Home | About Us | Current Issue | Ahead of print | Archives | Search | Instructions | Subscription | Feedback | Editorial Board | e-Alerts | Login 
Journal of Indian Association of Pediatric Surgeons
     Journal of Indian Association of Pediatric Surgeons
Official journal of the Indian Association of Pediatric Surgeons         
 Users Online:1443 
  Print this page Email this page   Small font sizeDefault font sizeIncrease font size

Table of Contents   
Year : 2021  |  Volume : 26  |  Issue : 4  |  Page : 234-239

Angiotensin-converting Enzyme Inhibitors: Can it be a Potential Treatment of Infantile Hemangioma

Department of Pediatric Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Submission21-Apr-2020
Date of Decision07-Jun-2020
Date of Acceptance20-Oct-2020
Date of Web Publication12-Jul-2021

Correspondence Address:
Dr. Archika Gupta
Department of Pediatric Surgery, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiaps.JIAPS_112_20

Rights and Permissions



Aims: The aim of the sudy was to evaluate potential role of oral captopril, an angiotensin-converting enzyme (ACE) inhibitor, and in treatment of infantile hemagioma (IH) and report our preliminary results.
Methods: This prospective study included 18 children with IH admitted in the department of pediatric surgery with no history of prior treatment of any type. Baseline blood pressure (BP), electrocardiogram, two-dimensional echocardiography, serum electrolytes, and renal function test (RFT) were noted. Oral captopril was started as first-line drug at a dose of 0.1 mg/kg orally 12 h with gradually increase of dosage up to 2.0 mg/kg 12 h over the period of 10 days with monitoring of BP, serum electrolytes, RFT, and occurrence of any side effect. If no side effects were noted and patients were stable, they were discharged and followed up until 6 months after stopping treatment. During follow-up, response to treatment was documented clinically and photographically. Development of any side effect was also noted.
Results: Excellent response to captopril was noticed in nine patients over 16–18 months. Four patients showed good response. Oral propranolol had to be administered alternatively in one patient showing fair response during the initial 4 months but no response afterward and in four patients showing no response at all. One patient developed an allergic reaction to propranolol and was started oral corticosteroid. These five patients had near complete resolution of lesion for the next 8–10 months.
Conclusions: ACE inhibitors might have a role, though slow, in the involution of IHs. Therefore, these may have the potential to emerge as an alternative treatment for IH in future after confirmation with randomized studies with propranolol.

Keywords: Angiotensin converting enzyme, angiotensin converting enzyme inhibitor, captopril, infantile hemangioma

How to cite this article:
Gupta A, Kureel SN, Pandey A, Singh G, Kumar A, Shandilya G, Rai RK, Gupta SK. Angiotensin-converting Enzyme Inhibitors: Can it be a Potential Treatment of Infantile Hemangioma. J Indian Assoc Pediatr Surg 2021;26:234-9

How to cite this URL:
Gupta A, Kureel SN, Pandey A, Singh G, Kumar A, Shandilya G, Rai RK, Gupta SK. Angiotensin-converting Enzyme Inhibitors: Can it be a Potential Treatment of Infantile Hemangioma. J Indian Assoc Pediatr Surg [serial online] 2021 [cited 2021 Jul 30];26:234-9. Available from: https://www.jiaps.com/text.asp?2021/26/4/234/321081

   Introduction Top

Infantile hemangiomas (IHs) are the most common benign vascular tumor occurring in 5%–10% of infants.[1] The exact pathogenesis of IH is still not well understood. Increased expression of proliferating cell nuclear antigen, vascular endothelial growth factor, basic fibroblast growth factor, type IV collagenase and insulin like growth factor 2 have been found to be associated with the proliferating phase, and increased expression of the antiangiogenic factor and tissue inhibitor of matrix metalloproteinase, increased mast cells, increased expression of the endogenous angiogenesis inhibitor and interferon b have been found to be associated with the involuting phase.[2],[3],[4],[5] Recently, studies have found the increased expression of a component of the renin-angiotensin system (RAS) in the endothelium of proliferating IH and regulation of IH endothelium by RAS.[6],[7],[8] Studies have been reported in literature exploring the critical role of captopril, an angiotensin-converting enzyme (ACE)-inhibitor, in the accelerated involution of IH.[9],[10],[11] While Tan et al.[9] demonstrated accelerated involution of IH by captopril and Zaher et al.[10] demonstrated mild-to-moderate response to captopril. Christou and Wargon[11] failed to demonstrate any beneficial effect of captopril in IH. We studied and evaluated effectiveness and side effects of captopril, an ACE-inhibitor in the treatment of problematic IH, and report our preliminary findings with its use.

   Methods Top

This study was conducted in the department of pediatric surgery of our tertiary academic referral center. From April 2017 to October 2019, oral captopril was administered as the first-line treatment to 18 consecutive children with problematic IH as systemic treatment after obtaining informed consent from both parents of the children. Ethical clearance was obtained from the institutional ethical committee. Oral captopril was used as first-line treatment in these 18 consecutive patients of IHs to find an alternative treatment. Prior to this, we had been using oral propranolol as first-line treatment, but few patients had side effects like bradycardia and hypoglycemia that usually resolved on reducing the dose of propranolol. Clinical indications of starting treatment were (i) ulceration, (ii) location at head, neck, trunk, and genitalia, and (iii) large size resulting in cosmetic disfigurement and distortion. Patients of IH with known cardiac anomaly or renal impairment, history of diuretic intake, or known allergy or side effects to drug to be given were excluded from the study. Two-dimensional echocardiography and electrocardiogram were done to rule out cardiac outflow tract abnormalities. Color Doppler ultrasonography was done in all case to confirm the diagnosis and to measure baseline size and extent of lesions. Baseline laboratory investigations, particularly renal function test (RFT) and serum electrolytes, and baseline digital photograph to document size and color of lesion on the visual analog scale (VAS) were also obtained. Patients were admitted for the initiation of captopril under monitoring. Baseline blood pressure (BP) was recorded. Initially, captopril was administered at a dosage of 0.1 mg/kg and was gradually escalated to 2.0 mg/kg 12 h over the duration of 1 week with 12 h monitoring of BP, daily monitoring of RFT, serum electrolytes, and noticing occurrence of any side effect. In the event of occurrence of adverse drug reactions such as hypotension or hyperkalemia, or deranged RFT, drug dosages would have to be reduced. Persistence of adverse drug reactions despite dose reduction or nonresponse required withdrawal of drug and addition of alternative therapy. Patients were discharged at a dosage of 2.0 mg/kg 12 h and were followed up every week for an initial 1 month, then every fortnightly for the next 2 months, then monthly for the next 3 months, then at 2-month interval till 6 months after stopping treatment. During follow-up visits, serial digital photograph was taken to document response to treatment on VAS. Dosages were adjusted according to the changes in body weight, monitoring of BP, RFT, and serum electrolytes, and occurrence of side effects. Color Doppler ultrasound was also done at the completion of treatment to see resolution in size/extent of lesion.

The outcome measurement was done by observing response to treatment in terms of percentage change in the size and color of the hemangioma after comparing the serial digital photograph with the baseline photograph using VAS, with scores ranging from 0 to 10 (on the VAS, 0 represented the baseline photograph [pretreatment] and score of 10 indicated completed resolution of lesion both for size and color) by an independent investigator who was not part of study and by comparing size and extent of lesion in pretreatment and posttreatment color Doppler ultrasound. Change in size and color was evaluated as per the following criteria: poor response: no improvement at all to <10% improvement (VAS score 0–1), fair response: 10 to ≤30% improvement (VAS score 2–3), good response: >30 to ≤60% improvement(VAS score 4–6), excellent response: >60%–90% improvement (VAS score 7–9), and complete response: 100% improvement (VAS score 10).

   Results Top

IHs were more common in females with the female-to-male ratio being 2.6:1 [Table 1]. The mean age at the start of treatment with captopril was 7.7 months (range – 3–13 months) [Table 1]. Out of 18 patients, four had scalp IH (one ulcerated), two had nose lesions, one had large periorbital lesions extending up to temporal region that was also ulcerated, two had IH over cheek, two had lip IH, one had disfiguring supraclavicular IH extending up to shoulder and suprascapular area, one had chest lesion, one had suprascapular lesion, and four had labial hemangioma (two ulcerated) [Table 1]. Six lesions (33%) were superficial and 12 lesions (67%) were mixed. No prior treatment of IH was administered in any patient. All ulcerated lesions (4/18) were treated initially with topical mupirocin ointment along with captopril. Healing of ulcer occurred in 12–15 days after start of treatment with captopril in all cases with ulcerated hemangioma. Following healing of ulcer, mupirocin was stopped and captopril continued. Softening of lesion was the earliest change noticed within 1 month after starting captopril therapy followed by appearance of fading in color in the 2nd month. A gradual decrease in size of the lesion became appreciable from 3rd month onward. The mean follow-up period was 24.7 months (range – 8–30 months). Among 18 patients, nine patients (50%) showed excellent response; however, the response was gradual and slow observed over the duration of 16–18 months (mean – 17.1 months) [Table 1]. In these nine patients showing excellent response to captopril therapy [Figure 1] and [Figure 2], captopril was tapered gradually over the duration of 6 months and there was with no rebound growth in follow-up after stopping the drug. Four patients (22%) showed good response to captopril treatment that was started 8–12 months before and are still continuing captopril treatment. One patient (6%) showed fair response during initial 4 months; thereafter, there was no response to treatment as evidenced by no change in the color and size of lesion on three consecutive follow-ups. The remaining four patients (22%) had no response to captopril at all in the initial 4 months. In all these patients, captopril was stopped and oral propranolol was administered alternatively in a dosage of 2.0 mg/kg 12 h. One patient developed allergic reaction (rashes and itching) to propranolol that did not resolve even on reducing dose of propranolol on 1 month follow-up and was administered oral corticosteroid in a dosage of 2.0 mg/kg 12 hourly alternatively finally. These five patients had near complete resolution of lesion in the next 8–10 months with gradual reduction of drug over the next 6 months [Table 1].
Figure 1: (a) Scalp hemangioma with scab formation over ulcer in a 5-month infant being treated with oral captopril treatment and showing (b) excellent response to captopril at 16 months follow-up after starting therapy

Click here to view
Figure 2: (a) A large left supraclavicular hemagioma extending up to left shoulder and left suprascapular region in a 10-month infant being treated with oral captopril treatment resulting in (b) excellent response to captopril at 18 months follow-up after starting therapy

Click here to view
Table 1: Summary of the demography of patients and response to treatment with captopril in them

Click here to view

There was no occurrence of side effects of captopril such as hyperkalemia, elevation of urea, or creatinine in any of the patients except in one who had mild elevation of creatinine, but it reverted to normal after slight dose reduction. One patient, who was administered oral propranolol due to nonresponse to captopril, had allergic reaction (skin rashes and itching) to it and was administered oral corticosteroid finally for resolution of lesion. No patient had any serious side effect or adverse reaction.

   Discussion Top

IHs are the most common benign vascular tumor and have a unique and characteristic natural history. These lesions usually appear few weeks after birth, initially involving a phase of rapid growth (proliferating-phase) spanning over duration of 5–12 months followed by plateau-phase and then phase of spontaneous slow regression (involution-phase) which may continue up to 10 years.[12] The color of IH also changes with its course and is very red in a proliferating-phase that gradually fades becoming purplish-red in the stabilization-phase, and eventually becomes grey and/or skin colored in the regression-phase. Majority of IH do not require any specific treatment other than observation and reassurance of the parents. However, a few (10%–15%) of them, especially those that are located on the head, face and neck or develop rapidly or interfering with normal function and appearance, require a prompt intervention to control rapid growth to prevent local disfigurement, functional impairment, or systemic complications.[1]

Various therapeutic modalities for complicated hemangiomas include medical treatment, cryotherapy, laser (flashlamp-pumped pulsed dye, argon, neodymium: yttrium-aluminum-garnet), embolization, operation, and radiotherapy.[12] Currently, pharmacotherapy forms the mainstay of treatment of complicated IHs and includes topical, intralesional, and systemic corticosteroids, oral propranolol, vincristine, cyclophosphamide and subcutaneous and topical interferon alfa-2a.[12] Before 2008, oral corticosteroids have been used as first-line therapeutic agent and interferon-alfa or vincristine as second- or third-line drug in treatment of complicated IH. However, since after incidental discovery of the role of propranolol in the accelerated involution of IH in 2008, while treating patients with congenital heart disease,[13] there has been great interest among physicians all over the world and propranolol has become first-line drug for the treatment of IH.[14] Even, the US Food and Drug Administration has now approved oral propranolol as a first line drug for treating problematic IHs.[15]

As the use of propranolol in infants with IH has increased, physicians must be aware of the side effects and adverse events of propranolol such as hypoglycemia, bradycardia, atrioventricular block, hypotension, bronchospasm, hyperkalemia, sleep disorders, alopecia, feeding, and intestinal disorders.[16] One should be cautious for looking hypoglycemia in infants as they are more prone to it due to low glycogen storage potential.[17],[18] It can be insidious and difficult to recognize because some symptoms that are associated with counter-regulatory epinephrine action such as sweating, shakiness, anxiety, hunger, and tachycardia may be absent, due to propranolol induced β-adrenergic blockage.

Itinteang et al.[6],[7] and Sulzberger et al.[8] found that IH consists of hemogenic endothelium regulated by RAS and that components of RAS are expressed by the endothelium of proliferating IH. This has led to proposal that targeting at other downstream products of RAS such as angiotensin-I, ACE, or angiotensin-II could achieve a more targeted treatment for IH.[6],[7],[8] Thus, few reports have explored the role of ACE inhibitors such as captopril, successfully used in the management of cardiac failure in children, in the treatment of IH.[9],[10],[11] Christou and Wargon found no benefit of captopril in the involution of IH.[11] However they started captopril as antihypertensive while patients were on steroid and continues while withdrawing streroid until 3 weeks after stopping steroid; thus, they used captopril alone treatment only for 3 weeks. Thus, they had not truly assessed the effect of captopril due to co-use of steroid in most of study duration and very short period of “captopril alone” treatment. Tan et al. also explored the role of captopril in the treatment of IF and found its role in the accelerated involution of IH.[9] Zaher et al. in their study found that efficacy of propranolol was significantly better and faster than that of captopril in the treatment of IH. However, they also added that captopril or other ACE inhibitors might be a potential treatment for IH.[10] Based on the finding of these studies, we have also studied the potential role of captopril, an ACE-inhibitor, in the involution of IH and found excellent response to captopril in nine and good response in four patients. However, the response was slower requiring prolonged duration of treatment as compared to that observed by Tan et al.[9] We propose that this might occur due to the use of smaller dosage of captopril in our study and varying growth characteristics of IHs. Maximum dosage of captopril was used in our study, though greater than that used by Tan et al.,[9] but was still much less than the maximum dose of captopril described for the treatment of cardiac failure in children that is up to 6 mg/kg in two/three divided doses.[19] Another limitation of our study was a smaller number of patients and we found good response to excellent response in 13 out of 18 patients. The rest of five patients showed either no response after initial fair response or no response at all required replacement with oral propranolol. Among these five patients, one patient needed replacement oral corticosteroid as there occurred allergic reaction to oral propranolol and all these five patients had excellent response finally. Therefore, larger prospective and multicentric studies with higher doses with careful monitoring will be required to prove the efficacy of the therapeutic effects of captopril or other ACE inhibitors in treatment of problematic IHs. Further, long-term comparative randomized studies with already established drugs such as propranolol or corticosteroids with larger number of patients will be conducted needed to better confirm the safety and efficacy of the drug. We have planned one randomized study of ACE inhibitors with propranolol and will come with results of the study in the near future.

   Conclusions/Key Message Top

ACE inhibitors might have a role, though slow, in the involution of IH, and therefore, these may have the potential to emerge as an alternative treatment for IH in future. To confirm the reliability of the present results, multicentric comparative randomized studies and studies with higher doses under monitoring to include a large number of patients will be required.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Xiao Q, Li Q, Zhang B, Yu W. Propranolol therapy of infantile hemangiomas: Efficacy, adverse effects, and recurrence. Pediatr Surg Int 2013;29:575-81.  Back to cited text no. 1
Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 1994;93:2357-64.  Back to cited text no. 2
Bielenberg DR, Bucana CD, Sanchez R, Mulliken JB, Folkman J, Fidler IJ. Progressive growth of infantile cutaneous hemangiomas is directly correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-beta. Int J Oncol 1999;14:401-8.  Back to cited text no. 3
Ritter MR, Dorrell MI, Edmonds J, Friedlander SF, Friedlander M. Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis. Proc Natl Acad Sci U S A 2002;99:7455-60.  Back to cited text no. 4
Razon MJ, Kräling BM, Mulliken JB, Bischoff J. Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 1998;5:189-95.  Back to cited text no. 5
Itinteang T, Tan ST, Brasch H, Day DJ. Haemogenic endothelium in infantile haemangioma. J Clin Pathol 2010;63:982-6.  Back to cited text no. 6
Itinteang T, Brasch HD, Tan ST, Day DJ. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution. J Plast Reconstr Aesthet Surg 2011;64:759-65.  Back to cited text no. 7
Sulzberger L, Baillie R, Itinteang T, de Jong S, Marsh R, Leadbitter P, et al. Serum levels of renin, angiotensin-converting enzyme and angiotensin II in patients treated by surgical excision, propranolol and captopril for problematic proliferating infantile haemangioma. J Plast Reconstr Aesthet Surg 2016;69:381-6.  Back to cited text no. 8
Tan ST, Itinteang T, Day DJ, O'Donnell C, Mathy JA, Leadbitter P. Treatment of infantile haemangioma with captopril. Br J Dermatol 2012;167:619-24.  Back to cited text no. 9
Zaher H, Rasheed H, El-Komy MM, Hegazy RA, Gawdat HI, Abdel Halim DM, et al. Propranolol versus captopril in the treatment of infantile hemangioma (IH): A randomized controlled trial. J Am Acad Dermatol 2016;74:499-505.  Back to cited text no. 10
Christou EM, Wargon O. Effect of captopril on infantile haemangiomas: A retrospective case series. Australas J Dermatol 2012;53:216-8.  Back to cited text no. 11
Kulungowski AM, Fishman SJ. Vascular anomalies. In: Pediatric Surgery. Coran AG, Adzick NS, Krummel TM, Laberge J, Shamberger RC, Caldamone AA, editors. 7th ed. Philadelphia: Elseviers Saunders; 2012. p. 1613-30.  Back to cited text no. 12
Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649-51.  Back to cited text no. 13
Marqueling AL, Oza V, Frieden IJ, Puttgen KB. Propranolol and infantile hemangiomas four years later: A systematic review. Pediatr Dermatol 2013;30:182-91.  Back to cited text no. 14
Püttgen K, Lucky A, Adams D, Pope E, McCuaig C, Powell J, et al. Topical timolol maleate treatment of infantile hemangiomas. Pediatrics 2016;138:e20160355.  Back to cited text no. 15
Pavlakovic H, Kietz S, Lauerer P, Zutt M, Lakomek M. Hyperkalemia complicating propranolol treatment of an infantile hemangioma. Pediatrics 2010;126:e1589-93.  Back to cited text no. 16
Bonifazi E, Acquafredda A, Milano A, Montagna O, Laforgia N. Severe hypoglycemia during successful treatment of diffuse hemangiomatosis with propranolol. Pediatr Dermatol 2010;27:195-6.  Back to cited text no. 17
Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA. Hypoglycaemia in a child taking propranolol for the treatment of infantile hemangioma. Arch Dermatol 2010;146:775-8.  Back to cited text no. 18
Scammel AM, Arnold R, Wilkinson JL. Captopril in heart failure secondary to a left to right shunt. Arch Dis Child 1988;63:360-3.  Back to cited text no. 19


  [Figure 1], [Figure 2]

  [Table 1]


Print this article  Email this article


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Article in PDF (970 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

    Conclusions/Key ...
    Article Figures
    Article Tables

 Article Access Statistics
    PDF Downloaded28    
    Comments [Add]    

Recommend this journal

Contact us | Sitemap | Advertise | What's New | Copyright and Disclaimer 

  2005 - Journal of Indian Association of Pediatric Surgeons | Published by Wolters Kluwer - Medknow 

Online since 1st May '05