CASE SERIES

Effect of captopril on infantile haemangiomas:A retrospective case seriesajd_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 blockersin the involution of infantile haemangioma (IH)remains unclear. It has been proposed that the renin-angiotensin pathway may play a role. We present aretrospective case series of 17 patients with IH whowere treated with oral corticosteroid therapy anddeveloped hypertension requiring treatment with theangiotensin converting enzyme inhibitor, captopril.All patients, with written documentation, demon-strated an improvement in their lesion at the start oforal corticosteroid therapy (n = 14). Captopril alonedid not sustain the corticosteroid-induced involutionwith a documented worsening of infantile haeman-gioma in seven out of 12 patients (58%).

Key words: angiotensin I converting enzyme, cap-topril, haemangioma, hypertension, infantile hae-mangioma, prednisolone, treatment.

INTRODUCTION

A recent proposition that the renin-angiotensin pathwayand hence that the angiotensin converting enzyme inhibitor(ACEi) may play a role in the involution of infantile hae-mangioma (IH)1 led us to analyse retrospectively a caseseries of patients with IH who developed hypertensionduring corticosteroid therapy and who were subsequentlytreated with captopril.IH is the most common benign tumour of infancy, occur-

ring in 2.6% of infants at 6 weeks of age.2 The naturalcourse of IH involves spontaneous involution over time.Indications for treatment include IH that interfere withfunction or may result in disfigurement. Up until 2008, sys-temic options for the treatment of IH were largely limited tocorticosteroids.3 Hypertension, a complication of systemic

corticosteroids, occurs in 45% of children.4 Recent observa-tional studies found that children with IH who were givenoral propranolol demonstrated a rapid improvement in thelesions.5,6 Clinical trials have supported this observation.7

The pathogenesis of IH remains unclear. Vasculogenesis,which involves the development of vessels that have differ-entiated from precursor cells in situ, may have an importantrole in IH development.8 The CD133 stem cell has beenidentified as the cell of origin in IH and an animal model forIH has been developed.9

The mechanism of action of propranolol in the involu-tion of IH remains speculative. The non-selective beta-adrenergic antagonism of b1receptors and b2 receptors bypropranolol results in the inhibition of adrenaline-mediatedvasodilation.10 This relative vasoconstriction leads to areduction in blood flow that may be responsible for the earlyeffect of the softening of the IH within a few hours of takingthe medication. In the proliferative phase, IH have anincreased expression of proangiogenic factors, includingvascular endothelial growth factor (VEGF). Propranololleads to a reduced expression of VEGF and an inhibition ofangiogenesis.10 Propranolol may also induce endothelialcell apoptosis. It has recently been suggested that the renin-angiotensin pathway may account for the propranolol-induced accelerated involution.1,11 Endothelial progenitorcells present in proliferating haemangiomas expressangiotensin converting enzyme (ACE) and angiotensin IIreceptor-2.1 These authors propose that renin drives hae-mangioma proliferation and that b-blockers supress reninactivity by decreasing ACE. This theory suggests that ACEinhibitors and other angiotensin receptor-blocking drugsmay have a role in the treatment of proliferating IH byinhibiting angiogenesis and vasculogenesis.We explore the potential role of ACEi in IHmanagement by

retrospectively looking at a cohort of IH patients exposedto the ACEi captopril for treatment of corticosteroid-inducedhypertension. Captopril is a highly specific competitive

Correspondence: Dr Elizabeth M Christou, Department of Paedi-atric Dermatology, Sydney Childrens Hospital, Randwick, NSW2031, Australia. Email: lizzy.christou@gmail.comElizabeth M Christou, MBBS. Orli Wargon, FACD.Submitted 23 November 2011; accepted 27 February 2012.

Abbreviations:

ACEi angiotensin converting enzyme inhibitorIH infantile haemangiomaVEGF vascular endothelial growth factor

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Australasian Journal of Dermatology (2012) , doi: 10.1111/j.1440-0960.2012.00901.x

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

inhibitor of ACEi, the enzyme responsible for the conversionof angiotensin 1 to angiotensin II.

METHODS

The study included all childrenwhowere seen in theDepart-ment of Paediatric Nephrology at Sydney Childrens Hospitalwith hypertension following oral corticosteroid therapy(prednisolone) for IH betweenOctober 2000 andMarch 2008and who were started on the ACEi captopril. Further handsearching of the vascular malformation clinic database andthe individual patient files was performed. A total of 19children were identified who met the inclusion criteria, buttwo of these patients were excluded because oral propra-nolol was introduced prior to the cessation of oral corticos-teroids. Their medical records were searched for details oftheir medical progress. At predefined time points in thepatientsmedical care, the subjective data on IHpresentationwas stratified into five categories (no change, mild improve-ment, moderate improvement, unknown or worse). Ethicsapproval for this research was obtained from the SydneyChildrens Hospital Network.

Data

Participants In total, 17 patients were included in thestudy. Of these 35% of the IH (n = 6) had ulceration prior tostarting oral corticosteroid treatment (Table 1). The indica-tion for starting oral corticosteroids in those without ulcer-ation included functional reasons in six patients (35%) andincreased growth in five patients (29%). The prednisolonedoses ranged from 12.5 mg/kg/day (mean 2 mg/kg, SD0.3) 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 acontributory factor.

Of the 16 patients where the start and end dates of oralsteroid therapy was documented, the mean durationof oral prednisolone was 140 days SD 74 (range 72378 days). Captopril was initiated 370 days (mean 25days SD 18) after prednisolone was first administered.Three patients developed hypertension that could not becontrolled with a single agent and they were treated withadditional therapy. One patient (with coarctation of theaorta) was treated with atenolol and two patients weregiven additional nifedipine.Two patients ceased their oral antihypertensive therapy

prior to the cessation of steroids (patients 2 and 9). Twopatients remained on captopril while being weaned off ste-roids, but for an unknown length of time (patients 5 and 10).The mean time on oral captopril after the cessation of ste-roids for the 13 remaining patients was 22 days (range 092days; SD26 days) and five of those patients had their cap-topril stopped within 1 day of ceasing steroids.Of the 17 patients in the study only three patients were not

given any other oralmedication. Of the 14 patients whowereadministered oral medication other than antihypertensivemedication during the time they were on oral steroids, eightpatients had ranitidine, five had omeprazole, one had Gavis-con (Reckitt Benckiser, West Ryde NSW, Australia), one hadpolaramine and three patients had antibiotics. In addition,five patients had topical therapy, including topical antibiot-ics, topical steroids and barrier creams.

Change in infantile haemangioma with treatment Afterstarting prednisolone, 14 patients with descriptive data alldemonstrated an improvement in the IH; eight patientsdemonstrated moderate improvement and six patients dem-onstrated mild improvement (Table 2). No patients wereworse or unchanged.

Table 1 Patients data

Patient Infantile haemangioma location Ulceration

Maximumsteroiddose (mg/kg)

Age at startingsteroid (days)

Period onsteroids(days)

Days afterstarting steroidsto startingcaptopril

Total periodon captopril(days)

1 Perianal, buttock Yes 2 71 97 70 282 Face, neck, lower lip, tongue, palate No 2 67 206 39 623 Nose, eyelid, inner canthus No 2 167 77 18 594 Eyelid, forehead No 2.2 91 153 15 1745 cheek No 2 69 NA 3 NA6 Lip, chin, cheeks, gingiva, tongue Yes 2.4 59 378 14 3657 Cheek Yes 2 60 165 27 1728 Nose, cheek, chin Yes 2 91 126 21 1259 Eyelid No 2 99 118 23 4710 Nose, cheek No 2 119 72 55 NA11 Nose, cheek, eyelid No 2.5 67 165 47 11812 Lumbar Yes 2 57 97 19 11913 Eyelid No 1 94 86 16 16214 Eyelid No 2 65 103 15 8915 Nose No 2 49 106 14 10616 Eyelid No 2 47 152 13 15917 Eyelid Yes 2 172 136 8 149

NA, data not available.

2 EM Christou and O Wargon

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

After 12 weeks on captopril plus prednisolone, 10patients had descriptive data available. None demonstratedmoderate improvement, 40% demonstrated mild improve-ment (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

haddescriptive data available. Nonedemonstratedmoderateimprovement, 39% patients demonstrated mild improve-ment (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 dataavailable. Nonedemonstrated amoderate improvement, onedemonstrated amild improvement (8%), 33% demonstratedno change (n = 4) and 58% patients were worse (n = 7).

Follow up

The mean follow-up time from the commencement ofsteroid treatment was 3.8 years SD 2.9 (range 0.19.2years). Three patients had undergone surgery, one patienthad received post-surgical vascular laser treatment and onepatient was treated with oral propranolol.

DISCUSSION

IH growth, ulceration or interference with function werethe main indications for steroid therapy and all patientsshowed an initial improvement in the IH after starting onoral prednisolone, consistent with published data.2

At time points 12 weeks and 1 month after starting capto-pril while on steroid therapy, 40% and 39% of patientsrespectively continued to show a mild improvement in theirIH, but three patients (30% and 23% respectively) deterio-rated at each time point. Being weaned from the steroidswhile on captopril resulted in a deterioration in 58% ofpatients, an improvement in 8% and no change in 33%. Thelimitations of this study include the fact that the mean timeon captopril alone was only 3 weeks and the possibility of adrug interaction with steroids cannot be ruled out. However,the deterioration in the IHwhile on captopril alone is likely tobe due to being weaned from the steroid, and from this smallretrospective case series it appears that captopril alone wasnot enough to sustain the improvement in the IH.

CONCLUSION

This small retrospective case series of patients with IHwho had been exposed to an ACEi has given us a uniqueopportunity to observe the potential effect of captopril onIH. The striking improvement observed with propranolol5

has not been replicated with captopril, suggesting thatthe inhibition of ACEi is not involved in haemangiomainvolution and the mechanism of action of propranololremains elusive.

REFERENCES

1. Itinteang T, Brasch HD, Tan ST, Day DJ. Expression of com-ponents of the rennin-angiotensin system in proliferatinginfantile haemangioma may account for the propranolol-induced accelerated involution. J. Plast. Reconstr. Aesthet. Surg.2010; 64:75965.

2. Dickison P, Christou E, Wargon O. A prospective study of infan-tile hemangiomas with a focus on incidence and risk factors.Pediatr. Dermatol. 2011; 28: 6639.

3. Bennett ML, Fleischer AB Jr, Chamlin SL, Frieden IJ. Oralcorticosteroid use is effective for cutaneous hemangiomas: anevidence-based evaluation. Arch. Dermatol. 2001; 137: 120813.

4. George ME, Sharma V, Jacobso J, Simon S et al. Adverse effectsof systemic glucocorticosteroid therapy in infants with heman-giomas. Arch. Dermatol. 2004; 140: 9639.

5. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, BoraleviF et al. Propranolol for severe hemangiomas of infancy. N.Engl. J. Med. 2008; 358: 264951.

6. Kim LH, Hogeling M, Wargon O, Jiwane A et al. Propranolol:useful therapeutic agent for the treatment of ulcerated infan-tile hemangiomas. J. Pediatr. Surg. 2011; 46: 75963.

7. Hogeling M, Adams S, Wargon O. A randomized controlled trialof propranolol for infantile hemangiomas. Pediatrics 2011; 128:e25966.

8. Ritter MR, Butschek RA, Friedlander M, Friedlander SF Patho-genesis of infantile haemangioma: new molecular and cellularinsights. Expert Rev. Mol. Med. 2007; 9: 119.

9. Khan ZA, Boscolo E, Picard A, Psutka S et al. Multipotentialstem cells recapitulate human infantile hemangioma in immu-nodeficient mice. J. Clin. Invest. 2008; 118: 25929.

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Table 2 Change in infantile haemangioma (IH) with therapy

nNo changen (%)

Mildimprovementn (%)

Moderateimprovementn (%)

Worsen (%)

Unknown(n)

Change in IH while on steroids at appointment prior to startingantihypertensives

17 0 6 (35) 8 (57) 0 3

Change in IH after 12 weeks on antihypertensives 17 3 (30) 4 (40) 0 3 (30) 7Change in IH after 1 month on antihypertensives 17 5 (39) 5 (39) 0 3 (23) 4Change in IH while being weaned from steroids onto captopril 15 4 (33) 1 (8) 0 7 (58) 3

Effect of captopril on IH 3

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