ABSTRACT

Corresponding Author:
Dr. Bornali Dutta,
C1, Crishna Cauvery Enclave,
D Neog Path,
Behind Dona Planet, ABC,
Guwahati-781005, Assam.
E-mail: dr.bornali.dutta@gmail.com

ABSTRACT

AIMS AND OBJECTIVES

Infantile Haemangiomas (IHs) are the most common soft tissue tumours of infancy, occurring in 4% to 10% of children under 1 year of age. Many treatment options exist ranging from the policy of “Benign neglect” to surgical excision. This retrospective study was done to evaluate the difference in efficacy, adverse effects of oral propranolol versus oral prednisolone in the treatment of potentially disfiguring or functionally threatening infantile haemangiomas and their recurrence after cessation of treatment.

SETTINGS AND DESIGN

Hospital record based study.

METHODS AND MATERIALS

A retrospective study was done on 60 patients of Infantile Haemangioma (IH) aged two weeks to one year of age involving both sexes. Patients who had received propranolol and oral prednisolone during the study period of 2012 to 2015 were selected and Group A and Group B comprised of thirty patients who had received propranolol (1 to 2.5 mg/kg/d) and oral prednisolone group (0.5-2 mg/kg/d) respectively for a minimum duration of 9 months. Parameters like dimension of the haemangioma, colour, consistency, ultrasonographic findings and photographic documentation were assessed from both hospital records and photographs available with the authors. A minimum of 80% improvement was considered as success with no relapse up to 1 month of stopping treatment.

Statistical analysis used: Descriptive statistical analysis and Fisher’s exact test by GraphPad Software Inc., San Diego, USA.

RESULTS

Mean initial reduction of size of infantile haemangiomas were significantly lower in propranolol treated group (In days) (6.6±3.5SD) than prednisolone treated group (9.66±4.9SD) (p<0.0169). The time taken for a change in consistency from the onset of treatment was significantly shorter for the propranolol treated patients (Median: 3.13±SD1.4), compared with prednisolone treated group (Median: 6.6±SD 3.9). In the propranolol group, a tendency for shorter ulcer duration was seen in patients starting the medicine at an earlier stage of disease. Flattening of the lesions were found more in Group A patients within 9 months of treatment compared to Group B (p=0.0641).

CONCLUSION

Propranolol had a consistent, rapid therapeutic effect compared to prednisolone with milder adverse effects and lower recurrence rate in the treatment of infantile haemangioma. Prednisolone was associated with a higher number of complications, thereby decreasing patient compliance. Propranolol reduced the duration of ulceration in IH and seemed to be more effective when started at an early phase. Further studies are needed in determining the most effective treatment dosage, optimum treatment duration and exact mechanism of action of propranolol in future.

KEYWORDS

Propranolol; Prednisolone, Beta-blocker, Infantile Haemangioma (IH), Ulceration, Adverse Effects.

INTRODUCTION

Infantile Haemangiomas (IHs) are the most common soft tissue tumours of infancy, occurring in 4% to 10% of children under the age of one year.^[1] Although IH is not believed to be familial, approximately 10% of the affected infants have a positive family history.^[2]

The natural history of IH is unique. Most IHs usually appear during the first few weeks of life, though approximately 30% of lesions do present since birth.^[3,4]

It proliferates during the first year of life and then involutes during the childhood period. Clinically, two features distinguish infantile haemangiomas from vascular malformations that neither proliferate nor involute.^[5-7]

Approximately 40% of them involutes spontaneously. Accordingly, belief supporting that most infantile haemangiomas should be left untreated along a policy of “Benign neglect” was considered and is still firmly encountered in practice. However, the unpredictable outcome and the possible serious complications after proliferation and proposed involution in addition to the consequences of cosmetic disfigurement associated with the psychologic trauma in parents and in the affected children later, all alleviate for prompt treatment of IH.^[6] Standard treatment options for IH include corticosteroids, laser surgery, cryosurgery, interferon and vincristine.^[7-9] Each of these treatment options has its restrictions and or side effects.^[10]

In 2008, Leaute-Labreze et al^[11] described their observation of the effect of propranolol on IH. Propranolol is a pure selective beta adrenergic antagonist, which competitively inhibits beta-1 and beta-2 adrenoceptors with the same affinity. On account of its lipophilic properties, propranolol also exhibits certain membrane stabilising characteristics. Since the accidental and innovative observation by Leaute-Labreze et al, the use of propranolol for treatment of IH has become a subject of extensive investigations.

There are no strict evidence-based studies to guide therapy of infantile haemangioma. There is paucity of data comparing efficacy of steroid and propranolol. In this retrospective, randomised study, we compared the efficacy of propranolol versus prednisolone in two groups of patients aged between two weeks to 12 months with cosmetically disfiguring or functionally life-threatening IHs.

MATERIALS AND METHODS

Sixty patients with infantile haemangiomas attending the outpatient departments of Paediatric Surgery and Dermatology of two tertiary care referral hospitals from October 2012 to September 2015 complying with the following criteria were included in the study.

Inclusion Criteria

• Age group - 2 weeks - 12 months of either sex.
• Patients with potentially disfiguring lesions in the body.
• Functionally threatening lesions of the limbs, genitalia or natural orifices.

Exclusion Criteria

• Uncomplicated lesions of trunk, extremities.
• Presence of heart disease, cardiac arrhythmia.
• Patients with obstructive lung disease.
• History of hypoglycaemia.
• Prematurity.

Patients were divided into two groups: Group A had received propranolol (1 to 2.5 mg/kg/d) and Group B had received prednisolone (0.5-2 mg/kg/d). Thirty patients were included in each group. Treatment was initiated during a short hospitalization of 48 hours. At inclusion, each lesion was evaluated clinically for size, colour and consistency. Lesions were categorized into superficial, mixed and deep according to the depth measured on Ultrasonography (USG). The maximum diameter in two axes perpendicular to each other was measured.

The lesion was photographed with and without flash with a standard 10 megapixel digital camera at 30-cm distance and approximately in 2-Mb resolution. Cardiac evaluation was done by doing Electrocardiogram (ECG) to rule out treatment contraindications. In patients with eye lid involvement, ophthalmologic examination was done. Clinical assessment with measurements was repeated at 24 and 48 hours and photographs after 48 hours of starting treatment.

Followup of the cases were done for another 12 months after cessation of therapy.

Group A

Propranolol tablet was crushed and mixed with glucose or honey preparing a homogeneous mixture. It was given at a starting dose of 1 mg/kg per day, in two divided doses for two months and increased to 2 mg/kg/d thereafter if tolerated well.

The drug was continued at 2 mg/kg/d for another 3 months. Maximum dose was kept at 2.5 mg/kg/d and was given only if the lesion did not improve further till the maximum period of 12 months from the start of treatment. Blood pressure, heart rate and blood glucose were monitored 1 hour after the first dose and 8 hourly thereafter during the first 24 hours of treatment and then at 48 hours. In the absence of side effects, the child was discharged after 48 hours and treatment was continued at home. The patients were called to the OPD at monthly intervals for assessing therapeutic response and side effects.

Group B

Commercially available prednisolone suspension was started at 0.5 mg/kg/d in two divided doses with antacid gel after feed for a period of 2 months. Therapeutic response and side effects were evaluated at monthly intervals. If sufficient response was not observed at the end of two months, the dose of the drug was increased at the rate of 0.5 mg/kg/d every two monthly to a maximum dose of 2 mg/kg/d. This maximum therapeutic dose was not allowed to exceed a period of two months. Then the dose was gradually tapered off in the same pattern. The maximum duration of treatment did not exceed more than 12 months.

RESULTS

There were 16 male patients (53%) and 14 female patients (47%) in Group A. There were 13 male patients (43%) and 17 female patients (57%) in Group B. The overall male/female numbers were 29/31. No patient was on any concomitant therapy at the time of initiation of treatment except antibiotic coverage for infected lesions. Mean age at the initiation of treatment was (8.9±SD4.7) in weeks in Group A compared to (6.5±SD4.2) in Group B.

Head and neck and face were the most common locations in 70% (n = 42). Front of the face was the most common site in head and neck region contributing 49% of total cases, followed by parotid (29%), lip (13.3%) and scalp (10%). The most common type of lesion was superficial (26; 43%), followed by mixed (18; 30%) and deep (16; 26%). Most lesions were noticed by parents in the second to fourth weeks of life as painless red swelling, which were proliferating rapidly. Complicated haemangiomas were seen in 16 patients. In Group A, ulceration with bleeding and ulceration without bleeding were found in 4 and 2 patients respectively. In Group B, ulceration with bleeding and tongue haemangioma with feeding difficulty were found in 9 and 1 patients respectively. Bleeding lesions were seen on the lip, labial and scapular region.

Healing of ulceration, assessed from reduction in size was earlier in Group A. Mean response time (Reduction in size of lesions) in patients receiving prednisolone was 10.78±7.8 days, which was significantly more (p<0.0169) than patients receiving propranolol. In Group A, 23 patients (76%) showed a reduction in size of haemangioma in less than 6 months compared to 13 patients from Group B (44%).

But after 6 months of age, only 7 (23%) patients in Group A compared to 17 patients in Group B (57%) responded to treatment. Table 1.

Flattening of the lesions in less than 9 months of starting treatment was common in Group A with 22 patients (73%) then Group B with only 8 patients (27%). Table 2.

In four patients in Group A with large ulcerated haemangiomas in neck with bleeding and two in facial region, bleeding stopped within 48 hours and ulcer healed within 2 months. In Group B, ulceration with bleeding was seen in nine patients (30%), which healed within 3 months. Five patients required antibiotic coverage to control infection in Group A and seven patients required antibiotic in Group B. All cases in Group A stopped growing, faded in colour and became smaller compared to 7 in Group B. Maximum reduction was seen in Group A in the first 6 months of treatment (23/30,76%). (Fig.1) Group B showed less reduction in size with 43% showing improvement. In Group A, there was significant two-dimensional reduction in size of the IHs. Significant change in consistency was noted within 48 hours in Group A compared to Groups B, which showed changes at 10 days of treatment.

The mean dose requirement (mg) at the end of the study was as follows: propranolol (Group A) 1.65±0.78SD, prednisolone (Group B) 1.50 ± 0.79SD. Three patient in Group B did not show any response till the end of the study in spite of receiving a maximum dose at 2 mg/kg/d.

Four patients from Group A had hypoglycaemia at the initiation of treatment, which was managed by frequent feeding. The fifth child had somnolence after the second dose of propranolol at 2 mg/kg with no evidence of hypoglycaemia, bradycardia or hypotension. No patient required discontinuation of treatment for any reason. Complications encountered in Group B were namely, Cushingoid appearance (n=12), GI upset (n=5), recurrence (n=6) and infection (n=3) (Fig. 2). Mean age (Months±SD) at the end of the study was 9.3±5.2 (Group A) and 10.1±4.3 (Group B). Mean duration (Months) of follow-up was 7.6±1.9 (Group A) and 8.11±3.3 (Group B). There was no statistical difference among the two groups. Completion of treatment was earlier in Group A, then Group B. The response time was significantly less in mixed type compared to superficial and deep varieties.

Patient compliance and parental satisfaction were 100% in Group A. Significantly higher numbers of complications were noted with poor treatment compliance in Group B.

P is <0.0169, considered significant by Fisher’s exact test.

Sensitivity: 76.67%.

Specificity: 56.67%.

PPV: 63.89%.

NPV: 70.83%.

P is <0.0641, considered not quite significant by Fisher’s exact test Sensitivity: 73.3%.

Specificity: 53.3%.

PPV: 61.1%.

NPV: 66.1%.

Fig. 1: Clinical Photographs of Patients in Groups A, Showing Change in Color and Size of the Lesion at Admission and 12 Months of Treatment (From Left to Right)

Fig. 2: Clinical Photographs of Patients in Groups B Showing Change

in Color and Size of the Lesion and Cushingoid Appearance at Admission

and 12 Months of Treatment (From Left to Right)

DISCUSSION

Infantile haemangioma is the most common vascular tumour in infancy with an incidence of up to 10% in white infants.^[1] It occurs 2.2 to 4.5 times more frequently in females and in up to 20% in premature infants.^{[12,13,14-17]} There were more males than females (31:29) in our study opposed to other literature where it is quoting female preponderance of 2.2 to 4.5 times more than males.^[1] Haemangiomas are benign growth of endothelial cells presenting anywhere in the skin, mucous membranes or underlying viscera. They most commonly occur in the head and neck region.^[18] In our study also head and neck haemangiomas accounted for 70% of the cases. Up to 10% of IHs may cause obstruction of the upper airway/eye, ulceration, bleeding, soft-tissue deformity and high-output heart failure.^[19]

The gold standard treatment of complicated IHs for a long time has been high-dose systemic corticosteroids. They have been shown to be anti-angiogenic in a number of in vitro settings.^[20] In addition, they may influence capillary vascular tone. Their use is limited to the proliferative phase, halting growth rather than producing significant involution.^[21] Even at a dose of 2-5 mg/kg per day, response rates range from 30% to 60%, mostly seen as stabilization or incomplete regression.^[22,23] While their efficacy is not disputed, complications are frequent. Cushingoid facies (71%), personality changes (21%), gastric irritation (21%), fungal infection (6%) and reversible myopathy were noted in 62 patients receiving systemic steroid therapy for problematic His.^[24,25]

While most of the complications are transient and limited, some may become much more serious, such as hypertension and hypertrophic obstructive cardiomyopathy. Rossler et al^[26] noted behavioural changes like irritability/insomnia (25%), poor height gain (8%) and hypertension (5%) during prednisone therapy. In our study, Group B patients treated with prednisolone led to Cushingoid appearance in 40% of patients. GI upset was complained in (16%). In addition, there was recurrence at the end of twelve months of treatment in six cases. While most complications regress with discontinuation of therapy, they cause a lot of anguish to parents or require withholding therapy for a while.

Recently studies using propranolol has shown excellent response in proliferative IH and has become an additional therapeutic option.^[27,28] Propranolol, a well-tolerated, nonselective, beta adrenergic receptor blocker had been commonly used for cardiologic indications in young children. In 2008, Leaute-Labreze et al^[11] reported the incidental finding that it could control the growth of IHs efficiently. Other studies done since then have shown an excellent effect and good tolerance.^[29] Within hours of starting therapy it produces vasoconstriction resulting in a reduction in the colour of the haemangioma. Its primary effect appears to be alteration in the progression of angiogenesis, perhaps by decreasing expression of Basic Fibroblast Growth Factor (bFGF) and Vascular Endothelial Growth Factor (VEGF). It may ablate catecholamine receptor signalling, decreasing cyclic AMP promoting involution by triggering apoptosis in endothelial cells.^[11,30]

Response rates to steroid therapy vary widely with many IHs failing to respond at all.^[22]. In our study, mean response time (Reduction in size of lesions) in patients receiving prednisolone was 10.78±7.8 days, which was significantly more (p 0.0169) than patients receiving propranolol. In 23 patients in Group A (76%) reduction in size was noted in less than 6 months compared to 13 patients in Group B (44%). But after 6 months of age, only 7 (23%) patients in Group A compared to 17 patients in Group B (57%) responded to treatment showing slower response in Group B.

Ahmed et al^[31] reported high efficacy and tolerance of propranolol treatment of IHs. The first noticeable effects of propranolol treatment were the changes in colour followed by softening of lesions and regression of size. Buckmilier et al^[27] evaluated 32 patients treated with propranolol (Dose 2 mg/kg/d) by clinical examination and photographs, revealing 50% of patients to be excellent responders. Minor adverse effects included somnolence in 27% of patients, gastroesophageal reflux in 9%. Qin et al^[32] treated 58 children with propranolol (Dose 1.0-1.5 mg/kg/d). The outcome was excellent in 17.2%, good in 60.4%, moderate in 20.7% and poor in 1.7% of cases. Bagazgoitia et al^[30] in a retrospective study treated 71 patients of IHs with propranolol (Dose 2 mg/kg). At 20 weeks, the average reduction was 60%, but after that less impressive size reduction was obtained.

Recently, severe hypoglycaemia was detected 3 cases on propranolol treatment for IH, emphasizing the importance of understanding and recognition of serious adverse effects.^[33] Ulceration is the most frequent complication of IHs occurring in up to 15% of patients and is a challenge to manage.^[34]

It can lead to pain, irritability, poor feeding or sleeping disorder, scarring, and disfigurement. It is also associated with bleeding (41%) and infection (16%).^[35] In our study, ulceration was seen in 15 (25%) patients with bleeding in 13 patients (21%). Four of the ulcerated haemangiomas healed completely within a month with propranolol. Another infected forearm haemangioma required discontinuation of prednisolone and healed in 2 months with propranolol only. This is comparable to the study conducted by Sans et al^[10] in 32 patients where painful ulcerations healed completely within 2 months of propranolol therapy. Two other small series of ulcerated IH have shown early and good response to oral propranolol at a dose of 1-2 mg/kg per day with no side effects.^[36,37]

Data regarding comparative efficacy of steroid and propranolol are very less in spite of high incidence of IHs. Effectiveness and side effects appear more favourable with propranolol compared to prednisolone in the management of IHs. Though the size of our groups are relatively small, the inference can be helpful to formulate a treatment plan for treating haemangiomas. More extensive clinical studies are required to understand better the efficacy and safety of propranolol and prednisolone in infants with cosmetically disfiguring or functionally deranged haemangiomas.

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