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ORIGINAL ARTICLE
Year : 2018  |  Volume : 19  |  Issue : 3  |  Page : 230-235

The efficacy of a combination of oral low-dose prednisolone with propranolol for the treatment of infantile hemangioma


Ashish Hospital and Research Centre, Jabalpur, Madhya Pradesh, India

Date of Web Publication28-Jun-2018

Correspondence Address:
Dr. Pradyumna Pan
Ashish Hospital and Research Centre, Jabalpur - 482 001, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_103_17

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  Abstract 


Background: Infantile hemangiomas (IHs) are very common vascular tumors. Corticosteroid and propranolol are drugs for the treatment of hemangioma. High dose given for longer duration causes higher side effects. Aim and Objective: The aim and objective of this study was to determine the outcome of a combination of low-dose oral prednisolone with oral propranolol for the treatment of IH. Methods: The study comprised 42 consecutive patients with IH managed with low-dose oral prednisolone and oral propranolol between 2013 and 2016. Patients fulfilling the inclusion criteria were registered through the outpatient department. Diagnosis was confirmed clinically and on Color Doppler. All the patients were given oral prednisolone at a dose of 1 mg/kg/day and propranolol at a dose of 1.5 mg/kg/day. Treatment was given for 4 months and then titrated down for 2 months before the cessation of treatment. Results: Distribution was more on head, face, and neck. The median age at the start of treatment was 4.7 months. Out of the total 42 patients, forty patients responded to therapy (95.2%). Results were found to be excellent in 57.14% of infants and good in 30.95%. Treatment failure was seen in 4.7%. Side effects were not serious and resolved when treatment was discontinued. Rebound growth occurred in two infants (4.7%). No patients suffered drug morbidity. Conclusion: The frequency of acceptable outcome of a combination of low-dose oral prednisolone with oral propranolol for the treatment of IH shows high efficacy, low severe complication rate, and rapid clinical improvement.

Keywords: Combined treatment, infantile hemangioma, oral prednisolone, oral propranolol


How to cite this article:
Pan P. The efficacy of a combination of oral low-dose prednisolone with propranolol for the treatment of infantile hemangioma. Indian J Paediatr Dermatol 2018;19:230-5

How to cite this URL:
Pan P. The efficacy of a combination of oral low-dose prednisolone with propranolol for the treatment of infantile hemangioma. Indian J Paediatr Dermatol [serial online] 2018 [cited 2019 Jul 18];19:230-5. Available from: http://www.ijpd.in/text.asp?2018/19/3/230/235492




  Introduction Top


Infantile hemangiomas (IHs) are the most common vascular malformations of infancy, being present in 5%–10% of infants.[1] IHs most commonly affect the head-and-neck region. Mostly, IHs are small, but they can be large, disfiguring lesions with serious complications. Hemangiomas might also involve the orbit, airway, or visceral organs.[2] They generally become evident within the 1st month of life and are characterized by an initial phase of rapid endothelial cell proliferation during the 1st year of life followed by a phase of slow involution.[3]

Until recently, the mainstay of treatment of IHs has been corticosteroids in various forms. The response rate was found to be 80%, with the greatest response occurring in children treated in the early proliferative phase of the lesion.[4] The standard treatment regimen is 2–4 mg/kg of oral prednisolone daily.[2] However, high dosage and long-term usage tend to result in serious side effects.

Propranolol is a nonselective beta-blocker. Its safety profile is well established when administered to appropriate patients.[5] Propranolol has been associated with adverse events such as bradycardia, hypotension, hypoglycemia, and bronchospasm.[6]

Oral prednisolone and propranolol have shown excellent results individually for the treatment of IH. However, the combination of the two drugs in lower doses may be used for the treatment of IH to avoid the complications associated with high doses of both drugs.


  Methods Top


It is a prospective, observational analysis conducted at Pediatric Surgery Unit from 2013 to 2016 after getting approval by the ethical committee and institutional review board. Forty-two patients fulfilling the inclusion/exclusion criteria were enrolled to determine the outcome of a combination of low-dose oral prednisolone with oral propranolol for the treatment of IH.

Patients with IH whose size >10 mm over the body surface were included. The exclusion criteria were a history or risk of asthma, reactive airway disease, impaired renal or liver function, heart defects, and hypersensitivity to propranolol. Lesions involving deep structures, previously treated either medically or surgically, and those who need urgent treatment due to threatening vital functions were excluded. Infants who did not adhere to the treatments or follow-up visits were also excluded from the study. Written informed consent and permission to use the photographs were derived from the parents/guardians of the patients after discussing the risks and benefits of the drugs.

The pretreatment workup before starting steroid therapy includes ruling out active infection or primary immunodeficiency disease. The patients received treatment with oral prednisolone at a dose of 1 mg/kg/day. All infants were hospitalized in our pediatric ward for 72 h in order to start treatment with oral propranolol under therapeutic control. It was started at a dose of 0.5 mg/kg/day and increased up to 1.5 mg/kg/day in two divided doses within 10 days with close monitoring of heart rate, blood pressure, and blood glucose. Parents were notified of the possible side effects and danger signs such as refusal to feed and lethargy, and were advised to report at the earliest if any of these signs appeared. Treatment was given for 4 months to all patients and then titrated down for 2 months before the cessation of treatment. In case of early response, drugs were titrated down for 4 weeks before cessation.

Follow-up of the patients was performed at 10th day after initiation of treatment, and then every month for 6 months. Heart rate, blood pressure, random blood sugar, and treatment compliance were checked during each visit. Serial monthly photographs were taken during the course of treatment to assess response to therapy for change in size and appearance toward resolution and any complications of therapy were recorded. The following data were collected: gender, type and location of lesions, age at therapy initiation, and end dates. The infants were divided into four groups according to their age at the initiation of treatment: 0–3 months, 4–6 months, 7–9 months, and 10–12 months. The treatment efficacy was assessed 6 months after treatment initiation. We evaluated the treatment efficacy based on (a) volume reduction, (b) color improvement, and (c) texture improvement. The evaluations were based on the photographs obtained before and after treatment. The results were categorized into four grades based on the Achauer system: scale I, poor response (0%–25% regression); scale II, fair response (26%–50% regression); scale III, good response (51%–75% regression); and scale IV, excellent response (76%–100% regression). The results of the therapy were evaluated through the visual analog scale (VAS) proposed by Zavulunov. The VAS scale is based on the evaluation, made by two independent observers, of photographic documentation acquired before, during, and after the treatment. The scale consists of values between 0 and 10, where 10 indicates the nonresponse of IH and 0 indicates that IH is no longer visible. A score of 5 means an IH decrease of 50% compared with its initial aspect. The consequences during therapy and at the end of the cessation of treatment were analyzed. In cases of multiple hemangiomas, each was evaluated separately.


  Results Top


The median age at the start of treatment was 4.7 months, ranging from 1.7 to 12 months [Table 1]. Twenty-eight patients (67%) had a solitary hemangioma and fourteen had multiple ones.
Table 1: Patient characteristics

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Twenty-four children had a cutaneous tumor and eighteen had a subcutaneous tumor. Deep ulceration was observed in seven children and bleeding in three on their initial clinical examination. Distribution of IH are shown in [Table 2].
Table 2: Distribution characteristics

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All infants exhibited immediate IH color lightening and noticeable softening in texture during hospitalization. A total of forty patients showed improvement after combined therapy, of which six patients were complete responders [Figure 1]. Two patients (4.7%) had growth of hemangioma despite therapy and were considered to be nonresponders [Figure 2]. There were seven patients of hemangiomas with ulceration, all were excellent responders. Ulcers healed within 15 days. Three infants who had bleeding responded within 10 days after initiation of the therapy.
Figure 1: (a-c) Complete response

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Figure 2: (a and b) No response to the treatment

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Clinical response was seen in 95.23% of the infants. Twenty-four patients had excellent [Figure 3] and thirteen had good response [Figure 4] and [Table 3]. The results of the therapeutic response evaluations at the cessation of the treatment were as follows:
Figure 3: (a-c) Excellent response

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Figure 4: (a-c) Good response

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Table 3: Therapeutic response

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An analysis by age at treatment initiation revealed that the group aged 4–6 months had a 98.48% clinical response rate and the group aged 0–3 months demonstrated an 84.93% clinical response rate.

VAS score were analyzed and shown in [Table 4]. The median of the VAS scores was 4 [Table 4].
Table 4: Visual Analog Scale score

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In two patients (4.7%), the residual IH began to grow slowly again after discontinuation of the therapy. The size increments were mild and responded to retreatment. These patients were aged 2 months, 16 days and 3 months, 7 days, respectively, when treatment was initiated. A second cycle of therapy was administered with the beneficial result and without any relapse. The age of those two patients at the beginning of the subsequent treatment was 10 months, 9 days and 11 months, 5 days, respectively. In two patients, treatments were prematurely stopped as there was no response at 12 weeks after initiating treatment. In three patients, the lesion had complete involution after 4 months.

None of our patients showed severe side effects at the beginning or during the treatment. We had six patients with side effects. One had transient decreased blood pressure (a decrease of >15% of mean arterial pressure). Two other children presented a lower heart rate after the initial dose of the drug. One patient presented with lethargy, refusal to feed, and excessive regurgitation of feeds 1 week following initiation of treatment. One patient presented with sleep disturbance and rash involving the face and trunk. One suffered from a hypoglycemia-induced seizure during an episode of gastroenteritis. There were no serious side effects related to cardiac events or bronchospasm.


  Discussion Top


IHs are the most frequent infantile vascular malformation, with a frequency of 4%–10%.[7] More than half of the cases are affected at birth, and the rest of them develop in the first weeks of life.

The pathogenesis of IH remains unknown. At present, there are three main hypotheses: the theory of tissue hypoxia, the theory of embolization of placental endothelial cells, and the theory of increased angiogenic and vasculogenic activity. The possibility that the three mechanisms could act together is not excluded.[8],[9]

Morphologically, hemangiomas are divided into superficial, deep, and mixed types. Superficial hemangiomas, when fully formed, are marked by bright red vascular plaques or nodules. Deep hemangiomas manifest as partially compressible, subcutaneous, bluish vascular swellings. Mixed hemangiomas have both superficial and deep components. Based on their distribution, IHs can also be classified into localized, segmental, indeterminate, and multifocal.[3],[10] Localized hemangiomas are spatially confined, while in segmental IH, there are clusters of lesions confined to a developmental segment or a large anatomic territory.[11] Hemangiomas >4 cm are defined as giant hemangiomas. In multifocal hemangiomas, infants have five or more noncontiguous lesions. They are usually associated with systemic involvement, especially the liver. Other sites of involvement include the central nervous system, lungs, kidneys, and eyes. IHs have a characteristic natural course; a rapid proliferative phase in infancy which is followed by a gradual involutory phase over the next several years.

Steroids used to be the first-line treatment for IHs over the past several decades. The mechanism of action of steroids is not entirely clear, though it is postulated to have an inhibitory effect on the production of vascular endothelial growth factor-A by stem cells in hemangiomas.[12] Steroids are more effective in the early proliferative phase and have a response rate of 70%–80%.[4],[13],[14] The usual recommended dose is 2–4 mg/kg/day, which should be continued until the cessation of growth or shrinkage of hemangioma followed by gradual tapering. Long-term steroid usage in higher dose >3 mg/kg is associated with many side effects. Boon et al. in their study identified cushingoid facies in 70.9%, dropped in growth curve for weight in 35%. Personality changes such as irritability, sleep disturbance, and restlessness were reported in 29% of their cases.[15] George et al. in a retrospective review found gastric irritation in 21% of patients and hypertension in 45%.[16]

Propranolol is a noncardioselective β-adrenergic receptor blocker, first reported as a treatment for IHs by Léauté-Labrèze et al. in 2008. The mechanism of action of propranolol on IH remains elusive. The effect of propranolol on growing IH is due to vasoconstriction, inhibition of angiogenesis, and induction of apoptosis.[17] In a meta-analysis, Liu et al. showed a response rate of 88.75%.[18] Léauté-Labrèze et al. noted side effects such as diarrhea 27%, sleep disorder 21%, bronchitis 16.8%, and cold hands and feet 9.9%.[19] Hypoglycemia, bradycardia, and bronchospasm are serious adverse effects.[20]

A target dose of 1–3 mg/kg has been recommended.[21] However, many researchers advocate a dose of 2 mg/kg/day. Similarly, few authors have used a maximum dose of 4 mg/kg/day.[22] It is generally administered at a low starting dose of 0.5–1 mg/kg/day which is gradually escalated to the optimal dose over a period of days to weeks. Hogeling et al. suggested a treatment course of at least 6 months which could be modified according to the morphological subtypes. A meta-analysis showed the overall response rate in the range of 82%–90% and mild side effects in the range of 16%–31%. Serious adverse effects were observed in the range of 3.4%–6.2%.[23],[24]

In our study, the dose of prednisolone was 1 mg/kg/day and that of oral propranolol was 1.5 mg/kg/day. The dosage of the drugs was kept in the lower side. This reduces the adverse effects of the drugs. The efficacy of combined therapy reached 95.2% in this series, similar to study by others.[25],[26] In responders, the first effects appeared during the first 24 h of treatment as changes in color (from bright red to purple) and consistency (softening of the lesion on palpation). After the initial response, IH continued to progressively improve both with respect to color and thickness. The highest significance of clinical improvement occurred in the first 2 months of treatment, but IH continued to improve in the following months. Patients who started treatment before 6 months of age showed the best results in terms of the VAS score at the end of treatment. Therefore, it appears that early recognition and early treatment of IH assure the best outcome. Ulcerations healed in a few days in all patients. Clinically significant regrowth of IH was observed in 2/42 patients (4.7%) and was treated with a second therapy regimen. The rate of relapse in our study was lower to that reported by others (12%–18%).[27] They also found that children at a risk of relapse were mostly those with segmental IH,[27] this was very close to what we found in our series. The percentage of IH that did not respond to the treatment was 2/42 (4.8%) in our series. This value is lower than the value of treatment failures estimated in the literature about propranolol and steroid use for IH (5.2%–9.6%).[28] Only two patients were subjected to operation for not responding to drug therapy. Sites of location were face and neck, with size of 4 cm × 5 cm and 3.5 cm × 6 cm, and height of the hemangioma was 1.8 cm and 2.3 cm, respectively, from the skin. Age of those two patients during the initiation of therapy was 6 months, 8 days and 7 months, 12 days. Histopathologically, no specific cause was detected. Late start of the treatment is the only common feature in nonresponders in our study.

In our series, we did, however, have six patients with mild side effects (14.28%). This value is lower than the overall value of adverse effects of steroid (19%–42%) and propranolol (16%–31%). Reported incidence for serious adverse effects is (3.4%-6.2%), in our study we did not encounter serious adverse effects.[23],[24]

One had transient reduced blood pressure (a decrease of >15% of mean arterial pressure). In this, we remained at a dosage of 1 mg/kg/day propranolol. Two other children presented a lower heart rate after the first dose of the drug. No additional clinical symptoms were noticed and the dose was increased to 1.5 mg/kg/day. One patient presented with lethargy and refusal to feed and excessive regurgitation of feeds 1 week following initiation of treatment. In two patients (3.2%), because of gastroenteritis and poor feeding, a short interruption of the therapy was needed as a precaution in order to decrease the risk of hypoglycemia. One patient presented with rash involving the face and trunk, sleep disturbance, and irritability, requiring a slight reduction of the propranolol dosage. All these cases responded to transient withdrawal of drug. One suffered from a hypoglycemia-induced seizure during an episode of gastroenteritis. In order to reduce the risk of hypoglycemia, therapy should be discontinued during illness, especially in the setting of restricted oral intake. There were no serious side effects related to cardiac events or bronchospasm.

With increasing experience with propranolol, in selected cases when not feasible to admit the patient to start treatment, the lowest dose should be started and increased to the target dosage as outdoor treatment protocol.

We educate the parents to look for the following:

  1. Sweating, shakiness, increased heartbeat, irritability, and hunger
  2. Propranolol should be administered during the day time hours with a feeding shortly after administration. Parents are instructed to ensure that their child is fed regularly and to avoid prolonged fasts
  3. Propranolol should be discontinued during illness, especially in the setting of restricted oral intake.



  Conclusion Top


IHs are the most frequent benign vascular malformations. They are a source of parental discomfort and anxiety and need to be carefully assessed from the treatment point of view. This study supports the use of low-dose prednisolone and propranolol in IHs. Only future prospective trials involving a larger number of patients and a longer follow-up period will reveal whether the combination of low-dose prednisolone and propranolol fulfills its therapeutic promise.

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], [Table 3], [Table 4]



 

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