Propranolol for vascular anomalies: Efficacy and complications in pediatric patients

Rahul Gupta

doi:10.4103/jiaps.jiaps_117_22



ORIGINAL ARTICLE

Year : 2023 \| Volume : 28 \| Issue : 3 \| Page : 194-205

Propranolol for vascular anomalies: Efficacy and complications in pediatric patients

Rahul Gupta
Department of Paediatric Surgery, SMS Medical College, Jaipur, Rajasthan, India

Date of Submission	20-Aug-2022
Date of Decision	25-Dec-2022
Date of Acceptance	28-Dec-2022
Date of Web Publication	02-May-2023

Correspondence Address:
Rahul Gupta
Associate Professor, Department of Paediatric Surgery, SMS Medical College, Jaipur, Rajasthan
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jiaps.jiaps_117_22

Abstract

Context: Congenital vascular anomalies are classically subdivided into vascular tumors and vascular malformations. The role of propranolol in the regression of infantile hemangioma (IH), a vascular tumor, is well establishe.
Aims: This study aimed to analyze the therapeutic efficacy and complications associated with oral propranolol and adjuvant therapy in the treatment of vascular anomalies.
Settings and Design: A prospective interventional study was undertaken over 10 years duration extending from 2012 to 2022 at a tertiary care teaching institute.
Materials and Methods: All children with cutaneous hemangiomas and lymphatic and venous malformations under 12 years of age, except those with contraindications for administration of propranolol, were included in the study.
Results: Out of 382 patients, there were 159 males and 223 females (male: female = 1:1.4). The majority (53.66%) were between ≥3 months and 1 year. There were 481 lesions in 382 patients. There were 348 patients with IH, and 11 were congenital hemangiomas (CHs). There were 23 patients with vascular malformations; lymphatic malformation (n = 19) and venous malformation (n = 4) were present. The size of the lesions ranged from 5 mm to 20 cm; 50.73% were 2–5 cm in size. Ulceration (>5 mm) was the most common complication present in 20/382 (5.24%) patients. Complications related to oral propranolol were seen in 23 (6.02%) patients. Drugs were given for a mean period of 10 months (range from 5 months to 2 years). At the end of the study, 282 (81.03%) out of 348 patients with IH showed an excellent response; 4 (36.36%) patients in the case of CH (n = 11) and 5 (21.74%) patients with vascular malformation (n = 23) showed excellent response.
Conclusion: The study validates the use of propranolol hydrochloride as the first-line agent for the treatment of IHs and congenital hemangiomas. It may have an additive role in lymphatic malformations, and venous malformations, as a part of a multimodality treatment approach for vascular malformations.

Keywords: Efficacy, infantile hemangiomas, propranolol, vascular anomalies, vascular malformations, vascular tumors

How to cite this article:
Gupta R. Propranolol for vascular anomalies: Efficacy and complications in pediatric patients. J Indian Assoc Pediatr Surg 2023;28:194-205

How to cite this URL:
Gupta R. Propranolol for vascular anomalies: Efficacy and complications in pediatric patients. J Indian Assoc Pediatr Surg [serial online] 2023 [cited 2023 Jun 1];28:194-205. Available from: https://www.jiaps.com/text.asp?2023/28/3/194/375515

Introduction

Congenital vascular anomalies are classically subdivided into vascular tumors and vascular malformations, depending on the intrinsic properties of endovascular cells.^[1],[2],[3] Propranolol is a nonselective beta-blocker with membrane stabilization activity. It has been used in the management of hypertension, arrhythmia, and thyrotoxicosis.^[4],[5],[6] Efficacy of propranolol in the regression of infantile hemangioma (IH) which is the most common soft tissue tumor is established. It was a serendipitous discovery in 2008 by Dr. Christine LéautéLabrèze and his team. This patient had facial hemangioma and was being treated for obstructive hypertrophic cardiomyopathy.^[6],[7] The use of systemic corticosteroids in the proliferative phase halts the growth of IH rather than its involution. A combination of propranolol and prednisolone has shown comparable efficacy to propranolol alone.^[8] The effect of propranolol on vascular malformations and other vascular anomalies has not been recognized.

Aims and objectives

This study aimed to analyze the therapeutic efficacy and complications associated with oral propranolol and adjuvant therapy in the treatment of vascular anomalies.

Materials and Methods

This prospective interventional study was conducted by the senior author (RG) at a pediatric surgery tertiary care teaching institute. The study was conducted over a 10-year duration extending from 2012 to 2022.

Inclusion criteria

All children with cutaneous hemangiomas and lymphatic and venous malformations under 12 years of age were included in the study.

Exclusion criteria

The exclusion criteria were as follows:

Patients having contraindications for administration of propranolol, i.e., allergy or hypersensitivity, arteriovenous (AV) block, sick sinus syndrome, heart failure, bronchial asthma, or bronchial obstruction
Arteriovenous malformations
Lymphatic malformations other than head-and-neck region
Patients with life-threatening hemangiomas/vascular malformations.

Methodology

Informed written consent was obtained from the patient's parents about the study. A thorough clinical evaluation of all the patients was performed including history, complete clinical examination, and local examination of the lesion(s) and comorbidities. In all patients, baseline blood investigation including complete blood counts and blood sugar was performed. Abdominal ultrasounds were performed on all the patients to exclude intra-abdominal malformations. A cardiac evaluation was performed with echocardiography. Heart rate and blood sugar were recorded at the initiation of treatment, in dose increments, and at monthly follow-up.

Oral propranolol hydrochloride was given to all the patients. Propranolol was available in 10 mg tablets. The 10 mg tablet was divided and crushed/powdered and then finally divided into 4 or 5 equal parts. It was then mixed with either mother's milk or any sugar-based liquid before administration. The initial dose was 0.5 mg/Kg/day and then gradually increased to 2.0 mg/Kg/day in 2–3 divided doses in the subsequent visits.

Other treatment modalities offered were oral prednisolone (5 mg/5 ml syrup), topical steroid preparations (beclomethasone dipropionate cream/hydrocortisone ointment), and surgery. Syrup prednisolone was given in the dose of 1.0 mg/Kg/day. All patients included in the study were monitored closely for side effects and severe adverse reactions.

The size, shape, contour, elevation, volume, and color of the vascular lesions were recorded on the first (baseline) clinical visit. Digital photographs of the lesion(s) were obtained at the initiation of treatment and each follow-up visit. Ultrasonography of the lesion(s) and/or CT scan were performed for further evaluation. The size, volume, type, and number of the lesion, phase of the hemangioma (IH), location, distribution, ulceration, and relationship to surrounding structures were noted along with the presence of any associated visceral hemangioma or associated malformation, and functional/esthetic problems. Patients were evaluated for color change (clearing/fading) according to the Visual Analog Scale. Ultrasounds of the lesion(s) were performed on days 15/30, and at 3–6 months on follow-up visits. The resolution of the target lesion(s) (hemangioma/vascular malformation) was observed. Change in size was evaluated on day 15/1 month, and 1 monthly follow-up.

Change in size and color was evaluated as per the ensuing criteria:

No response: no improvement at all to <10% improvement
Mild response: 10 to <50% improvement
Good response: 50 to <75% improvement
Excellent response: >75% improvement, i.e., excellent response was defined as a minimal degree of telangiectasis, erythema, skin thickening, and soft-tissue swelling.

Statistical evaluation

All the medical records, clinical data, complications, and responses to therapy were recorded in the Excel sheets. Charts were prepared on patients' details, clinical presentation, radiological workup, treatment modalities, therapeutic response, complications, follow-up details, and outcomes. Statistical analysis was done by using SPSS, Inc., Chicago, IL, USA, Program version 16. P < 0.05 was considered statistically significant.

Results

There were a total of 400 patients diagnosed with vascular anomalies in the outpatient department. Out of 400 patients, 382 gave consent to the study. There were 159 males and 223 females with male: female ratio = 1:1.4. Only 95 (24.87%) of patients reported ≤3 months age group; the majority, i.e., 205 (53.66%), were between ≥3 months and 1 year of age group [Table 1]. More than three-fourth of patients (78.53%) were ≤1-year age group, while 42 (10.99%) were >2 years of age [Table 1]. The median age at initiation of treatment was 6 months. Out of 382, 50 (13.09%) patients had multiple lesions. There were a total of 481 lesions in 382 patients [Table 1]. The head-and-neck region constituted the maximum number (270/481, 56.13%) of lesions. Out of 382 patients, scalp involvement was present in 94 (24.61%) cases, lips 26 (6.8%), parotid 15 [3.92%, [Figure 1]], eyelid 11 (2.88%), and external genitalia 12 (3.14%).

Table 1: The distribution, types, and demographic details of vascular anomalies in the present series

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Figure 1: Clinical photographs showing IH involving the parotid region with mixed subtype on D1 (A1) and at 6 months with excellent response (A2); mixed subtype on D1 (B1 and B2) and at 4 months (B3) with excellent response; superficial subtype on D30 (C1) and at 3 months with excellent response (C2); superficial subtype on D1 (D1) and at 6 months with excellent response (D2) (on D = on Day). IH: Infantile hemangioma

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The size of the lesions ranged from 5 mm to 20 cm [Figure 2] and [Figure 3], with a maximum number (244, 50.73%) of patients between 2 and 5 cm in size [Table 1]. The most common presenting complaint was cosmetic disfigurement 304 [79.58%, [Figure 3]] followed by swelling 46 [12.04%, [Figure 4]] and pain over the lesion 26 [6.81%, [Figure 5]] and bleeding 1 (0.26%). There were 2 (0.52%) patients with impairment of vision and 3 (0.79%) patients with difficulty swallowing, as shown in [Table 1]. On further evaluation, 2 (0.52%) patients had painful ulceration in the face and 8 (2.09%) patients had large disfiguring hemangioma in the face [Figure 2] and [Figure 3].

Figure 2: Clinical photographs showing facial IH (mixed subtype) on D1 (A1), at 6 weeks with ulceration (A2), at 10 weeks with ulceration during involution (A3 and A4); at 10 months with residual scarring (A5); supra-orbital IH (deep subtype) on D1(B1), at 10 weeks (B2) and at 5 months with excellent response (B3) (on D = on Day). IH: Infantile hemangioma

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Figure 3: Clinical photographs showing large, highly vascular facial IH (mixed subtype) involving the eyelids and lips with painful central ulceration on D1 (A1 and A2), at 1.5 years (A3, A4) with good response; large, highly vascular facial IH (mixed subtype) involving the eyelids and lips with ulceration and visual impairment on D1 (B1), at 14 months (B2) with excellent response. Clinical photographs showing large scalp and hemifacial IH (superficial subtype) on D1 (C1 and C2), at 8 months (C3), and at 10 months with good response (C4) (on D = on Day). IH: Infantile hemangioma

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Figure 4: Clinical photographs showing IH involving the forearm and dorsum of hand (superficial subtype) on D1 (A1), at 6 months (A2) with excellent response; forearm and hand (mixed subtype) on D1 (B1), at 11 months (B2) with excellent response; forearm and arm (mixed subtype with ulceration) on D1 (C1) and at 9 months (C2) with good response (on D = on Day). IH: Infantile hemangioma

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Figure 5: Clinical photographs showing large CH, RICH subtype involving the arm near the elbow joint with large scab over the central ulceration on D1 (A1), at 4 weeks (A2), at 8 months with excellent response (A3); CH over medial aspect of right thigh on D1 (B1), at 3 months (B2), at 8 months with excellent response (B3); abdominal wall CH on D1 (C1), at 1 month (C2), and at 3 months with good response (C3) (on D = on Day). CH: Congenital hemangioma, RICH: Rapidly involuting congenital hemangioma

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There were 359 patients with hemangiomas, out of which 348 [96.94%, [Figure 4]] were IH, and 11 [3.06%, [Figure 5] and [Figure 6]] were congenital hemangiomas (CHs).

Figure 6: Clinical photographs showing highly vascular large CH on D1 (A1), at 3 months (A2), at 4 months (A3), and at 2 years (A4) with excellent response; large CH on D1 (B1 and B2), at 8 months (B3) (on D = on Day). CH: Congenital hemangioma

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Out of a total of 348 IH, 263 (75.57%) were superficial, and 85 [24.43%, [Figure 4]] were deep and mixed types. There were 23 patients with vascular malformations, lymphatic malformation [n = 19, [Figure 7]], and venous malformation [n = 4, Figure 7], as shown in [Table 1].[

Figure 7: Clinical photographs showing cystic hygroma on D1 (A1), at 2 months (A2), and at 5 months (A3) with excellent response. Clinical photographs showing microcystic lymphatic malformation of tongue on D1 (B1 and B2) and at 2 months (B3). Clinical photographs showing venous malformation involving the anterior abdominal wall on D1 (C1), at 2 months (C2), at 3 months (C3), and at 5 months (C4) with excellent response (on D = on Day)

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Associated malformations were present in 34 (8.9%) out of 382 patients in our series. More than one malformation was present in a few patients. Cardiac anomalies were the most common (22/34, 64.71%) in this group followed by umbilical hernia (3/34, 8.82%), as shown in [Table 2]. Visceral (liver) hemangiomas were seen in 2 (5.88%) patients. Liver hemangioma was present in a 4-month-old female with IH (5 lesions) involving the left parotid region, cheek, anterior part of the neck involving the submandibular region, supraclavicular region, and nape of the neck. This patient had mitral regurgitation with left ventricular function of 35%. The other infant with liver hemangioma was a 3-month-old male with IH involving the back (isolated lesion).

Table 2: The type of associated malformations, complications, treatment regimen, and complications related to propranolol therapy in the present series

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PHACES association was present in a 1-month-old female with hemangiomas of the face, scalp, chest wall, microcardia, atrial septal defect, tricuspid regurgitation (TR), eye defects, and absence of sternum. Cervical and intracranial arterial anomalies were ruled out with cerebral magnetic resonance imaging before starting propranolol therapy.

There were 29 patients (7.59%) with complications related to the anomaly. Ulceration (>5 mm) was the most common complication present in 20/382 (5.24%) patients. Involvement of face (4), perineum (2), forearm (2), chest wall (2), and ear lobule (2) was present out of 20 patients.

Patients were divided into 4 treatment groups after a thorough discussion with the parents [Table 2]: (a) oral propranolol-only (325), oral propranolol + topical steroid (39), (c) oral propranolol + oral prednisolone (8), and (d) oral propranolol + oral prednisolone + topical steroid (10).

Oral propranolol in divided doses was given to all patients (100%); the initial dose was 0.5–1 mg/Kg and then gradually increased to 2.0 mg/Kg/day. Oral prednisolone (1.0 mg/Kg/day) was added to treatment in 18 (4.71%) patients, especially in ulcerated IH lesions during the early stages and AV malformations. It was given for a maximum period of 2–4 weeks. Topical steroid (hydrocortisone/beclomethasone ointment) was prescribed in 49 (12.82%) patients. It was prescribed for a maximum period of 2–4 months. Propranolol was given for a mean period of 10 months (range from 5 months to 2 years).

Complications related to propranolol therapy were seen in 23 (6.02%) patients [Table 2]. Diarrhea, nausea, and vomiting were seen in 5 (1.3%) patients related to propranolol therapy. Lethargy, dullness, and somnolence were also seen in 5 (1.3%) patients. Transient coldness of extremities (4, 1.05%) was taken care of by an appropriate covering of parts without discontinuation of treatment. Hypersensitivity reaction with widespread urticarial rashes was present in one (0.26%) patient.

The earliest effect was a change in color followed by softening and regression in size of IH after 2–3 weeks. All patients with superficial IHs (n = 263) showed a change in color of the lesion from bright red to dull gray red and arrest of growth within the 1^st month of therapy. Furthermore, all superficial IHs became softer and dull red at the end of the 1^st month. Out of 85 with deep and mixed IHs, the response was slow, delayed, and mixed response [Figure 4]. A gradual decrease in the size of IHs was noticed both clinically and ultrasonographically in all 348 patients during the study period.

The details of response to propranolol and adjuvant therapy and various vascular anomalies are given in [Table 3]. Among the four groups, the excellent response was highest (78.77%) in the oral propranolol-only group. At the end of the study, 282 (81.03%) out of 348 patients with IH showed an excellent response. In all the patients, ulcers started to heal on the first follow-up visit at 15 days. Complete healing was recorded on the next follow-up visits at 1 and 2 months. Patients with ulcers had residual mild atrophic scarring. Those patients with IH with ulcers over the axilla, neck, and labia majora had laxity of the skin of the local part after complete regression. Furthermore, large IH with focal small ulcers over the forearm and face regressed with residual telangiectasia [Figure 4]. Nasal cartilage erosion was seen in 2 (6.9%) patients during the proliferative phase, and further erosion was halted by the therapy.

Table 3: The response to treatment combination among vascular anomalies in the study

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In the case of CH (n = 11), there were excellent responses in 4 [36.36%, [Figure 6]] patients. In patients with vascular malformation (n = 23), excellent response was present in 5 (21.74%) patients. In lymphatic malformation (n = 19), excellent response was present in 4 [21.05%, [Figure 7]] patients. The response to the treatment was least in the venous malformation [n = 4, [Figure 7]] group with 1 (25%) patient each in all 4 response groups [Table 3].

Recurrence in the form of tiny lesions was noticed in 5 (1.47%) patients after completion of the study period in the IH (n = 348) group. Mild responders 2 (0.56%) in the hemangioma were referred for surgical excision. Vascular malformations were referred to the radiology department for sclerotherapy.

Discussion

The updated International Society for the Study of Vascular Anomalies/biologic classification divides vascular anomalies into vascular tumors and vascular malformations.^[2],[9],[10] Hemangiomas are vascular tumors, classified as infantile or congenital; the former subtype is much more common. As per their names, IHs develop after birth, while CHs are fully developed at birth.^[10],[11] IHs are the most common pediatric tumor affecting about 4%–10% of infants and also the most common vascular tumor. More than 50% of IHs occur in the head-and-neck regions (as appreciated in our series) and approximately 25% have multiple lesions.^[6] Multiple lesions were present in 14.37% (50/348) of IHs in our series. CHs are categorized as rapidly involuting CH [RICH, [Figure 6]] and noninvoluting CH. RICH (including ones with impending ulceration) in our series showed involution with the initiation of propranolol therapy.

Vascular malformations can be low flow (i.e., capillary, lymphatic, or venous) or high flow (i.e., arterial). A combination of these elements may be present.^{[9],[10],[11]}

IHs may complicate bleeding, ulceration (s), scaring, airway obstruction, and visual, auditory, and cardiac compromise (failure) in 10% of patients. These complications are more common during the involution than the proliferative phase.^[12],[13] In our study, we observed more complications during the proliferative phase. As per literature, ulceration is common in perineal and perioral regions.^[13] In our study, it was more commonly present on the face followed by perineum, forearm, chest wall, and ear lobule.

The liver was the most common (2/348, 0.57%) extracutaneous site among the IH patients in our series, which was similar to the previously published studies.^[13] There were 5 IH lesions in one of these patients. Multiple cutaneous hemangiomas have long been recognized to herald the presence of hepatic hemangiomas.^[13]

The approach to the treatment of IH and vascular malformations should be individualized by carefully weighing the risk of treatment and the potential benefits, based on the size of the lesion, morphology, location, presence, or possibility of complications.^[14] Furthermore, the main goals for treatment of IH are prevention of complications, induction of involution with minimal scarring, and lessening side effects of systemic treatment.^[12],[15] Propranolol, a nonselective beta-blocker, is understood to inhibit the growth of blood vessels by decreasing vascular endothelial growth factors (VEGFs) and other proangiogenic cytokines responsible for the growth of IH. Propranolol causes vasoconstriction (inhibiting release of nitric oxide), inhibition of angiogenesis (reduced expression of VEGF, etc.), and induction of apoptosis (capillary endothelial cells, through caspase-9, caspase-3, p53, and BAX).^[16],[17] These effects lead to reduced vessel density.^[18] In vitro studies reveal decreased expression of GLUT-1 with propranolol. It leads to the resolution of ulcerated IH and also that IH is resistant to steroid treatment.^[18]

Corticosteroids which were the previous gold standard act by halting additional IH proliferation, rather than inducing shrinkage of the tumor. It can be a primary treatment or as an adjunct to propranolol (primary treatment).^[19] Significant morbidity was earlier seen in 10% of cases treated with corticosteroids alone.^[20] In this series, none of the side effects were observed with a short duration of low-dose oral steroid (prednisolone) therapy in addition to oral propranolol therapy in 4.71% of patients.

As per the previous literature, IHs are the only vascular tumor that responds to propranolol therapy.^[18],[19] However, as per our experience, CHs also respond to propranolol. In our study, in lymphatic malformations, especially involving the neck (cystic hygroma early in infancy), an excellent response was present in 4 (21.05%). Lymphatic malformation of the base of the tongue responded good to therapy [Figure 7]. Excellent response was also seen in 1 (25%) out of 4 patients with venous malformation.

As per the standard guidelines, propranolol therapy should be initiated for infants >8 weeks of age (gestationally corrected) and continued for the entire proliferative phase (1 year or longer). A phase 2–3, multicenter, randomized, double-blind trial recommended oral propranolol solution for IH at the safe dose of 3 mg/kg in infants.^[21] As per one Chinese research group, the efficacy of low-dose propranolol up to 0.75–1 mg/kg has been reported.^[22] The therapeutic dosage of propranolol in IH ranges between 1 and 3 mg/kg/day in 3 divided doses, as per various studies.^[23] Heart rate and blood pressure monitoring for 2 h after the first dose and postdose increment has been recommended.^[13],[24] Recently, topical 0.5% timolol maleate drops/hydrogel have also shown good results in IH.^[23]

The color change is the first sign of arrest of growth. This sign is appreciated by most of the parents and was observed in 100% of IH cases. Padhiyar et al. have also described a color change in 100% of superficial IHs at 1 month, which was also seen in our series.^[6] Hogeling et al. and Padhiyar et al. have reported the arrest of growth with propranolol at 4 weeks and 1 month, respectively.^[6],[25] Al Dhaybi et al. observed a reduction in the size of the lesion within 2 months in 100% of cases.^[26] Padhiyar et al. have reported a decrease in size in 68% of superficial IHs at 1 month and 92% of patients at 3 months; there was no response among the deep and mixed variants.^[6]

More than 60% improvement was observed in 76% of patients while complete response (>90% improvement) was noted in 68% of patients among superficial IH as per Padhiyar et al.^[6] In our series, a lesser response was observed in patients with late initiation of treatment (>9 months) and with deeper lesions. Liu et al. detected a statistically better response in deep-seated IH than in the superficial type, which is in contrast to the study done by Padhiyar et al. in which mixed and deep types did not respond in terms of decreasing size.^[6],[27] Deep hemangiomas present as protruding tumors that are below the skin and usually appear bluish in color. Mixed hemangiomas (25%–35%) are a combination of both components, superficial and deep.^[6],[27] As per our experience, mixed and deep types of IH require a longer duration of treatment; also, most of these patients had a good response (50%–70% improvement) to the propranolol therapy.

Propranolol therapy (2 mg/Kg/day) was also effective both in stopping the growth and inducing rapid involution of liver hemangiomas in our series. The results were consistent with other series.^[28],[29]

In patients with CH, a decrease in size was appreciated in 81.81% of patients with excellent to good response, while in 18.18% of cases, the response was mild after therapy at 1-1.5 years. Although it was difficult to differentiate it from its routine involution in 81.81% of cases, initiation of involution started just after the beginning of propranolol therapy. This line can be rewritten without the hypothesis in the background.Furthermore it may be hypothesised that the clinical response in these patients may be attributed to vasoconstriction, inhibition of angiogenesis and induction of apoptosis.

As per the literature, propranolol therapy is stopped after expected clinical response or beyond the stage of the proliferation of IH (12–18 months of age).^[12],[15] As per multicenter, randomized, double-blind, adaptive, phase 2–3 trial at a dose of 3 mg per kilogram per day, the final response was achieved at 6 months.^[21] The mean duration of therapy ranged from 5.5 months to 10.5 months.^{[6],[7],[26],[30]} In our series, the duration of propranolol therapy ranged from 5 months to 2 years (mean = 10 months). In our study, large and deeply penetrating intraparotid IH was present in one case which required propranolol therapy for 2 years. The long treatment up to 2 years was also contemplated in deep IH.

Propranolol administration should be slowly tapered to lessen the hazards of (i) rapid regrowth of primary lesions, lesions with partial regression, and (ii) a hyperadrenergic withdrawal response.^[31],[32] We recommend that propranolol treatment should be stopped in patients with complete regression and those with partial regression over 2 weeks and 4 weeks, respectively.^[32]

The side effects of oral propranolol therapy for IH generally range from 2.1% to 13.5%.^{[21],[22],[33],[34]} In our series, complications related to propranolol therapy were present in 6.02% of patients. Side effects are sleep disturbance, restlessness, agitation, somnolence, coldness of extremities (feet and hands), nausea, vomiting, and diarrhea. Serious cardiovascular adverse effects such as atrioventricular block, bradycardia, hypotension, and cardiac arrest were not present in our series. Respiratory disorders include breathing difficulty, wheezing (bronchospasm), bronchial hyperactivity, and/or bronchitis/bronchiolitis.^[5],[21] Metabolic disorders, e.g., hypoglycemia, hypoglycemic seizures (as seen in one of our cases), and infrequently deep coma may be present with propranolol therapy.^[35] Hyperkalemia is present with ulcerative IH. These are usually seen with a dose >2 mg/kg/day.^[36],[37] de Graaf et al. observed 35 adverse events among 28 infants (a high percentage) undergoing well-controlled propranolol therapy including “isolated diastolic hypotension,” hypoglycemic seizures, and hypoglycemia.^[21],[38]

Hypoglycemia is one of the grave side effects of propranolol therapy. It is reported in both newborns and toddlers due to low glycogen storage, often associated with poor breastfeeds or decreased oral intake, or concomitant systemic infection.^[39] To prevent the risk of propranolol-induced hypoglycemia, propranolol should be administered during the daytime, preferably with food (just before or after). As per studies, patients who developed hypoglycemia were given higher doses of propranolol than those taking relatively small doses.^[40] Furthermore, infants <3 months are at a higher risk of propranolol-induced hypoglycemia; they must be closely observed for 24 h after the first dose.

Hypotension and bradycardia may precipitate into a hypoglycemic coma. Among the early clinical signs of hypoglycemia, e.g., jitteriness, irritability, poor feeding, cyanotic spells, hypothermia, and lethargy which may be masked by propranolol (beta-blockage). Sweating is an exception and the most consistent sign in such patients. Sweating (1.05% in our series) as a warning sign was explained to the parents. In these patients, propranolol was temporarily discontinued for a few days and then the dose was tapered to half of the previous dose.

It has also been recommended to discontinue propranolol therapy during periods of illness or poor oral intake or fasting.^[24],[41] Furthermore, frequent feeding should be recommended and the baby should not be allowed prolonged periods of sleep, especially during the initiation of propranolol therapy. As the smaller children have limited glycogen stores, compounded with their inability to express the symptoms, hypoglycemia may be detrimental.^[35]

Hypoglycemic coma signifies a life-threatening emergency that necessitates rapid intervention for the preservation of brain functions. Repetitive and sustained hypoglycemia in infants may lead to permanent impairment of brain growth and function.^{[35],[42],[43]}

Major complications were low in our series, with a single case of hypoglycemic seizures. This was because of our strict protocol of clinical evaluation, echocardiography by an experienced pediatric cardiologist, ultrasonography by a pediatric radiologist, and patient monitoring and parental education. We recommended pretreatment evaluation, close monitoring, especially after starting and during the therapy, and comprehensive parental (caretaker) education regarding the appropriate dosage, timing, withholding, and warning signs of adverse effects with the administration of the medication. Initial low dosage is important for reducing the complications, as per our experience. The response to treatment in the oral propranolol-only group was better than propranolol with adjuvant therapy groups. This is postulated to be due to a greater proportion of uncomplicated IH and lymphangiomas in the former group, while complicated IHs were more in the latter group.

The relapse rate after cessation of treatment with propranolol ranges from 4.5% to 8%.^[6],[22] It is high with segmental IH and deep subtypes. Ahogo et al. reported a very high relapse rate of 12% with propranolol therapy.^[44]

Only 10% of IHs treated with propranolol required surgery, whereas 29% of those treated with steroids.^[45] Surgery is indicated in life-threatening lesions, airway and visual obstruction, cosmesis for residual fibrofatty lesions, and persistent scars after the involution phase and when the mass is unresponsive to medical therapy. Propranolol therapy reduces the extent of surgery required for excision.^[45]

As per the authors, propranolol should be the first-line therapy in IH, CHs, selected lymphangiomas, and venous malformation irrespective of age, location, extent, and phase of growth in pediatric patients. It helps in reducing its size and complications.

Conclusion

Propranolol hydrochloride therapy reduces the color intensity, size, and thickness of IH and congenital hemangiomas. It decreases the size and volume of selected lymphangiomas. The study validates the use of propranolol hydrochloride as the first-line agent for the treatment of IHs and congenital hemangiomas. It is both effective and safe. It may have an additive role in lymphatic malformations, and venous malformations, as a part of a multimodality treatment approach (steroid/sclerotherapy/surgery) for vascular malformations. Further research and randomized clinical trials are required to establish its role. Topical and oral steroids have an additive therapeutic role in shortening the natural course of the disease. Starting treatment early after birth was more advantageous for size reduction. Deeper and mixed types of IH respond to a higher dose and longer duration of therapy. Serious adverse effects of propranolol therapy for vascular anomalies are infrequent, but early identification of these adverse effects, especially hypoglycemia, can be of great importance for patient management and prognosis. Sweating is an important presentation of hypoglycemia in these patients. Education of parents and concerned physicians regarding sweating as a warning sign and when to temporarily withhold the treatment may be practiced.

Acknowledgment

I am sincerely thankful to Dr. R.B. Goyal (Former HOD), Dr. Arun K. Gupta (Former HOD), Dr. Praveen Mathur (Former HOD), Dr. Monika Boipai (Former M.Ch. resident), and the faculty of the Department of Paediatric Surgery, SMS Medical College, Jaipur, Rajasthan, India, for helping in our endeavor. I am thankful to Dr. Anu Bhandari, Senior Professor, Radiodiagnosis for the radiological evaluation. I am also thankful to the unit of Paediatric cardiology for the cardiac evaluation.

Declaration of patient consent

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

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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