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      Oral Propranolol in Infantile Hemangiomas: Analysis of Factors that Affect the Outcome

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          Abstract

          Aim:

          The primary treatment for the subset of infantile hemangiomas (IHs) which develops complication is pharmacological intervention, and propranolol has become a popular choice. Here, we evaluated the efficacy and safety of propranolol in a clinical cohort of IHs and analyzed clinical characteristics associated with a good outcome.

          Materials and Methods:

          We retrospectively reviewed a total of 52 IHs patients, between ages 1 and 48 months (median age: 7.5 months), who were treated with oral propranolol, with dose ranging from 2 to 3 mg/kg/day. Efficacy was evaluated using mean percentage reduction, visual analog scale (VAS), and parental satisfaction levels at week 2 and months 1, 2, 6, and 12. The adverse effects were noted and responses after 6 months were graded. Statistical analyses of the outcome were also performed for the responses with regard to age at propranolol initiation, site of lesion, and mean duration of treatment.

          Results:

          A therapeutic response with at least 50% mean percentage reduction in size was noted in 84.6% at the end of 6 months. VAS score and parental satisfaction levels correlated well with mean percentage reduction (63.7 ± 15.6) at 6 months. Patients aged <6 months and those with cephalic lesions exhibited a greater therapeutic response rate with shorter overall mean duration of the treatment.

          Conclusions:

          Oral propranolol at 2–3 mg/kg/day dosing has shown to be effective and safe for IHs in pediatric age group. Intervention in the early proliferative phase, with especially, the cephalic lesions result in better resolution rates with shorter duration of overall treatment.

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          Most cited references20

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          Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action.

          Infantile haemangiomas (IH) are the most common benign tumours of infancy. Although most IH are innocuous and 85-90% regress spontaneously, some may become life- or function-threatening and require immediate treatment. Previous standard therapeutic options include physical measures (laser surgery, cryosurgery) and systemic corticosteroids, in severe cases also vincristine, alpha-interferon or cyclophosphamide, all bearing the risk of serious side-effects. Oral propranolol is a very recent therapeutic option for complicated IH with impressive efficacy and generally good tolerance. The effects of propranolol on IH were discovered by chance, and very little is known about its mechanisms of action in IH. Here we present a summary of current knowledge of how propranolol interferes with endothelial cells, vascular tone, angiogenesis and apoptosis. Early, intermediate and long-term effects of propranolol on IH can be attributed to three different pharmacological targets. Early effects (brightening of the haemangioma surface within 1-3 days after start of therapy) are attributable to vasoconstriction due to decreased release of nitric oxide. Intermediate effects are due to the blocking of proangiogenic signals (vascular endothelial growth factor, basic fibroblast growth factor, matrix metalloproteinase 2/9) and result in growth arrest. Long-term effects of propranolol are characterized by induction of apoptosis in proliferating endothelial cells, and result in tumour regression.
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            A randomized controlled trial of propranolol for infantile hemangiomas.

            Propranolol hydrochloride is a safe and effective medication for treating infantile hemangiomas (IHs), with decreases in IH volume, color, and elevation. Forty children between the ages of 9 weeks and 5 years with facial IHs or IHs in sites with the potential for disfigurement were randomly assigned to receive propranolol or placebo oral solution 2 mg/kg per day divided 3 times daily for 6 months. Baseline electrocardiogram, echocardiogram, and laboratory evaluations were performed. Monitoring of heart rate, blood pressure, and blood glucose was performed at each visit. Children younger than 6 months were admitted to the hospital for monitoring after their first dose at weeks 1 and 2. Efficacy was assessed by performing blinded volume measurements at weeks 0, 4, 8, 12, 16, 20, and 24 and blinded investigator scoring of photographs at weeks 0, 12, and 24. IH growth stopped by week 4 in the propranolol group. Significant differences in the percent change in volume were seen between groups, with the largest difference at week 12. Significant decrease in IH redness and elevation occurred in the propranolol group at weeks 12 and 24 (P = .01 and .001, respectively). No significant hypoglycemia, hypotension, or bradycardia occurred. One child discontinued the study because of an upper respiratory tract infection. Other adverse events included bronchiolitis, gastroenteritis, streptococcal infection, cool extremities, dental caries, and sleep disturbance. Propranolol hydrochloride administered orally at 2 mg/kg per day reduced the volume, color, and elevation of focal and segmental IH in infants younger than 6 months and children up to 5 years of age.
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              Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution.

              Infantile haemangioma is a benign tumour of the microvasculature characterised by excessive proliferation of immature endothelial cells. It typically undergoes rapid proliferation during infancy followed by spontaneous slow involution during childhood often leaving a fibro-fatty residuum. In 2008, propranolol, a non-selective β-blocker, was serendipitously discovered to induce accelerated involution of a proliferating infantile haemangioma. However, the mechanism by which propranolol causes this dramatic effect is unclear. Using immunohistochemical staining, we show that the CD34+ endothelial progenitor cells of the microvessels in proliferating infantile haemangioma express angiotensin-converting enzyme and angiotensin II receptor-2, but not angiotensin II receptor-1. We have also shown using our in vitro explant model that the cells emanating from proliferating haemangioma biopsies form blast-like structures that proliferate in the presence of angiotensin II. We present here a plausible model involving the renin-angiotensin system that may account for the propranolol-induced accelerated involution of proliferating infantile haemangioma. Copyright © 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                J Indian Assoc Pediatr Surg
                J Indian Assoc Pediatr Surg
                JIAPS
                Journal of Indian Association of Pediatric Surgeons
                Wolters Kluwer - Medknow (India )
                0971-9261
                1998-3891
                Jul-Sep 2019
                : 24
                : 3
                : 170-175
                Affiliations
                [1]Department of Pediatric Surgery, IMCH, Government Medical College, Kozhikode, Kerala, India
                Author notes
                Address for correspondence: Dr. Sarath Kumar Narayanan, Department of Pediatric Surgery, IMCH, Government Medical College, Kozhikode - 673 008, Kerala, India. E-mail: drsharat77@ 123456gmail.com
                Article
                JIAPS-24-170
                10.4103/jiaps.JIAPS_12_18
                6568152
                31258264
                61c6acc9-0b55-4c45-9df3-9fadbab6329b
                Copyright: © 2019 Journal of Indian Association of Pediatric Surgeons

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                : January 2018
                : January 2019
                Categories
                Original Article

                Surgery
                hemangioma,propranolol,treatment
                Surgery
                hemangioma, propranolol, treatment

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