treatment, PSV: 65 cm/s, RI: 0.53; B: One month after treatment, the size of the hemangioma was reduced by
30%. PSV: 55 cm/s, RI: 0.69; C: One month after treatment, the size of the hemangioma was reduced by 70%. PSV: 27 cm/s,
RI: 0.74

3 DISCUSSION
IH is the most common tumor of infancy. Its typical
natural history is characterized by an early rapid growth
following birth and a slow spontaneous regression phase
within 3 to 7 years[4].
However, 10%15% of cases are associated with
the long-term esthetic risk, or threatened physiological
functioning that may cause substantial parental distress
and need interventions.
The efficacy of oral propranolol in treating IHs was
discovered serendipitously by Laut-Labrze in 2008,
and a limited number of clinical trials have confirmed
this biological effect of propranolol on proliferating IHs.
We also conducted the research on treatment of IHs
with oral propranolol since Jan. 2009, and the result was
encouraging[5].
However, inconvenience in tablet oral taking, unfa-

vorable treatment compliance and side-effects of systemic propranolol therapy were noted during our research.
In order to resolve the aforementioned problems and
yet maintaining the efficacy of propranolol, we proposed
to apply topical propranolol hydrochloride (3% gel) to
IHs.
Of 51 children admitted, 86.27% were considered
medium or better in terms of efficacy. The response of
superficial hemangiomas was better than that of deep or
mixed ones (P<0.05), but no significant differences between different lesion sites were found (P>0.05). As
compared with pretreatment, the PSV was markedly reduced and RI was significantly increased after treatment
(P<0.05).
The tumor of a deep type case, who received
one-month treatment, continued growing, which may
result from the rapid proliferative phase the tumor is in,
and poor permeability of thick tissue caused by deep

926
location. Additional oral propranolol (1 mg/kg, three
times every day) was prescribed for three months, and
the tumor regressed completely.
Three children receiving 2-month treatment didnt
get favorable recession after the tumor stopped expanding. They were asked to seek oral treatment instead.
All the other 47 patients finished the propranolol gel
treatment as scheduled. We found that topical propranolol gel has the similar effect on IHs as systemic
treatment by comparing with previous study, but the recession takes longer. It was considered to be due to the
poor drug absorption by skin and improper dose.
Whether the response resulted from the self-limiting
feature of IHs or the effect of propranolol gel awaits to
be further studied. Strict clinical double-blinded, randomized, placebo-controlled trials will be of help to resolve it.
Previous studies showed that propranolol also increased regression of hemangiomas in stable stage[6].
After receiving the treatment, all the tumors showed a
reduction or cessation in growth, decreased size and
faded color of IHs. Also, a reduction in PSV and an increase in RI were noted as compared with pretreatment.
Hence we thought that the propranolol gel played an
important role in changes aforementioned.
As a non-selective beta blocker, it was only 2 years
since propranolol was used to treat IHs. The potential
adverse effects should be highly concerned, as temporary
bradycardia, hypotension, hypoglycemia, bronchospasm,
hyperkalemia, etc. No bradycardia, hypotension, or hypoglycemia occurred in any of the 51 children enrolled
during the treatment. Two of them had skin redness in
the local area where the gel spread, and 1 case had red
rash around the tumor, which may be drug solvent related. These symptoms disappeared without any interference. We consider that propranolol gel is safe in treating IHs, however large samples and long term follow-up
are required.
The effects of propranolol on IHs were found by
chance, and the exact action mechanism of propranolol
in the treatment of hemangiomas remains unclear.
The underlying mechanism may involve[7]: in the
early stage, reduction in release of NO contributing to
less vasoconstriction makes the color of the tumors faded
and the tumor softer. As for medium stage, propranolol
blocks the angiogenesis signal by down-regulating the
RAF mitotic original to activate protein kinase pathway,
which slows down tumor growth. The long-term effect is
realized mainly by inducing the apoptosis of proliferative
capillary endothelial cells and degradation of the tumor

J Huazhong Univ Sci TechnolMed Sci 32(6):2012

cells. Itinteang[8] presented that propranolol might intervene the onset and development of the IHs by influencing the RAS. Of IHs, the PSV was reduced, and RI increased after treatment as compared with pretreatment,
which may be associated with decreased NO release by
the vascular tissue of the hemangiomas, resulting in the
vasoconstriction of the tumor. The best response of superficial type could be attributable to the direct contact
and action of propranolol and the highest absorption, but
the mechanism needs further exploration.
As more and more clinical researches focusing on
the action mechanism of propranolol in treatment for IHs,
further exploration of the efficacy and safety of the drug
on IHs is needed.
Our research shows that propranolol gel is effective
and safe in treating superficial IHs, especially for superficial hemangiomas in different sites.
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(Received Aug. 15, 2012)