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ORIGINAL ARTICLE
Year : 2018  |  Volume : 19  |  Issue : 3  |  Page : 224-229

Efficacy and safety of propranolol on the proliferative phase of infantile hemangioma: A hospital-based prospective study


1 Department of DVL, Hospital and Research Centre, Gujarat Cancer Society Medical College, Ahmedabad, Gujarat, India
2 Hospital and Research Centre, Gujarat Cancer Society Medical College, Ahmedabad, Gujarat, India

Date of Web Publication28-Jun-2018

Correspondence Address:
Dr. Nayan H Patel
Department of DVL, Hospital and Research Centre, Gujarat Cancer Society Medical College, Room No 35, Opp. D.R.M. Office, Near Chamunda Bridge, Naroda Road, Ahmedabad - 380 025, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_75_17

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  Abstract 


Background: Propranolol may be more effective and safer than previously established therapies, and it may be used as a first-line therapy for infantile hemangioma (IH). Propranolol is thought to inhibit the growth of blood vessels by decreasing vascular endothelial growth factor. Aims and Objectives: The aim of this study is to study the efficacy and safety of propranolol in IH and for standardization of dose in tablet form. Materials and Methods: A total of 23 patients with 30 IH s were recruited in the study prospectively, after ruling out any contraindications for oral propranolol and obtaining consent from parents. Patients with <7 kg weight were given oral propranolol 5 mg twice daily and >7 kg weight were given 5 mg thrice daily. Patients were evaluated according to visual analog scale and ultrasonographically on day 0, day 30, day 60, and day 90. Results: Out of a total of 30, 25 (83.33%) were superficial, 3 (10%) were deep, and 2 (6.66%) were mixed hemangioma. All patients with superficial hemangiomas showed a change in the color of the lesion and arrest of growth within the 1st month of therapy and a gradual decrease in size was noticed in 23 (92%, n = 25) patients during the study period except in 2 (8%). Complete clearance was noticed in 68% of patients of superficial hemangioma at the end of the study period. Out of 25 patients, a total of 5 (20%) patients had ulceration at the time of presentation which started to heal within 15 days of therapy. Five (16.66%, n = 30) patients with deep and mixed variety showed arrest of growth but no decrease in size. No side effects were seen except temporary coldness of extremity in 1 (3.33%) patient. Conclusion: Propranolol is safe and effective for treatment of proliferative phase of superficial hemangiomas with very less side effects compared to oral steroids and other recommended therapies, and unavailability of syrup can be overcome by giving tablet in fixed dosage.

Keywords: Efficacy, fixed dosage, infantile hemangioma, propranolol, safety


How to cite this article:
Padhiyar JK, Patel NH, Gajjar TP, Buch MD, Shah YB, Solanki R. Efficacy and safety of propranolol on the proliferative phase of infantile hemangioma: A hospital-based prospective study. Indian J Paediatr Dermatol 2018;19:224-9

How to cite this URL:
Padhiyar JK, Patel NH, Gajjar TP, Buch MD, Shah YB, Solanki R. Efficacy and safety of propranolol on the proliferative phase of infantile hemangioma: A hospital-based prospective study. Indian J Paediatr Dermatol [serial online] 2018 [cited 2019 Jul 20];19:224-9. Available from: http://www.ijpd.in/text.asp?2018/19/3/224/223318




  Introduction Top


Infantile hemangioma (IH) is the most common pediatric tumor. It is more common in girls, with the ratio being 3:1–5:1, and it is even higher for severe complicated lesions. IH is more common in infants with history of chorionic villous sampling and prematurity. More than 50% of hemangioma occurs in the head-and-neck regions, with cosmetically less acceptable residua after involution phase.[1] IHs are divided into three categories as follows: focal, segmental, and indeterminate according to their distribution. Superficial, deep, and mixed types have been described according to the level of involvement, with the superficial type being the most common (50%–60%). Approximately 25% have multiple lesions.[2]

Proliferation phase of IH generally has a duration of 5–12 months, followed by plateau phase and involution phase which may continue up to 10 years. Color changes from bright red to dull gray red in involution phase once growth is arrested. Complications such as obstruction of airway, vision and auditory canal, and heart failure are more common during involution phase. Ulceration and disfigurement are seen more commonly during involution phase though it can occur during proliferation phase too. Prevention of life-threatening complication, regression with minimum disfigurement, avoidance of aggressive and scaring therapy, and minimizing the adverse effects of systemic therapy are the main goals for treatment of IH.

The effect of propranolol in the treatment of hemangioma was first discovered by Dr. Christine Léauté-Labrèze et al. accidentally while treating patients with congenital heart disease.[3]

Propranolol – a nonselective beta-blocker – may be more effective and safer than previously established therapies (oral steroids, vincristine, interferon ɣ, pulse dye laser, radiotherapy, imiquimod), and it may be used as a first-line therapy for IH. Propranolol is thought to inhibit the growth of blood vessels by decreasing vascular endothelial growth factor and other proangiogenic cytokines which are thought to be responsible for the development of IH, though its specific mechanism for regression of hemangioma still remains uncertain. Typical dosage of propranolol in IH has been 2–3 mg/kg in various studies, though there are studies showing the efficacy of low dose of propranolol up to 0.75–1 mg/kg.[4] Side effects such as sleep disturbance, agitation, breathing difficulty, hypotension, bradycardia, hypoglycemia, the coldness of extremities, nausea, and vomiting have been described with oral propranolol. Dose up to 8 mg/kg are used in various cardiological conditions in the pediatric population without any major adverse effects. Side effects and adverse events are rare, and they are seen with dose >2 mg/kg/day.[5],[6],[7] Hypoglycemia is of particular worry as infants are more susceptible for this side effect due to low glycogen storage.[8],[9],[10],[11]

The United States Food and Drug Administration has approved a solution of propranolol hydrochloride named Hemangeol in March 2014 for its use in hemangioma, as it has been claimed to be especially developed for safe and effective use in children.

This study was conducted with the aim to evaluate efficacy and safety of propranolol in the proliferating phase of IH, especially in the Indian setup as there are not enough studies available for Indian patients. Fixed dosage according to weight was tried for nonavailability of syrup in our region, and to the best of our knowledge, it is not available in syrup form in India till date. Oral steroids are very effective but have lots of systemic side effects including inhibition of linear growth in children.[12] Hence, this study was initiated in search of safe and effective therapy and for standardization of dose in tablet form in pediatric age group.


  Materials and Methods Top


Twenty-three patients with 30 IHs were recruited in the study prospectively after ruling out any contraindications for oral propranolol and obtaining consent from both parents. The study was approved by the institutional ethics committee, and it was also registered with CTRI (Clinical trial registry of India). After ethics committee approval, patients were enrolled from August 2013 to July 2016. Informed consents were obtained from both parents at the time of study entry and consent for using patients' data was also obtained at the same time.

Patients were included in the study according to the following inclusion and exclusion criteria.

Inclusion criteria

  • Infants (0–12 months)
  • Presenting with hemangioma having the following characteristics:

    • Superficial/deep/mixed mucocutaneous hemangioma in proliferative phase
    • Maximum linear size at least in one dimension >1.5 cm on the face, 5 cm outside face, and 1 cm if it is ulcerated
    • Without functional impairment requiring treatment or oral corticosteroid
  • Consent of both parents (or the person having parental authority in families).


Exclusion criteria

  • Indication of treatment with corticosteroids for indications other than hemangioma
  • Indication of treatment with beta-blocker for indications other than the hemangioma
  • Patients having contraindications for the administration of propranolol
  • Patients with an associated visceral hemangioma.


Random blood sugar, blood pressure, and heart rates were taken at each visit. Electrocardiogram was taken at the baseline visit. Patients with <7 kg weight were given oral tablet propranolol 5 mg twice daily and more than 7 kg weight were given 5 mg thrice daily after thoroughly mixing it in water. If patients achieved weight of 7 kg after starting therapy, then propranolol dose was increased from 5 mg twice a day to thrice a day for a total of 3 months of duration or till complete regression whichever is earlier. Propranolol tablets are available in various strengths, with minimum strength being 10 mg. Hence, patients were advised to take half tablet twice or thrice per day according to weight as mentioned above. We used the tablet Inderal® (propranolol hydrochloride) 10 mg for the study. Color and size of the lesions were recorded on baseline visit on day 0 both clinically and ultrasonographically. Patients were evaluated for change in color and change in size according to the visual analog scale and ultrasonographically on follow-up visits after starting therapy on day 30, day 60, and day 90. Change in size was evaluated as per the following criteria.

  • No response: no improvement at all to <10% improvement
  • Mild response: 10 to <30% improvement
  • Moderate response: 30 to <60% improvement
  • Excellent response: 60 to <90% improvement
  • Complete response: 90%–100% improvement


In addition, patients with ulcer at the time of presentation were also examined on the 15th day. All patients included in the study were monitored closely for the side effects and adverse reaction.

Six patients with larger size (>10 cm—maximum linear span at least in one dimension) of hemangioma who responded in the study period (90 days) but did not show complete regression were given oral propranolol beyond the study period till complete improvement, with a total duration ranging from 9 months to 12 months.


  Results Top


A total of 23 patients, 5 males and 18 females, with total 30 hemangiomas were recruited in the study. The mean age at initiation of treatment was 2.46 months. It was more common in female, with the female to male ratio being 3.6:1. Six (26.08%) patients had multiple hemangiomas. Distribution and types of hemangiomas are summarized in [Table 1].
Table 1: Distribution and type of hemangiomas (n=30)

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Out of a total 30, 25 (83.33%) were superficial, 3 (10%) were deep, and 2 (6.66%) were mixed hemangioma.

All patients with 25 superficial hemangiomas (n = 25) showed a change in color of the lesion from bright red to dull gray red and arrest of growth within the 1st month of therapy. All lesions became softer and dull red at the end of the 1st month. A gradual decrease in size was noticed both clinically and ultrasonographically in 23 patients during the study period except in two. Response in patients with superficial hemangioma at day 30, day 60, and day 90 is summarized in [Table 2]. At the end of the study, 68% of patients with superficial hemangioma showed complete response [Figure 1], while 8% of patients with superficial hemangioma did not show any response.
Table 2: Response at day 30, day 60, and day 90 in patients with superficial variety of hemangioma (n=25)

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Figure 1: Complete response (>90% improvement). Vulval hemangima (a) day 0, (b) day 30, (c) day 90. Lip hemangioma (d) day 0, (e) day 30, and (f) day 90

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Six (24%, n = 25) patients with larger size (>10 cm—maximum linear span at least in one dimension) of superficial hemangioma who responded in the study period (90 days) but did not show complete regression were given oral propranolol beyond the study period till complete improvement, with a total duration of treatment ranging from 9 months to 12 months.

A total of five (20%, n = 25) female patients with superficial hemangioma had ulceration at the time of presentation. Out of these five patients, two had lesions on the vulva, two patients had lesions on the face, and one patient had lesion on the chest. In all the patients, ulcers started to heal as early as 15 days and complete healing was recorded on the first follow-up visit at 1 month. Three patients with ulcers had residual mild atrophic scaring and out of these three, two patients with hemangioma with ulcer over the labia majora had laxity of skin of local part after complete regression [Figure 1] and [Figure 2]. One patient with large hemangioma with focal tiny ulcers over the face regressed with residual telangiectasia [Figure 3]. None of our patients had postinflammatory hyperpigmentation after regression of lesion.
Figure 2: Vulval hemangioma with large ulcer (a) day 0, (b) day 90, (c) at 9 months healing with scaring and laxity

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Figure 3: Large hemangioma with tiny ulcers (a and b) day 0, (c and d) day 90, (e and f) at 6 months, and (g and h) at 10 months

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Size of the lesions was measured ultrasonographically by maximum linear size in all three dimensions. The average size of the lesion was 91.44 cm3, with the smallest size being 2.7 cm3 and highest size being 749.49 cm3. The mean rate of decrease by ultrasonography was 0.46 cm3/month, with the highest rate being 3.47 cm3/month in patients with superficial hemangioma.

Recurrence in the form of tiny lesions (<6 mm3) was noticed in two (8%, n = 25) patients after completion of the study period.

Five (16.66%, n = 30) patients with deep and mixed variety of IH showed arrest of growth but no decrease in size clinically as well as by ultrasonography, though a change in color in superficial component of mixed hemangioma was observed [Figure 4].
Figure 4: Mixed hemangioma (a) day 0 and (b) day 90

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No side effects or adverse reactions were found in the study group, except that one patient (3.33%) had transient coldness of extremities which was taken care by an appropriate covering of parts without discontinuation of treatment.


  Discussion Top


Léauté-Labrèze et al.[3] were the first to describe rapid anatomical shrinkage as early as 24h after treatment initiation. Al Dhaybi et al.[13] observed a reduction in lesion size within 2 months in all cases. Hogeling et al.[14] have reported the arrest of growth at 4 weeks in the propranolol group, which is comparable in our study. In our study, we observed a change in color (100% in all superficial hemangioma, n = 25), arrest of growth (100% in all types of hemangioma, n = 30), and decrease in size at first follow-up visit at day 30 (68% of superficial hemangioma and 0% in other types). A gradual decrease in size in superficial hemangiomas was noticed in 68% at 1 month and in 92% of patients at last visit at day 90. Eight percent of patients of superficial hemangioma did not show any decrease in size may be due to the lower dosage of propranolol. At the end of the study, complete response (>90%) improvement was noted in 68% of patients. Purkait et al.[15] reported a single case of multiple capillary hemangioma responded with a decrease in size to three fourth of the original size at the end of 3 months' therapy. Castaneda et al.[16] described satisfactory result (>80% improvement) in 96% of patients with a mean duration of therapy of 10.5 months.

Snir et al.[17] reported the mean duration of treatment in their study was 7.3 ± 3.5 months in their study in patients with capillary hemangioma. Léauté-Labrèze et al. have reported the mean duration of treatment of 6.5 months, while Al Dhaybi et al. have reported the same to be 5.5 months. The study period was 3 months only, maybe that was the reason we needed to extend therapy in six patients with the larger size of superficial hemangiomas who showed regression of lesion but not complete regression. With the extension of therapy to a total duration of 9–12 months including the study period, these six patients showed complete regression of the lesions.

Five patients (16.66%, n = 30) with mixed and deep variety of IH did not respond in terms of decreasing size, though they showed arrest of proliferative phase, again maybe due to a low dosage of the drug and lesser duration of therapy compared to another study. Price et al.[18] have mentioned that deep and mixed variety of hemangiomas have longer proliferation period up to 1 year, which may be the reason for rebound or relapse in this type of hemangiomas and they require a longer duration of treatment. However, this finding is in contrast with a study by Qin et al.[19] and Liu et al.[20] in which they observed a statistically better response in deep-seated hemangioma than in superficial type. This may be due to variation in ethnicity and genetic background of the study population. Few studies only described the phase of hemangioma, which again may be the factor affecting the outcome. After extensive literature search, we could not find many studies which divide the result according to types of hemangioma.

Ma et al. have reported low dose of propranolol 0.75–1 mg/kg as effective therapy in Chinese patients. Literature review suggests a dose up to 2–3 mg/kg can be given in patients of IH with monitoring of side effects. Due to nonavailability of syrup in our setup, we needed to fix the dosage in tablet form, and to the best of our knowledge, it is not available in syrup form in India. Hence, for comparison of a dose of our study, we could not find appropriate literature.

Ma et al. reported that mild side effects such as diarrhea, restless sleep, nausea, cold extremities, and hypoglycemia, occurred in 13.5%, while there was no side effect observed in our study except temporary coldness of extremities in one (3.33%, n = 30) patient which was managed symptomatically without stopping treatment. Hogeling et al. did not observe any major side effects such as hypotension, bradycardia, or hypoglycemia. Snir et al. observed side effects such as agitation, fever, and sleep disturbance which were managed by pediatrician without a change in the treatment protocol. They did not report hypotension, bradycardia, or hypoglycemia, but they had to reduce dose in three patients due to breathing difficulty, vomiting, nausea, and diarrhea. They further concluded that less side effects in their study were due to proper evaluation before treatment and close monitoring after starting therapy. Similarly, fewer side effects in our study might be due to proper pretreatment evaluation and close monitoring during therapy and the low dosage we used compared to other studies.

Ma et al. reported a relapse rate of 4.5% at 4–5 months. In this study, the relapse rate was 8% after the study period after complete regression.


  Conclusion Top


Propranolol is safe and effective for treatment of proliferative phase of hemangioma, especially in superficial type. Deep and mixed variety of hemangimas may respond to a higher dose and longer duration of therapy. Administration of drug requires multidisciplinary approach by both dermatologist and pediatrician for the screening of patients. Side effects and adverse events are considerably negligible; hence, it can be administered safely for IH after ruling out contraindications of the drug in a child. Unavailability of syrup can be overcome by giving tablet in fixed dosage.

Ours is a prospective, nonrandomized study. Hence, more randomized, double-blinded studies with larger sample size on Indian patients are needed for further consideration for using the drug as first-line therapy for IH, especially for deep and mixed types.

Level of evidence for this study: Level II-1.

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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]


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