INTRODUCTION — Infantile hemangiomas (IHs) are benign tumors of vascular endothelium [1-3]. They are the most common vascular tumors of childhood. They are characterized by a growth phase and involution phase. Despite their benign and self-limited nature, some IHs can cause complications such as ulceration or life-altering disfigurement. In addition, they may compromise vital organ function or herald a number of underlying developmental anomalies including, but not limited to, the central nervous system, cardiovascular system, or spine. Infants with cutaneous hemangiomas, most often in the setting of multiple hemangiomas or a solitary, segmental hemangioma, occasionally have additional hemangiomas of the liver, brain, respiratory tract, or gastrointestinal tract. Rarely, visceral hemangiomas can be symptomatic and associated with life-threatening complications.
The management of IHs will be discussed below. The epidemiology, pathogenesis, clinical features, complications, and evaluation are discussed separately. Other vascular tumors of childhood are also discussed separately.
●(See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)
●(See "Infantile hemangiomas: Evaluation and diagnosis".)
●(See "Tufted angioma, kaposiform hemangioendothelioma (KHE), and the Kasabach-Merritt phenomenon".)
GENERAL APPROACH — The approach to treatment of IH should be individualized, based upon the size of the lesion(s), morphology, location, presence or possibility of complications, potential for scarring or disfigurement, the age of the patient, and the rate of growth or involution at the time of evaluation [4,5]. The potential risk(s) of treatment must be carefully weighed against the potential benefits.
Consultation with and/or referral to a pediatric dermatologist, vascular anomalies team, or other knowledgeable specialist is warranted for children with hemangiomas with actual or potential risk for complications and/or when therapy is being considered [6]. Such infants should be referred as soon as possible during the early hemangioma proliferation phase, ideally by one month of age [7]. (See 'Risk stratification and indications for referral/intervention' below.)
The management of IH involves clinical examination(s) and education of the family. Depending on the clinical situation and the parents' or caregivers' level of concern, the patient may need to be re-evaluated frequently during the proliferative phase and again before school entry. Serial photographs of the hemangioma can help to monitor the clinical course.
Education of the family should include information about the natural course; potential complications; treatment indications and timing; and risks, benefits, and expectations of available treatment options for IH. The family should be provided with realistic expectations about the duration of involution and the possibility of permanent, residual changes. In some studies, complete involution has been noted at a median age of four years [8,9]. However, this timeline is highly variable and dependent on hemangioma size, morphology, and location. It must also be emphasized that, in many cases, involution does not result in normal-appearing skin. More than one-half of children with untreated hemangiomas experience permanent, residual changes such as scarring, atrophy, redundant skin, discoloration, and telangiectasias [10].
Finally, the family should be provided with anticipatory guidance regarding ways to respond to comments and queries from family members and strangers and how to teach their children to respond when closer to school age, if necessary. Parents or caregivers are commonly subject to inappropriate comments from strangers, including accusations of child abuse [11]. Often children, who are usually just curious about the hemangioma, are satisfied to know simply that, "It is a birthmark, it doesn't hurt, and it will get better" [11]. Addressing the psychosocial aspects of care and providing families with emotional support and reassurance is essential for the successful management of hemangiomas [4,11-13].
When treatment is indicated, the choice of treatment modality depends on the above factors, as well as the availability of certain modalities and the experience of the treating clinician.
RISK STRATIFICATION AND INDICATIONS FOR REFERRAL/INTERVENTION — Clinicians should classify an IH as high risk if there is evidence of or potential for the following [7]:
●Life-threatening complications (eg, hemangiomas that compromise vital organ function of the airway, liver, or gastrointestinal tract)
●Functional impairment (eg, periorbital hemangiomas that compromise vision) or ulceration
●Associated structural anomalies (eg, PHACE [posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies] syndrome or LUMBAR [lower-body hemangioma and other cutaneous defects; urogenital anomalies, ulceration; myelopathy; bony deformities; anorectal malformations, arterial anomalies; and renal anomalies] syndrome) (see "PHACE syndrome" and "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Lumbosacral lesions')
●Risk of permanent disfigurement, especially when a hemangioma is located in a cosmetically sensitive area
●Very large (≥5 cm), rapidly growing cutaneous hemangiomas
Examples of high-risk lesions that may require early intervention include [1,7,14]:
●Large, plaque-like (segmental) or combined, superficial, and deep hemangiomas, especially in trauma-prone locations, which are prone to ulceration and resultant scarring.
●Any lesion of the face, especially when of significant size or segmental; hemangiomas of the lip crossing the vermillion (picture 1), nose ("Cyrano nose"), and auricle are particularly prone to disfigurement.
●Large, nodular, superficial hemangiomas, especially those that exhibit a sharp, "cliff-like" border (picture 2) or pedunculated lesions (hemangiomas extending from a smaller base), have the greatest risk of leaving permanent fibrofatty tissue that may require surgical revision.
THE INFANTILE HEMANGIOMA REFERRAL SCORE — The Infantile Hemangioma Referral Score (IHReS) tool has been developed to help primary care physicians identify problematic hemangiomas that should be referred to expert centers [15].
GOALS OF TREATMENT — The goals of hemangioma treatment include [4]:
●Prevention or reversal of life-threatening or function-threatening complications
●Prevention or minimization of disfigurement from residual skin changes
●Minimization of psychosocial distress for the patient and family
●Adequate treatment of ulceration to minimize scarring, bleeding, infection, and pain
Importantly, topical and systemic medical therapies for hemangiomas are most effective when initiated as early in the hemangioma growth phase as possible, ideally within the first two to three months after birth.
LOW-RISK AND UNCOMPLICATED HEMANGIOMAS
Active nonintervention — Active nonintervention (serial observation) is a reasonable approach for many uncomplicated hemangiomas, especially in noncosmetically sensitive locations, because all true IHs involute spontaneously over time. However, the decision not to pursue medical and surgical therapy is not necessarily a passive intervention, since the growth and involution of the hemangioma may need to be monitored and the psychosocial implications, particularly of facial hemangiomas, may need to be anticipated and addressed [11]. Serial photographs of the lesion may be helpful to monitor the involution process and outcome.
Local therapies — Local pharmacotherapy is primarily used in the treatment of small and superficial IHs and is not indicated for the treatment of larger, complicated lesions. Data on the efficacy of topical therapies, including topical beta blockers and corticosteroids, are limited.
Topical beta blockers
Overview of indications — Topical beta blockers (topical propranolol, topical timolol, topical carteolol) may be used for the treatment of thin (<2 mm in thickness), superficial hemangiomas (eg, hemangiomas of minor cosmetic concern located on the face) as an alternative to observation, particularly if parents or caregivers desire treatment. Topical beta blockers may also have a role in the treatment of ulceration (when minor) and in minimizing rebound growth in children who are being tapered off oral propranolol [16-18]. (See 'Rebound growth' below and 'Ulcerated hemangiomas' below.)
If a decision is made to use topical beta blockers, we use topical (ophthalmic) timolol maleate gel forming solution 0.5%. A thin layer (typically one to two drops dependent on surface area) is applied to the hemangioma surface two to three times per day until the patient is 12 months of age or stable improvement is achieved.
Efficacy — Limited evidence suggests that topical beta blockers may have some efficacy in the treatment of superficial hemangiomas. A meta-analysis of observational studies and two large, cohort studies suggested that topical propranolol 1% (not available in the United States), topical timolol 0.5%, and topical carteolol were effective for the treatment of superficial IH, with response rates of approximately 70 to 80 percent [19-21]. However, in a randomized trial, timolol maleate was not more effective than placebo for the treatment of IH in the early proliferative phase [22]. In this study, 69 infants (mean age 48 days) with focal or segmental hemangiomas received either two drops of timolol maleate solution 0.5% administered topically every 12 hours for 24 weeks or two drops of a saline-based placebo [22]. At 24 weeks, 11 patients (42 percent) treated with timolol achieved the primary outcome of complete or nearly complete resolution of hemangiomas compared with 11 patients (36 percent) in the placebo group, but this difference was not statistically significant. In the intention-to-treat analysis, the odds ratio of complete or almost complete response versus no response was 1.36 (95% CI 0.41-3.13). Treatment was generally well tolerated. Three patients in the timolol group had hypotension one hour post-treatment and one patient had bradycardia, but all were asymptomatic during episodes.
Safety — Topical timolol is generally well tolerated. In a large, multicenter, retrospective study that included 731 children with hemangiomas predominantly superficial and located in the head/neck area treated with topical timolol 0.5% one drop twice daily for an average of 9.5 months, adverse effects occurred in 25 patients (3.4 percent) and included local irritation (n = 12), ulceration (n = 4), and bronchospasm (n = 3) [20]. None of the children experienced cardiovascular adverse effects or required drug discontinuation.
Topical and intralesional corticosteroids — High-potency topical corticosteroids (eg, clobetasol propionate ointment) have been used in the past for thin, superficial hemangiomas and/or minor ulceration [23]. They are now infrequently used since the introduction of topical timolol. In the author's experience, topical corticosteroids may be helpful for the treatment of minor and/or recurrent ulceration. Adverse effects of long-term use of topical corticosteroids include skin atrophy, hypopigmentation, and hypertrichosis.
The use of intralesional corticosteroids, such as triamcinolone acetonide 10 to 40 mg/mL, is limited to well-localized hemangiomas [24]. Individual doses should not exceed 3 mg/kg [25]. For eyelid hemangiomas, intralesional corticosteroids should only be administered by an ophthalmologist or other experienced specialist.
A response is usually noted within two weeks, with continued response over the ensuing six to eight weeks [26]. Serial injections administered at four- to eight-week intervals are sometimes needed. Rebound growth has been reported following injections [25].
Adverse effects of intralesional corticosteroids most commonly include local skin atrophy from inadvertent leaks to normal surrounding skin. Adrenal suppression from systemic absorption is also a possibility, even with localized use [27-29].
HIGH-RISK AND COMPLICATED HEMANGIOMAS — High-risk/complicated hemangiomas include large hemangiomas at increased risk of scarring or disfigurement (eg, large, segmental, and/or facial hemangiomas), life-threatening hemangiomas (eg, airway hemangiomas), hemangiomas carrying functional risks (eg, periocular hemangiomas), and hemangioma ulceration that does not respond to standard wound care (see 'Risk stratification and indications for referral/intervention' above). In such cases, systemic therapy is typically required.
When to start treatment — We agree with the recommendation of the American Academy of Pediatrics' Clinical Practice Guideline for the Management of Infantile Hemangiomas that infants with high-risk hemangiomas should start treatment or be referred to a specialist at an early age, ideally by four weeks of age [7]. The rationale for early intervention (eg, before the completion of the hemangioma's rapid growth phase) is based on the observation that the most rapid growth of superficial hemangiomas typically occurs between 5.5 and 7.5 weeks of age and that hemangioma precursors are present at birth in nearly two-thirds of the patients [30].
Treatment started as soon as feasible and before the completion of the proliferative phase, which in most cases occurs by five months of age, may help prevent poor outcomes. Although oral propranolol may show some benefit for hemangiomas that have passed the proliferative phase, the effects are generally significantly smaller. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications" and "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Natural history'.)
First-line therapy
Propranolol — Propranolol, a nonselective beta blocker, is the first-line agent for hemangiomas with the potential to impair function or cause permanent disfigurement, if there are no cardiac, neurovascular, or other contraindications (algorithm 1) [1,31]. In 2014, propranolol hydrochloride oral solution was approved by the US Food and Drug Administration for the treatment of proliferating IH requiring systemic therapy [32].
Propranolol inhibits the growth and induces the regression of IHs [33]. Potential mechanisms of action for propranolol may include vasoconstriction, decreased expression of vascular endothelial growth factor and basic fibroblast growth factor, and/or triggering of apoptosis [34,35].
Efficacy — In 2008, the serendipitous observation that the use of propranolol to treat heart failure in two young children with IHs was associated with a change in color, softening, and decrease in size of the hemangiomas led to the initiation of larger observational studies and randomized trials. All studies demonstrated improvement with propranolol [33,36-42]:
●In a large, randomized trial, 456 infants aged five weeks to five months with a proliferating hemangioma of at least 1.5 cm received placebo or propranolol (1 mg/kg per day or 3 mg/kg per day) for three or six months [42]. Children with high-risk hemangiomas were not included for ethical reasons. The primary outcome was complete or nearly complete resolution of the hemangioma at week 24, assessed by centralized, blinded evaluation of digital photographs. Complete or nearly complete resolution of the target hemangioma was observed in 60 percent of patients treated with propranolol 3 mg/kg per day for six months and in 4 percent of patients treated with placebo. Ten percent of patients in whom treatment was successful required systemic retreatment during follow-up. Mild adverse effects, including diarrhea, sleep disorders, bronchial hyperreactivity, cold extremities, upper respiratory tract infection, and fever, occurred in over 90 percent of patients receiving propranolol and in 76 percent of patients receiving placebo. Serious adverse events suspected to be related to propranolol were rare (occurred in single patients only) and included second-degree atrioventricular block, bronchiolitis, hemangioma worsening/ulceration, and bradycardia.
●A 2016 network meta-analysis of 18 randomized trials and cohort studies including 1265 children aged two weeks to nine years evaluated the relative expected rates of clearance associated with beta blockers and corticosteroids [43]. Oral propranolol in doses ranging from 1 to 4 mg/kg per day had the largest mean estimate of expected clearance (95 percent, 95% Bayesian credible interval [BCI] 88-99) relative to oral corticosteroids (43 percent, 95% BCI 21-66) and placebo or observation (6 percent, 95% BCI 1-11).
●A 2018 systematic review concluded that, compared with placebo, oral propranolol is effective in inducing complete or almost complete hemangioma clearance without a significant increase in the risk of adverse events [44].
Oral propranolol has also been used to treat IHs beyond the proliferative phase [45,46]. In a multicentric, retrospective study, 42 children aged 7 months to 10 years with documented cessation of hemangioma growth were treated with propranolol 1.5 to 3 mg/kg per day for one to eight months [45]. In all children, the rate of involution increased with propranolol compared with the rate of involution during active nonintervention before treatment.
Pretreatment evaluation — Treatment with propranolol should be undertaken in consultation with a pediatric dermatologist or other specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children (algorithm 1). The pretreatment evaluation (typically outpatient) should include:
●History – History, with focus on cardiovascular and respiratory abnormalities (eg, poor feeding, dyspnea, tachypnea, diaphoresis, wheezing, heart murmur) and family history of heart block or arrhythmia.
●Physical examination – Physical examination including cardiac and pulmonary assessment and measurement of heart rate and blood pressure. It should be noted that heart rate is generally more reliable than blood pressure, since obtaining accurate blood pressure readings in infants can be challenging. (See "The pediatric physical examination: General principles and standard measurements", section on 'Vital signs'.)
●Electrocardiogram – Electrocardiogram is indicated in children with:
•Heart rate lower than normal for age (table 1)
•History of arrhythmia or arrhythmia detected during examination
•Family history of congenital heart disease or maternal history of connective tissue disease
●Imaging studies – In children with large, segmental head or neck hemangiomas who are at risk of having PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies) syndrome, imaging studies, including cardiac ultrasound or cardiac magnetic resonance imaging (MRI), should be obtained to rule out severe, cardiovascular anomalies that would be a contraindication to propranolol use. In these patients, baseline head/neck MRI with angiography is also preferred prior to propranolol initiation.
While there is no evidence that propranolol increases risk of stroke in infants with PHACE syndrome and cerebrovascular anomalies, consultation with an experienced neurologist or neurovascular specialist is advised in patients with PHACE syndrome categorized as high risk for stroke based on neuroimaging findings [47]. In some higher-risk cases, it has been suggested that propranolol may still be considered, albeit modified with lower initial dosing and slower upward titration. (See "PHACE syndrome", section on 'Propranolol'.)
Contraindications — Propranolol treatment is contraindicated in infants and children with:
●Cardiogenic shock
●Documented chronic and significant sinus bradycardia
●Documented chronic and significant hypotension
●Greater than first-degree heart block
●Heart failure
●History of bronchospasm or wheezing
●Hypersensitivity to propranolol
●Preterm infants with corrected age <5 weeks (postnatal age in weeks minus number of weeks preterm)
Initiation of treatment and dosing — In most cases, even in otherwise healthy babies as young as four weeks of age and in preterm infants four weeks of corrected gestational age, treatment can be initiated and managed in an outpatient clinical setting by a clinician with experience in the diagnosis and management of IHs (algorithm 1) [48].
However, in accord with an expert consensus panel, we suggest that hospitalization for the initiation of oral propranolol be considered in the following circumstances [31]:
●Infants <4 weeks of age
●Infants of any age with inadequate social support
●Infants of any age with comorbid conditions affecting the cardiovascular or respiratory system, including symptomatic airway hemangiomas
●Infants of any age with conditions affecting blood glucose maintenance
We generally start treatment with oral propranolol at 1 mg/kg per day in two divided doses, increasing to 2 mg/kg per day given in two divided doses after one week, and then up to 3 mg/kg per day divided twice daily, dependent on hemangioma severity and response. To reduce the risk of hypoglycemia, propranolol is administered immediately after feeding. Administering propranolol after feeds is safer than before feeds, in case the feed is inadequate, and is therefore recommended.
In case of intercurrent illness associated with poor feeding, treatment should be temporarily held and then resumed at the last prescribed dose. If children present with severe respiratory symptoms, including wheezing, propranolol should also be temporarily held and then resumed at a lower dose and titrated up more gradually with close monitoring. (See 'Adverse effects' below.)
Monitoring
●In clinic – Since the effect of oral propranolol peaks at one to three hours after administration, an expert consensus panel has recommended that patients be monitored with measurement of heart rate and blood pressure at one and two hours after the initial dose and after every dose increase of 0.5 mg/kg/day [31]. This is in accord with the US Food and Drug Administration and European Medicines Agency recommendations. (See "The pediatric physical examination: General principles and standard measurements", section on 'Heart rate' and "Evaluation and diagnosis of hypertension in infants between one month and one year of age", section on 'Blood pressure measurement'.)
However, in clinical practice, many experts (including the author) and other guidelines do not monitor heart rate and blood pressure in clinic after the first dose and after dose increases (algorithm 1) [49-52].
This approach is supported by data from a large, retrospective study of 783 children who initiated propranolol treatment at a median age of 112 days and had heart rate and blood pressure obtained before treatment, at one and two hours after first dose, and, if available, after dose escalation [53]:
•No symptomatic bradycardia or hypotension requiring immediate intervention or drug discontinuation occurred during monitoring.
•Mean heart rate change from baseline to one hour was -8.19/min and from baseline to two hours was -9.24/min, but none of the children had a heart rate below the normal range for age.
•At initiation and escalation, a decrease in systolic blood pressure below the normal values was noted in 16 of 3141 measurements (0.51 percent).
•Between initiation and escalation visits, a decrease in diastolic blood pressure below normal values was noted in 118 of 2382 measurements (4.95 percent).
Later in the course of therapy, three infants experienced a serious adverse event: two episodes of symptomatic hypoglycemia and one respiratory event (pneumonia) [53].
●At home – Parents or caregivers should be educated about recognizing the signs of serious adverse effects, which include hypotension, bradycardia, wheezing, and hypoglycemia [54]. Early clinical signs of hypoglycemia include:
•Sweating
•Jitteriness
•Irritability
•Cyanosis
•Poor feeding
•Hypothermia
•Lethargy
Importantly, all these clinical signs may be masked by beta blockers except for sweating. Thus, sweating may be the most reliable, early sign of hypoglycemia to watch for.
Routine screening of serum glucose is not indicated because the timing of hypoglycemic events is variable, unpredictable, and almost invariably associated with continued intake of propranolol during a fasting state. In addition, asymptomatic hypoglycemia was not detected in studies that included a random serum glucose as part of routine monitoring [31]. (See "Approach to hypoglycemia in infants and children", section on 'Clinical features'.)
Assessment of response and treatment duration — Children with IHs treated with propranolol should be followed at regular intervals for response assessment and dose adjustment for weight gain. Although a significant response (reduction in size) is often seen after three to four months of propranolol treatment, many experts continue therapy beyond the proliferative phase. Thus, treatment is generally continued until 6 to 18 months of age but varies depending on the hemangioma size, location, complications, and response and when (at what age) treatment was initiated.
An open-label, phase 3, multicenter study evaluated the rate of hemangioma resolution in children with high-risk hemangiomas treated with oral propranolol up to the age of 12 months [55]. In this study, 43 children aged 35 to 150 days with hemangiomas that were life threatening (with periorbital, nasal, labial, laryngotracheal, or limb joint location), disfiguring, or ulcerated and nonresponsive to wound care received oral propranolol 3 mg/kg per day in two divided doses for at least six months or up to the age of 12 months if complete success (defined as hemangioma disappearance or persistence of only a minimal degree of telangiectasias, erythema, skin thickening, soft tissue swelling, and absence of functional impact) was not achieved. Complete success was achieved by 34 patients (76 percent, 95% CI 61.7-86.3 percent) treated for a minimum of six months and up to a maximum of 12 months of age. After the first six months of treatment, success was achieved by only 21 patients (47 percent, 95% CI 32.7-61.1 percent).
A lack of response to treatment with propranolol is rare. In a French, retrospective, multicenter study including 1130 children treated with propranolol, 10 children (0.9 percent) had propranolol-resistant hemangiomas [56]. Resistance was defined as continued growth during the proliferative phase or no involution during the postproliferative phase after >4 weeks of oral propranolol at greater than 2 mg/kg per day. Five of the 10 children who did not respond to propranolol had hemangiomas in the postproliferative phase and were older than eight months at the start of treatment. Three children with hemangiomas in the proliferative phase showed a rapid response to adjuvant systemic corticosteroids.
Rebound growth — Rebound growth after propranolol discontinuation has been noted in approximately 14 to 25 percent of children [57-59]. The factors associated with the risk of relapse are not completely understood. Of note, rebound growth has been noted in one patient after administration of the beta-adrenergic receptor agonist salbutamol 10 months after stopping propranolol treatment [60].
Some children with rebound growth may need a second course of propranolol. Topical beta blockers may be used to treat mild relapses. However, mild relapses do not require treatment in most cases, and parents or caregivers can be reassured about the eventual involution of the lesion.
In a single-institution study including 158 children with hemangiomas located predominantly in the head and neck region who were treated with propranolol for 3 to 12 months, relapse occurred in 40 children (25 percent) 0.5 to 5 months after treatment cessation [59]. In one-half, the relapse was mild and did not require retreatment. Factors associated with an increased risk of relapse included segmental distribution and increased depth of the hemangioma.
Adverse effects — Children treated with propranolol should be closely monitored for adverse effects. In a review of 906 French children (median age 114 days) treated with propranolol for complicated hemangiomas, one or more adverse reactions occurred in 81 children (9 percent) [61]. Serious adverse effects (cardiac, respiratory, and hypoglycemia) occurred in 24 patients (2.6 percent).
Serious adverse effects of propranolol therapy for hemangiomas, which include hypoglycemia, hypotension, bradycardia, bronchospasm, and hyperkalemia, are infrequent [42,62,63]. Restless sleep, constipation or diarrhea, and cold extremities or acrocyanosis are more commonly reported [63]:
●Hypoglycemia – Of the potential serious adverse effects, hypoglycemia is the most worrisome. To reduce this risk, propranolol should be administered during the daytime hours shortly after a feeding. Propranolol should be discontinued during periods of illness with poor oral intake [31,54,64]. Patients noted to be at increased risk for propranolol-induced hypoglycemia include children who were previously treated with prolonged courses of systemic glucocorticoids and patients with high-output cardiac failure secondary to a large liver hemangioma [64,65]. Symptomatic hypoglycemia during propranolol use has also been reported in older children and, thus, is not age dependent [64].
●Cardiovascular/respiratory – A study using data from the French national medical administrative database, covering nearly 100 percent of the French population, confirmed an overall good safety profile of oral propranolol for children <3 years without underlying cardiovascular disease ("healthy") [66]. Among 1484 healthy children who received at least two deliveries of oral propranolol, only two children (0.13 percent) had a cardiovascular adverse effect compared with 11 of 133 children (8.3 percent) with an underlying congenital cardiovascular disease (standardized morbidity ratio [SMR] 2.8, 95% CI 0-6.7, and SMR 6.0, 95% CI 2.5-9.6, respectively). A moderately increased risk of respiratory adverse events was observed among healthy children exposed to propranolol (SMR for bronchiolitis 1.6, 95% CI 1.1-2.1).
●Sleep behavior/neurologic – There have been concerns regarding the effects of propranolol on the central nervous system, such as sleep disturbance and agitation. However, studies examining sleep behavior in infants treated with propranolol found a modest or no increase in sleep disturbance compared with infants not taking propranolol [67,68]. Moreover, a study assessing the cognitive and memory functions at age 5 to 7.5 years in children treated with propranolol during infancy did not find any difference in performance on standardized tests compared with the general population in the same age range [69].
Telemedicine recommendations for initiation of oral propranolol — The Hemangioma Investigator Group has published recommendations regarding the appropriate use of telemedicine for the initial evaluation, treatment initiation, dosing, and follow-up evaluation for patients with IHs requiring treatment with oral propranolol [70]:
●Candidates for telemedicine initiation − The Hemangioma Investigator Group suggests that telemedicine initiation of oral propranolol may be considered for infants at standard risk who meet the following criteria [70]:
•Adjusted gestational age >5 weeks.
•Normal birth weight.
•Normal cardiovascular examination within the previous four weeks (including >1 documented heart rate after nursery discharge).
•Normal respiratory examination within the previous four weeks.
•Healthy in the 24 to 48 hours prior to scheduled telemedicine visit (especially no respiratory and gastrointestinal signs and symptoms).
•IH pattern and distribution do not confer risk of PHACE syndrome or LUMBAR (lower-body hemangioma and other cutaneous defects; urogenital anomalies, ulceration; myelopathy; bony deformities; anorectal malformations, arterial anomalies; and renal anomalies) syndrome.
•Lack of ulceration or minimal/superficial ulceration.
•Caregiver is able to understand instructions and demonstrate comprehension (eg, by repeating instructions provided during visit).
•Multiple IHs with normal liver ultrasound and without cutaneous IH conferring higher risk.
●In-person evaluation – The Hemangioma Investigator Group recommends in-person evaluation for infants at high risk:
•Corrected gestational age <5 weeks
•Abnormal cardiovascular examinations or investigations or those who lack documentation of this in the postnatal period
•Medium to high risk of PHACE syndrome (ie, large, segmental, facial or scalp IH in segments S1, S3, S4)
•Medium to high risk of LUMBAR syndrome (ie, segmental, perineal, and/or lumbosacral body IH with or without visible, associated, anatomic abnormalities)
•Significant IH ulceration
•Ongoing poor oral feeding or poor weight gain
•IH with symptoms of airway compromise (eg, stridor) or beard area IH at high risk for airway IH
•Known pulmonary disease, including ongoing respiratory compromise (eg, dyspnea, frequent wheezing or history of bronchospasm)
•Persistent or ongoing hypoglycemia
•Known or suspected congenital heart disease or suggestive symptoms
•Extensive hepatic hemangiomas
•Known brain malformations
•History of congenital heart disease or sudden death in first-degree relative
•Maternal history of connective tissue disorder
●Initiation via telemedicine and dosing – For patients who are candidates for telemedicine initiation, the Hemangioma Investigator Group suggests a starting dose of 0.5 mg/kg per day divided twice daily and increasing every three to four days by 0.5 mg/kg per day to the target dose of 2 to 3 mg/kg per day divided twice daily.
Sequential/concurrent use of propranolol and topical timolol — Sequential or concurrent use of oral propranolol and topical timolol may allow for a shorter duration of oral propranolol therapy, thus reducing the risk of potential adverse effects, facilitating the tapering of oral propranolol, and preventing rebound growth [18,71]. (See 'Topical beta blockers' above.)
In a retrospective study of 559 children treated at a single institution with propranolol only, timolol only, propranolol to timolol, timolol to propranolol to timolol, and timolol to propranolol, those who received propranolol followed by timolol had a median treatment course 2.2 months shorter than those receiving propranolol alone [18]. None of the children in the propranolol to timolol group needed to restart propranolol compared with 13 percent of those treated with propranolol alone.
Other oral beta blockers — A few trials suggest that atenolol (a selective beta-1 blocker) and nadolol (a nonselective beta blocker) may be as effective as propranolol for the treatment of proliferative hemangiomas, potentially with a lower rate of adverse effects such as bronchoreactivity and sleep disturbances [72-76]. However, their use is limited by the lack of a widely available oral formulation suitable for infants:
●In a large, randomized, open-label trial, 377 infants (mean age 10 weeks) with problematic hemangiomas were treated with propranolol 2 mg/kg per day in three divided doses or atenolol 1 mg/kg per day in a single dose for at least six months and then followed up for two years [77]. At six months in the intention-to-treat population, the primary outcome of "any response" was achieved in 93.7 percent of infants in the propranolol group and in 92.5 percent of infants in the atenolol group (difference 1.2 percent, 95% CI -4.1 to 6.6 percent). At 96 weeks, a complete or nearly complete response was noted in 82.1 percent of infants in the propranolol group and in 79.7 percent of infants in the atenolol group (difference 2.4 percent, 95% CI -5.5 to 10.4 percent). Adverse events occurred more frequently in the propranolol group than in the atenolol group (70 versus 44 percent) and included diarrhea, sleep disturbance, cool extremities, and bradycardia. Severe adverse events occurred with similar frequency in the two groups (2.6 percent in the propranolol group and 1.6 percent in the atenolol group).
●A randomized trial compared propranolol and nadolol in escalating doses up to 2 mg/kg/day in 71 infants aged one to six months with problematic IHs [76]. At 24 weeks, the mean size of involution compared with baseline was 97.9 percent in the nadolol group versus 89.1 percent in the propranolol group (difference 8.8 percent, 95% CI 2.7-14.9 percent). The mean color fading was 94.5 percent in the nadolol group versus 80.5 percent in the propranolol group (difference 14 percent, 95% CI 7.2-30 percent). Both medications were well tolerated. Adverse events occurred with similar frequency in the nadolol and propranolol groups (77 and 94 percent, respectively) and included predominantly upper respiratory infections, diarrhea, vomiting, and sleep disturbance.
Second-line therapies
Systemic corticosteroids — Treatment of complicated hemangiomas with systemic corticosteroids has been largely supplanted by treatment with systemic beta blockers. However, systemic corticosteroids remain a treatment option for patients with complicated hemangiomas for whom treatment with beta blockers is contraindicated. (See 'Contraindications' above.)
In select, severe cases, combining beta blockers with a short course of systemic corticosteroids may be considered in order to shorten the response time [78]:
●Dosing – The usual starting dose for prednisolone is 1 to 3 mg/kg per day. A single morning dose is preferred to minimize adrenal suppression. A response (stabilization with or without regression) is usually seen within the first few weeks [79,80].
Treatment is generally continued for several months or more, depending upon the indications for treatment, the response, and the child's age at initiation [13]. Prednisone should be slowly discontinued since abrupt discontinuation or rapid tapering of glucocorticoids while a hemangioma is still in its active growth phase may result in rebound proliferation and to avoid adrenal insufficiency [12].
●Efficacy versus propranolol – In a few studies, systemic corticosteroids have been shown to have an efficacy similar to that of oral propranolol in inducing volume reduction of IHs [81-83].
In a small, noninferiority, randomized trial, 34 children aged 0.3 to 8.2 months with hemangiomas located predominantly on the face were randomly assigned to treatment with propranolol 2 mg/kg/day in three divided doses or prednisolone 2 mg/kg/day in a single dose for 16 weeks [81]. A response to treatment, broadly defined as stop of progression and volume decrease, was achieved by 96 and 92 percent of patients in the propranolol and systemic corticosteroid groups, respectively. Adverse effects were generally mild and occurred with equal frequency in both groups.
●Adverse effects – Adverse effects of systemic corticosteroids are more likely to develop with higher doses and courses of six months or longer and resolve with drug tapering:
•The most common complication is the development of a cushingoid facies, which usually begins within the first one to two months of treatment [84].
•Personality changes (eg, depressed mood, agitation, insomnia, restlessness) develop in approximately one-third of infants, usually during the first two weeks of therapy [84].
•Delayed skeletal growth, which may be more readily apparent since a child grows most rapidly during the first year of life, results from a temporary inhibition of collagen synthesis. However, nearly all children catch up to the normal growth curve once therapy has been discontinued, usually by two years of age [84,85].
•Gastric upset occurs in at least 20 percent of infants and can be relieved with histamine 2 (H2) blockers or proton pump inhibitors, which many clinicians initiate routinely along with glucocorticoids [84].
•Serious corticosteroid complications, such as aseptic necrosis of the femoral head, hypertension, osteoporosis, and cataracts, are extremely rare in children [84].
•Supraphysiologic doses of glucocorticoids may suppress the hypothalamic-pituitary-adrenal axis. "Stress doses" of glucocorticoids may be necessary for infants who require medical or surgical hospitalization while undergoing glucocorticoid therapy for IH [86].
Systemic corticosteroids have immunosuppressive effects and can increase the risk for infections [87-89]. We do not routinely administer Pneumocystis pneumonia (PCP) prophylaxis to children being treated with systemic glucocorticoids for IH. However, PCP prophylaxis may be warranted in infants who have other risk factors for PCP (eg, premature infants with significant, concomitant medical problems). (See "Glucocorticoid effects on the immune system" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV".)
Live-virus vaccines (eg, measles, mumps, rubella [MMR]; varicella; rotavirus) should not be administered while infants are taking supraphysiologic glucocorticoid doses. In addition, because the varicella vaccine is not administered until children are at least one year of age, infants receiving glucocorticoid therapy should avoid exposure to individuals with varicella infection. (See "Standard immunizations for children and adolescents: Overview", section on 'Infants and children'.)
Immunization for diphtheria and tetanus may not be effective in some patients when administered during systemic glucocorticoid therapy [87]. Diphtheria and tetanus titers can be used to confirm protection.
Surgical therapies — When a hemangioma poses primarily cosmetic concerns, therapeutic intervention must be tailored on an individual basis. In addition to systemic, topical, and intralesional medications, therapeutic options include laser therapy and surgery.
Pulsed dye laser — The pulsed dye laser cannot be expected to affect thicker, superficial hemangiomas or those with deep involvement, since the depth of laser penetration is only 1.2 mm. The most accepted use of pulsed dye laser in the management of hemangiomas is the treatment of ulceration and postinvolution erythema and telangiectasias [5]. Small, thin, superficial hemangiomas early in the proliferative phase may also be appropriate candidates for pulsed dye laser [90]. The indications, efficacy, and adverse effects of pulsed dye laser therapy for IHs are discussed in detail elsewhere. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Infantile hemangiomas'.)
Excisional surgery — Surgical excision is generally reserved for involuted lesions with residual scars or loose skin; hemangiomas in cosmetically sensitive areas with inadequate involution by school age; and pedunculated, cutaneous hemangiomas (because of the likelihood of residual loose skin) [8,79,91]. Excisional surgery may also be considered for severely ulcerated hemangiomas that prove refractory to medical therapy. In cases without complication, but for which there is uncertainty about the outcome, the benefits and risks of surgical intervention must be carefully considered since the results of spontaneous involution are often better than a surgical scar [80,92].
Embolization — Rarely, large, visceral (especially hepatic) hemangiomas or those complicated by severe bleeding have been treated with arterial embolization after failure of medical therapy [91].
SPECIAL SITUATIONS
Periocular hemangiomas — Periocular hemangiomas (and especially those that are larger than 1 cm, involve the upper medial eyelid, and have a deep component) can compromise vision and cause amblyopia, astigmatism, or strabismus [93]. These hemangiomas should be evaluated and monitored by an ophthalmologist experienced with hemangiomas and their treatment [26]:
●Superficial, periocular hemangiomas have been successfully treated with topical beta blockers [94,95]. Surgical excision may also be an option for small, localized lesions [96-99].
●Vision-threatening cases are generally treated systemically with propranolol or, less commonly, with intralesional corticosteroids [24,37,100-103]. Intralesional corticosteroids should be managed by a specialist, most often an ophthalmologist with knowledge and experience in this area. Rare but serious side effects, including eyelid necrosis, central retinal artery occlusion, and adrenal suppression, have been reported [104-108].
Ulcerated hemangiomas
Wound care and topical agents — Gentle and meticulous local wound care is the mainstay of ulcer therapy and is particularly important for lesions in locations subject to trauma and infection, such as the perineum (picture 3). Local wound care reduces pain and helps to prevent secondary infection [109]. Commonly used therapies include topical antibiotics, barrier creams, and nonstick dressings [110]:
●Wound care − Very gentle debridement of crusted wounds with saline soaks two to three times daily may also be helpful, since crusting prevents re-epithelization and favors infection. For ulcerated hemangiomas in the diaper area, gentle cleansing with diaper changes is recommended. When possible, wipes should be avoided and the area cleansed in the bath or by using a spritz bottle with soapy water and gently patted dry, followed by a thick layer of barrier ointment, which can be explained to parents/caregivers as similar to "frosting on a cake."
●Topical therapies − There are a few reports of successful use of topical timolol for the treatment of ulcerated hemangiomas [17,111-113]. In one retrospective analysis of 30 children with hemangiomas with focal to 3 cm ulcerations predominantly located in intertriginous areas, treatment with one drop twice daily of timolol 0.5% gel led to ulcer resolution in 21 patients after an average of 93 days [17]. (See 'Topical beta blockers' above.)
Topical metronidazole gel or gentamicin ointment, often used in combination with topical mupirocin, have proved to be safe and efficacious for ulceration, particularly in intertriginous or moist areas, such as the perineum [109].
Oral propranolol — We suggest oral propranolol in addition to meticulous wound care and appropriate analgesia for the treatment of ulcerated hemangiomas that may cause permanent disfigurement, interfere with daily life activities (eg, diaper changes, bathing, feeding, sleeping), and/or are unresponsive to wound care and pain and infection control. (See 'Propranolol' above.)
A beneficial effect of propranolol at standard doses for ulcerated hemangiomas has been reported in several case series [114-118]. However, it has been suggested that lower doses of oral propranolol (ie, less than or equal to 1 mg/kg/day) may be associated with shorter healing times [119].
In a large, retrospective, cohort study that included 436 patients with ulcerated IH (median age at ulceration was 13.7 weeks), treatment included timolol and wound care, wound care and pulsed dye laser, systemic beta blockers, or multimodal therapy [119]. Among the 87 patients who received propranolol and had dosing information available, after adjusting for IH size, a dose of propranolol greater than 1 mg/kg/day was associated with a twofold risk of longer healing time compared with a dose less than or equal to 1 mg/kg/day (hazard ratio [HR] 2.04, 95% CI 1.11-3.73).
Analgesia — The pain associated with ulceration can be severe. Affected infants commonly suffer from sleep disturbance and increased irritability. Use of oral acetaminophen (without codeine) or a topical anesthetic agent (ie, lidocaine hydrochloride 2% to 5% ointment) may be warranted. To avoid the risk of lidocaine toxicity, parents or caregivers should be instructed to apply only a pea-sized amount of lidocaine to the affected area no more than three times per day. (See "Pain in children: Approach to pain assessment and overview of management principles", section on 'Pharmacologic therapy'.)
Eutectic mixture of local anesthetics (EMLA) should be avoided in infants less than three months of age because it contains prilocaine hydrochloride, which has been associated with infantile methemoglobinemia. (See "Methemoglobinemia", section on 'Topical anesthetics'.)
Pulsed dye laser — Pulsed dye laser 595 nm can be used as an adjunctive treatment for ulcerated hemangiomas that fail to heal after medical therapy and optimal wound care [1]. Treatment can be repeated at two- to four-week intervals. (See "Laser and light therapy for cutaneous vascular lesions", section on 'Infantile hemangiomas'.)
Airway hemangiomas — Because of the small caliber of the infant airway, a growing airway hemangioma can lead to life-threatening airway obstruction. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Airway hemangiomas'.)
Systemic propranolol is generally the first line of therapy for children with symptomatic airway hemangiomas [36,120-122]. Laser ablation, intralesional steroids, and/or surgical debulking are occasional second-line therapies [123]. Rarely, tracheotomy may be required.
In a multicenter study, 27 infants aged one to five months with airway hemangiomas were treated with oral propranolol 2 mg/kg per day for a median time of 15 months (range 7 to 34 months) [124]. Eleven children were treated with propranolol alone, whereas 16 children received intralesional corticosteroid injection at the time of propranolol initiation. Stridor generally resolved within a day of initiation of propranolol treatment. However, additional therapy, including systemic steroids, laser ablation, or surgical excision, was required in 16 children because of recurrence of respiratory symptoms.
High-output failure — Infants with significant hepatic or very large cutaneous hemangiomas may rarely develop high-output heart failure within the first several months of life. Treatment in such cases may include systemic propranolol and/or glucocorticoids, hepatic arterial embolization in selected hepatic cases, and/or treatment of heart failure (with fluid restriction, diuretics, and digoxin as indicated) [125-128].
PHACE syndrome — The presence of severe arterial anomalies may restrict or modify the use of propranolol in a small subset of patients with PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies) syndrome (MIM #606519) [129]. In addition to large, facial hemangiomas, patients with this disorder may manifest abnormalities of the cerebral, cervical, and cardiac vasculature. (See "PHACE syndrome".)
It is known that a small percentage of patients with PHACE syndrome and severe cerebral or cervical anomalies develop acute arterial ischemic stroke, most often during infancy or toddlerhood [130]. Thus, a theoretical concern has been raised that propranolol-induced hypotension and reduced cerebrovascular perfusion in patients with already compromised cerebral vasculature could increase the risk of stroke in this population, though this has not been demonstrated in clinical practice.
While propranolol may certainly be contraindicated in the setting of significant cardiovascular anomalies, this is usually not the case for the majority of patients with cerebrovascular anomalies, unless those anomalies place the infant in the high-risk category for stroke (table 2) [129]. The risks and benefits of propranolol treatment for patients with PHACE syndrome who have high-risk magnetic resonance angiography (MRA) features should be discussed in consultation with neurology and/or cardiology specialists [31]. If the potential benefits of propranolol treatment are deemed to outweigh the risks, propranolol should be given at the lowest possible dose, with slow upward dose titration and three-times-daily dosing [31]. This schedule is aimed at minimizing abrupt changes in systolic blood pressure, which is a known risk factor for stroke. (See "PHACE syndrome", section on 'Propranolol'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infantile hemangiomas and PHACE syndrome".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Hemangioma (The Basics)")
SUMMARY AND RECOMMENDATIONS
●General approach − The approach to the treatment and choice of treatment modality for infantile hemangioma (IH) should be individualized depending upon the size and location of the lesion(s), presence of complications, potential for scarring or disfigurement, rate of growth or involution at the time of evaluation, potential risk(s) and benefits of treatment, availability of the various modalities, and experience of the treating clinician. The Infantile Hemangioma Referral Score (IHReS) tool has been developed to help primary care physicians identify problematic hemangiomas that should be referred to expert centers. (See 'General approach' above and 'Risk stratification and indications for referral/intervention' above.)
●Goals of treatment − The goals of treatment include the prevention or reversal of life- or function-threatening complications; prevention or minimization of disfigurement, bleeding, infection, and pain; and minimization of psychosocial distress for the patient and family. Medical therapies for hemangiomas are most effective when initiated as early in the hemangioma proliferative phase as possible, ideally within the first two to three months after birth. (See 'Goals of treatment' above.)
●Low-risk/uncomplicated infantile hemangiomas − We suggest active nonintervention for uncomplicated hemangiomas that are not disfiguring (Grade 2C). Active nonintervention requires regular monitoring of the clinical course and attention to the psychosocial implications for the child and family. (See 'Active nonintervention' above.)
For thin, superficial, uncomplicated hemangiomas in cosmetically sensitive locations, topical timolol may also be considered. (See 'Topical beta blockers' above.)
●High-risk/complicated infantile hemangiomas − We recommend oral propranolol as the first-line agent for the treatment of complicated hemangiomas with the potential to impair function or cause disfigurement (eg, periorbital hemangiomas) (Grade 1A). Treatment is generally started with 1 mg/kg per day and then gradually increased to the target dose of 2 to 3 mg/kg per day (algorithm 1). The most significant side effect of oral propranolol is hypoglycemia. This risk can be minimized by educating caregivers to always administer the medication after an adequate feed and to hold propranolol when oral intake is poor or absent. (See 'Propranolol' above.)
Systemic corticosteroids are alternative agents for patients with complicated hemangiomas for whom treatment with beta blockers is contraindicated or may be used as combined therapy in severe, select cases. Surgical excision is generally reserved for involuted lesions with residual scars or loose skin; hemangiomas with inadequate involution in cosmetically sensitive areas; and pedunculated, cutaneous hemangiomas. (See 'Second-line therapies' above.)
●Periocular infantile hemangiomas − Children with periorbital IH should be evaluated and monitored by an ophthalmologist who is experienced in the treatment of hemangiomas. (See 'Periocular hemangiomas' above.)
●Ulcerated infantile hemangiomas − We suggest oral propranolol in addition to meticulous wound care and appropriate analgesia for the treatment of ulcerated hemangiomas that may cause permanent disfigurement, interfere with daily life activities, or do not respond to wound care measures (Grade 2C). (See 'Ulcerated hemangiomas' above.)
