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Australasian Journal of Dermatology (2012) ,

doi: 10.1111/j.1440-0960.2012.00901.x

CASE SERIES

Effect of captopril on infantile haemangiomas:

A retrospective case series
ajd_901

1..3

Elizabeth M Christou and Orli Wargon

Department of Paediatric Dermatology, Sydney Childrens Hospital, Randwick, New South Wales, Australia

ABSTRACT
The mechanism of action of beta adrenergic blockers
in the involution of infantile haemangioma (IH)
remains unclear. It has been proposed that the reninangiotensin pathway may play a role. We present a
retrospective case series of 17 patients with IH who
were treated with oral corticosteroid therapy and
developed hypertension requiring treatment with the
angiotensin converting enzyme inhibitor, captopril.
All patients, with written documentation, demonstrated an improvement in their lesion at the start of
oral corticosteroid therapy (n = 14). Captopril alone
did not sustain the corticosteroid-induced involution
with a documented worsening of infantile haemangioma in seven out of 12 patients (58%).
Key words: angiotensin I converting enzyme, captopril, haemangioma, hypertension, infantile haemangioma, prednisolone, treatment.

INTRODUCTION
A recent proposition that the renin-angiotensin pathway
and hence that the angiotensin converting enzyme inhibitor
(ACEi) may play a role in the involution of infantile haemangioma (IH)1 led us to analyse retrospectively a case
series of patients with IH who developed hypertension
during corticosteroid therapy and who were subsequently
treated with captopril.
IH is the most common benign tumour of infancy, occurring in 2.6% of infants at 6 weeks of age.2 The natural
course of IH involves spontaneous involution over time.
Indications for treatment include IH that interfere with
function or may result in disfigurement. Up until 2008, systemic options for the treatment of IH were largely limited to
corticosteroids.3 Hypertension, a complication of systemic

Correspondence: Dr Elizabeth M Christou, Department of Paediatric Dermatology, Sydney Childrens Hospital, Randwick, NSW
2031, Australia. Email: lizzy.christou@gmail.com
Elizabeth M Christou, MBBS. Orli Wargon, FACD.
Submitted 23 November 2011; accepted 27 February 2012.

corticosteroids, occurs in 45% of children.4 Recent observational studies found that children with IH who were given
oral propranolol demonstrated a rapid improvement in the
lesions.5,6 Clinical trials have supported this observation.7
The pathogenesis of IH remains unclear. Vasculogenesis,
which involves the development of vessels that have differentiated from precursor cells in situ, may have an important
role in IH development.8 The CD133 stem cell has been
identified as the cell of origin in IH and an animal model for
IH has been developed.9
The mechanism of action of propranolol in the involution of IH remains speculative. The non-selective betaadrenergic antagonism of b1receptors and b2 receptors by
propranolol results in the inhibition of adrenaline-mediated
vasodilation.10 This relative vasoconstriction leads to a
reduction in blood flow that may be responsible for the early
effect of the softening of the IH within a few hours of taking
the medication. In the proliferative phase, IH have an
increased expression of proangiogenic factors, including
vascular endothelial growth factor (VEGF). Propranolol
leads to a reduced expression of VEGF and an inhibition of
angiogenesis.10 Propranolol may also induce endothelial
cell apoptosis. It has recently been suggested that the reninangiotensin pathway may account for the propranololinduced accelerated involution.1,11 Endothelial progenitor
cells present in proliferating haemangiomas express
angiotensin converting enzyme (ACE) and angiotensin II
receptor-2.1 These authors propose that renin drives haemangioma proliferation and that b-blockers supress renin
activity by decreasing ACE. This theory suggests that ACE
inhibitors and other angiotensin receptor-blocking drugs
may have a role in the treatment of proliferating IH by
inhibiting angiogenesis and vasculogenesis.
We explore the potential role of ACEi in IH management by
retrospectively looking at a cohort of IH patients exposed
to the ACEi captopril for treatment of corticosteroid-induced
hypertension. Captopril is a highly specific competitive

Abbreviations:
ACEi
IH
VEGF

2012 The Authors

Australasian Journal of Dermatology 2012 The Australasian College of Dermatologists

angiotensin converting enzyme inhibitor

infantile haemangioma
vascular endothelial growth factor

EM Christou and O Wargon

inhibitor of ACEi, the enzyme responsible for the conversion

of angiotensin 1 to angiotensin II.

METHODS
The study included all children who were seen in the Department of Paediatric Nephrology at Sydney Childrens Hospital
with hypertension following oral corticosteroid therapy
(prednisolone) for IH between October 2000 and March 2008
and who were started on the ACEi captopril. Further hand
searching of the vascular malformation clinic database and
the individual patient files was performed. A total of 19
children were identified who met the inclusion criteria, but
two of these patients were excluded because oral propranolol was introduced prior to the cessation of oral corticosteroids. Their medical records were searched for details of
their medical progress. At predefined time points in the
patients medical care, the subjective data on IH presentation
was stratified into five categories (no change, mild improvement, moderate improvement, unknown or worse). Ethics
approval for this research was obtained from the Sydney
Childrens Hospital Network.

Data
Participants In total, 17 patients were included in the
study. Of these 35% of the IH (n = 6) had ulceration prior to
starting oral corticosteroid treatment (Table 1). The indication for starting oral corticosteroids in those without ulceration included functional reasons in six patients (35%) and
increased growth in five patients (29%). The prednisolone
doses ranged from 12.5 mg/kg/day (mean 2 mg/kg, SD
0.3) at between 47172 days of age (mean 85 days, SD 37).
Corticosteroid-induced hypertension was diagnosed in all
but one patient in whom coarctation of the aorta was a
contributory factor.

Table 1

Of the 16 patients where the start and end dates of oral

steroid therapy was documented, the mean duration
of oral prednisolone was 140 days SD 74 (range 72
378 days). Captopril was initiated 370 days (mean 25
days SD 18) after prednisolone was first administered.
Three patients developed hypertension that could not be
controlled with a single agent and they were treated with
additional therapy. One patient (with coarctation of the
aorta) was treated with atenolol and two patients were
given additional nifedipine.
Two patients ceased their oral antihypertensive therapy
prior to the cessation of steroids (patients 2 and 9). Two
patients remained on captopril while being weaned off steroids, but for an unknown length of time (patients 5 and 10).
The mean time on oral captopril after the cessation of steroids for the 13 remaining patients was 22 days (range 092
days; SD26 days) and five of those patients had their captopril stopped within 1 day of ceasing steroids.
Of the 17 patients in the study only three patients were not
given any other oral medication. Of the 14 patients who were
administered oral medication other than antihypertensive
medication during the time they were on oral steroids, eight
patients had ranitidine, five had omeprazole, one had Gaviscon (Reckitt Benckiser, West Ryde NSW, Australia), one had
polaramine and three patients had antibiotics. In addition,
five patients had topical therapy, including topical antibiotics, topical steroids and barrier creams.

Change in infantile haemangioma with treatment After

starting prednisolone, 14 patients with descriptive data all
demonstrated an improvement in the IH; eight patients
demonstrated moderate improvement and six patients demonstrated mild improvement (Table 2). No patients were
worse or unchanged.

Patients data

Patient

Infantile haemangioma location

Ulceration

Maximum
steroid
dose (mg/kg)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

Perianal, buttock
Face, neck, lower lip, tongue, palate
Nose, eyelid, inner canthus
Eyelid, forehead
cheek
Lip, chin, cheeks, gingiva, tongue
Cheek
Nose, cheek, chin
Eyelid
Nose, cheek
Nose, cheek, eyelid
Lumbar
Eyelid
Eyelid
Nose
Eyelid
Eyelid

Yes
No
No
No
No
Yes
Yes
Yes
No
No
No
Yes
No
No
No
No
Yes

2
2
2
2.2
2
2.4
2
2
2
2
2.5
2
1
2
2
2
2

Age at starting
steroid (days)

Period on
steroids
(days)

Days after
starting steroids
to starting
captopril

Total period
on captopril
(days)

71
67
167
91
69
59
60
91
99
119
67
57
94
65
49
47
172

97
206
77
153
NA
378
165
126
118
72
165
97
86
103
106
152
136

70
39
18
15
3
14
27
21
23
55
47
19
16
15
14
13
8

28
62
59
174
NA
365
172
125
47
NA
118
119
162
89
106
159
149

NA, data not available.

2012 The Authors
Australasian Journal of Dermatology 2012 The Australasian College of Dermatologists

Effect of captopril on IH
Table 2

Change in infantile haemangioma (IH) with therapy

Change in IH while on steroids at appointment prior to starting

antihypertensives
Change in IH after 12 weeks on antihypertensives
Change in IH after 1 month on antihypertensives
Change in IH while being weaned from steroids onto captopril

After 12 weeks on captopril plus prednisolone, 10

patients had descriptive data available. None demonstrated
moderate improvement, 40% demonstrated mild improvement (n = 4), 30% demonstrated no change (n = 3) and 30%
of patients were worse (n = 3).
After 1 month of captopril and prednisolone, 13 patients
had descriptive data available. None demonstrated moderate
improvement, 39% patients demonstrated mild improvement (n = 5), 39% demonstrated no change (n = 5) and 23%
were worse (n = 3).
Of the 15 patients who remained on captopril while being
weaned from prednisolone, 12 patients had descriptive data
available. None demonstrated a moderate improvement, one
demonstrated a mild improvement (8%), 33% demonstrated
no change (n = 4) and 58% patients were worse (n = 7).

Follow up

No change
n (%)

Mild
improvement
n (%)

Moderate
improvement
n (%)

Worse
n (%)

Unknown
(n)

17

6 (35)

8 (57)

17
17
15

3 (30)
5 (39)
4 (33)

4 (40)
5 (39)
1 (8)

0
0
0

3 (30)
3 (23)
7 (58)

7
4
3

CONCLUSION
This small retrospective case series of patients with IH
who had been exposed to an ACEi has given us a unique
opportunity to observe the potential effect of captopril on
IH. The striking improvement observed with propranolol5
has not been replicated with captopril, suggesting that
the inhibition of ACEi is not involved in haemangioma
involution and the mechanism of action of propranolol
remains elusive.

REFERENCES
1.

2.

The mean follow-up time from the commencement of

steroid treatment was 3.8 years SD 2.9 (range 0.19.2
years). Three patients had undergone surgery, one patient
had received post-surgical vascular laser treatment and one
patient was treated with oral propranolol.

3.

4.

DISCUSSION
IH growth, ulceration or interference with function were
the main indications for steroid therapy and all patients
showed an initial improvement in the IH after starting on
oral prednisolone, consistent with published data.2
At time points 12 weeks and 1 month after starting captopril while on steroid therapy, 40% and 39% of patients
respectively continued to show a mild improvement in their
IH, but three patients (30% and 23% respectively) deteriorated at each time point. Being weaned from the steroids
while on captopril resulted in a deterioration in 58% of
patients, an improvement in 8% and no change in 33%. The
limitations of this study include the fact that the mean time
on captopril alone was only 3 weeks and the possibility of a
drug interaction with steroids cannot be ruled out. However,
the deterioration in the IH while on captopril alone is likely to
be due to being weaned from the steroid, and from this small
retrospective case series it appears that captopril alone was
not enough to sustain the improvement in the IH.

5.

6.

7.

8.

9.

10.

11.

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2012 The Authors

Australasian Journal of Dermatology 2012 The Australasian College of Dermatologists