Treatment of Infantile Hemangiomas With Beta-Blockers
Sonal Shah, MD, Ilona J. Frieden, MD
Skin Therapy Letter. 2013;18(6)
Abstract and Introduction
Abstract and Introduction
Infantile hemangiomas (IH) are the most common tumors occurring in early childhood, with a prevalence of approximately 5–10% of infants. While the natural history of IH is to spontaneously involute, a significant minority of IH require therapy with the aim to prevent disfigurement, functional impairment, or ulceration. In 2008, propranolol, a non-selective beta (β)-blocker, was reported to be highly effective in treating IH. Since that time there have been more than 200 articles published regarding the efficacy and potential toxicity of β-blockers, both systemic and topical, for the treatment of IH. Based on these finding, β-blockers appear to be highly effective in treating IH and are well tolerated, though side effects have been reported. When therapy is appropriately monitored, β-blockers have been proven to be a safer and superior alternative to systemic steroids.
Infantile hemangiomas (IH) are the most common tumor occurring in early childhood, with a prevalence of approximately 5–10% of infants. The vast majority of IH undergo rapid proliferation during infancy, particularly in the first weeks to months of life, followed by a slow involution period that lasts several years.[2–4] Because involution occurs spontaneously, most IH do not require treatment. Clinical characteristics including size, location, and subtype (e.g., segmental or very prominent dermal component) can predispose infants to complications including permanent disfigurement, ulceration, and functional impairment, leading to significant morbidity.[5–7] Treatment is indicated to reduce morbidity and prevent or minimize complications.
Until recently, corticosteroids in various forms, including topical, intralesional, or most commonly systemic, were the mainstay in IH treatment; however, response to therapy was varied. In addition, adverse effects with systemic steroids, such as development of Cushingoid features, gastroesophageal reflux, hypertension, growth retardation, and increased susceptibility to infection were major considerations when deciding whether or not to initiate therapy.[5,6,8,9]
In 2008, Labreze et al. reported on the serendipitous observation that propranolol, a non-selective beta (β)-blocker, was efficacious in treating 11 patients with IH. Since that time, there have been more than 200 published articles regarding the use of β-blockers in IH – both systemic and topical, which has revolutionized the therapeutic approach to this common condition.
Pathogenesis of Infantile Hemangiomas
IH are neoplasms of benign endothelial cells. For decades it was assumed that these vascular tumors were manifestations of angiogenesis, i.e., the sprouting of new blood vessels from pre-existing ones. However, recent emerging evidence indicates that they may develop via vasculogenesis, the de novo formation of blood vessels from progenitor cells.[11,12] Local or systemic hypoxemia may be a common denominator in hemangioma growth. Both placental and perinatal abnormalities may be potentiating factors that induce increased blood vessel formation and, thus, contribute to the development of IH.[12–14]
In recent years, several review articles have summarized many of the advances in understanding the pathogenesis of IH.[11,15–17] Vascular endothelial growth factor (VEGF) regulation appears to play a central role in the proliferation of hemangiomas. Another remarkable insight is the recognition that endothelial cell precursor cells of IH represent a fetal, rather than postnatal phenotype, with the capability of transforming to adipocytes. Although much more work is needed, uncovering the pathogenesis of IH has occurred at a far greater pace in the past decade and a half than in prior history.
Mechanism of Action of β-blockers on Infantile Hemangiomas
The exact mechanism of action of β-blockers for the treatment of IH is not yet completely understood, however, it is postulated to inhibit growth by at least four distinct mechanisms: vasoconstriction, inhibition of angiogenesis or vasculogenesis, induction of apoptosis, and recruitment of endothelial progenitor cells (EPCs) to the site of the hemangioma.[18–21] Of note, β-adrenergic receptors are expressed on endothelial cells of IH, which are found in abundance in the proliferative phase of IH.
Vascular tone results from a complex interplay of a variety of chemokines in the body and their interaction with receptors located on endothelial cell surfaces. Several studies have demonstrated that activation of β-adrenergic receptors promotes vasodilation.[19,22] The use of β-blockers to mitigate the interaction of adrenaline mediated activation of β2-receptors results in vasoconstriction, which leads to reduced blood flow within the hemangioma. Clinically, propranolol can induce a noticeable change in color, as well as softening of the IH, often within the first few days or even hours after initiating therapy.
Activation of β-adrenergic receptors leads to increased release of VEGF, which appears to promote both angiogenesis and vasculogenesis in IH. Inhibition of these receptors by β-blockers results in reduced VEGF production, thereby limiting proliferation of vasculature and possibly arresting growth.
β-adrenergic receptors are thought to play a role in apoptosis. Blockade of β-receptors have been shown to induce apoptosis in cultured endothelial cells, which is hypothesized to contribute to the effectiveness of propranolol in the treatment of IH. In addition, newer literature also reports that beta blockage can also promote involution of IH through regulation of the renin-angiotensin pathway. As well, β-blockers may decrease migration of EPCs, such that they are prevented from migrating to areas predisposed to hemangioma formation.
Mechanism of Action of β-blockers on Infantile Hemangiomas
Although β-blockers are not (yet) US FDA-approved for the treatment of IH, there are more than 200 articles reporting their use in over 1200 patients. Many are single case reports or small series with diversified clinical settings, dosages, duration, and assessment of outcomes. To date, one randomized control trial has been published involving 40 infants with IH who received either propranolol 2 mg/kg/day divided three times daily or placebo. In the propranolol group, infants younger than 6 months and children up to 5 years of age showed reduced volume, elevation, and improved coloration in localized and segmental IH, with excellent tolerability. Two comparative effectiveness studies comparing propranolol and corticosteroids have also been published. The first study, a retrospective chart review, looked at 110 patients treated with either propranolol or corticosteroids. Propranolol was shown to be more clinically effective than oral steroids, with better tolerance and less adverse effects, and also resulted in fewer surgical interventions. In the second study, 12 IH patients treated with propranolol were retrospectively matched to those treated with prednisone based on type, location, and size of IH, as well as age at initiation of treatment. Propranolol was demonstrated to be superior when compared to prednisone at 1, 2, and months of treatment based on evaluation of serial photographs, with all patients in the propranolol group exhibiting good to excellent response.
The majority of these articles were included in two systematic reviews published in late 2012. Although slightly different methodologies were used, similar conclusions were derived, therefore supporting the significant efficacy of β-blockers in the treatment of IH. The first review assessed findings from studies of IH using corticosteroids compared with propranolol. This metaanalysis found a pooled response rate in the corticosteroid studies of 69% versus 97% for propranolol (p<0.001). The second review included all case series with a minimum of 10 patients treated with propranolol. Forty-one studies were included with a total of 1264 patients analyzed. This investigation provided more details about the methods by which propranolol in currently used. Propranolol was started at a mean age of 6.6 months, at an average dose of 2.1 mg/kg/day, with a mean duration of treatment of 6.4 months. The calculated pooled response rate of 98% in this systematic review was essentially identical to the previous analysis.
A relatively large retrospective study (42 patients) reported on the effectiveness of propranolol in IH patients who were beyond the proliferative growth phase (e.g., patients who were >12 months of age or had documented cessation of tumor growth). Propranolol at a mean dose of 2.1 mg/kg/day was found to be effective in reducing the clinical appearance of IH in children even up to the age of 10 years – a statistically significant finding that also serves to highlight the success of delayed propranolol initiation in promoting involution. The use of propranolol did not lead to any adverse effects that necessitated discontinuation of therapy.
Hemangiomas in Special Anatomic Sites
Particular areas of IH involvement that may lead to functional impairment include the periocular region, airway, and liver. A systematic review focusing specifically on the use of propranolol for periocular involvement noted effectiveness in 96 of 97 patients. A meta-analysis looking at propranolol for airway hemangiomas identified 13 studies comprising 36 patients that showed propranolol to be effective in promoting resolution of airway hemangiomas; additionally, superior efficacy was demonstrated over steroids. Several case series have reported on the benefits of propranolol for the treatment of hemangiomatosis, particularly with liver involvement. One study noted improvement in 8 infants with diffuse hemangiomatosis and liver involvement. In instances where heart failure associated with hypothyroidism was also a consequence, complete resolution was noted.
Ulceration, which is the most common complication of IH, can cause significant morbidity due to the development of severe pain, bleeding, scarring, and risk of infection. A recent study looked at 33 children with ulcerated IH (76% received previous therapy with no improvement), who were treated with propranolol at doses ranging from 2–3 mg/kg/day. Complete healing was noted at a mean of 5.7 weeks and average time to achieving pain control was 14.5 days. However, 4 infants experienced recurrence of ulceration following cessation of therapy.
Upon discontinuation of propranolol, several reports have noted rebound growth or recurrence of IH. The systematic review by Marqueling et al. observed a rate of 17% for rebound growth. A recent study reported rebound growth in 5 of 26 patients (19%) after discontinuation of propranolol. Time from withdrawal of medication to recurrence ranged from 0–6 months, with recurrence appearing in the deep component in the majority of IH. Rebound growth has been attributed to early treatment withdrawal or a prolonged proliferative phase of IH. Predictive factors that may predispose infants to rebound growth have yet to be identified, however, studies are currently underway to better characterize these contributing factors, which may aid in determining which infants are at increased risk for recurrence.
Propranolol has long been used in the pediatric population for a variety of different conditions including in neonates and infants for supraventricular tachycardia, neonatal hyperthyroidism, and arrhythmias. Doses used have range from as low as 1 mg/kg/day to doses as high as 8 mg/kg/day. This experience combined with that for treating IH have demonstrated a good safety profile and the majority of patients tolerated the doses used to treat IH (1–3 mg/kg/day) with minimal adverse events (AEs). In a recent systematic review, there were 371 total AEs reported in 1189 patients. Though this review did not allow for precise percentages, as some studies failed to report them, it was possible to determine the frequency of AEs among the studies that did so. The most common AEs included sleep disturbance (136 patients), acrocyanosis (61 patients), hypotension (39 patients, although only 5 were deemed "symptomatic"), bradycardia (8 patients, 1 of which was symptomatic), and respiratory events including infections, wheezing, and stridor (35 patients). The most concerning side effect of propranolol is symptomatic hypoglycemia, which was noted in 4 patients, one of whom developed hypoglycemic seizures. Blockade of β-receptors can lead to hypoglycemia due to decreased glycogenolysis, gluconeogenesis, and lipolysis. Although a rare but potentially serious side effect, patients on propranolol may be at risk for hypoglycemia during prolonged periods of fasting or poor oral intake (e.g., during an acute illness), which can occur at any point during therapy. Frequent feedings, as well as administration of the medication following feeds, and avoidance of long periods of sleep can help to minimize this risk.
Initiation of Propranolol
Consensus guidelines for initiation and monitoring of propranolol have recently been published. For infants younger than 2 months of age, brief inpatient hospitalization for monitoring during induction of treatment is generally recommended. For infants over 2 months of age, propranolol can be initiated in an outpatient setting unless there are medical co-morbidities or inadequate social support. After a careful history and physical examination to exclude any reactive airway or cardiac disease, baseline heart rate and blood pressure are obtained. Initial dosing of propranolol starts at 0.5 mg/kg/day divided three times daily, increasing slowly to a maximum of 2 mg/kg/day. Heart rate and blood pressure are monitored before and throughout the course of dose escalation, as well as at 1 and 2 hours following the initial dose. Parents should be informed of the risks of hypoglycemia and advised to feed infants every 4–6 hours.
Other β-blockers for the treatment of IH are under investigation, including atenolol, acebutolol and nadolol.[35–37] Head-to-head trials comparing the efficacy of these particular agents to propranolol are yet to be performed.
For superficial or small IH, in which systemic therapy may not be indicated, topical β-blockers, specifically timolol gel forming solution (GFS), have proven to be a useful alternative. In a recent multicenter retrospective study looking at the efficacy of timolol 0.5%-0.1% GFS applied twice daily for superficial IH, 72 of 73 patients exhibited some improvement, the mean duration of therapy was 3.4 months and treatment was well tolerated. However, some caution must be exercised with the use of topical timolol due to its increased potency of between 4 and 10 times greater than propranolol, as well, topical absorption would bypass first-pass metabolism in the liver. To date, a small amount of topical timolol (e.g., 1 drop applied twice a day to intact skin overlying a hemangioma) appears to be safe, but the exact level of systemic absorption is not yet known. Thus, a conservative and cautious approach should be practiced in administering topical timolol while awaiting further information about potential side effects.
Propranolol and other β-blockers have revolutionized the treatment of IH and led to new insights in the pathophysiology and management of this disease. While propranolol is undeniably effective, more studies are needed to elucidate its mechanism of action and confirm optimal dosing, duration of therapy, and safey, as well as determine risks for rebound growth.
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