Propranolol therapy

In a large industry-sponsored randomized trial, 456 infants aged 5 weeks to 5 months with proliferating infantile hemangiomas of at least 1.5 cm received either a placebo or propranolol (1 mg/kg per day or 3 mg/kg per day) for 3 or 6 months. After interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg/kg per day for 6 months was selected for the final efficacy analysis.[92][Level of evidence B3]

In a large industry-sponsored randomized trial, 456 infants aged 5 weeks to 5 months with proliferating infantile hemangiomas of at least 1.5 cm received either a placebo or propranolol (1 mg/kg per day or 3 mg/kg per day) for 3 or 6 months. After interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg/kg per day for 6 months was selected for the final efficacy analysis.[92][Level of evidence B3]

Of patients who received the selected regimen, 88% showed improvement by week 5, compared with 5% of patients who received the placebo.

In a large industry-sponsored randomized trial, 456 infants aged 5 weeks to 5 months with proliferating infantile hemangiomas of at least 1.5 cm received either a placebo or propranolol (1 mg/kg per day or 3 mg/kg per day) for 3 or 6 months. After interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg/kg per day for 6 months was selected for the final efficacy analysis.[92][Level of evidence B3]

Adverse events occurred infrequently.

A retrospective study of 635 infants with infantile hemangiomas who were treated with propranolol (2 mg/kg per day) had the following results:[97][Level of evidence C3]

A retrospective study of 635 infants with infantile hemangiomas who were treated with propranolol (2 mg/kg per day) had the following results:[97][Level of evidence C3]

The overall response rate was 91%, with most patients demonstrating regression.

A retrospective study of 635 infants with infantile hemangiomas who were treated with propranolol (2 mg/kg per day) had the following results:[97][Level of evidence C3]

Two percent of patients had side effects, none of which were severe.

A meta-analysis that evaluated 5,130 patients from 61 studies concluded that propranolol was more effective and safer than were other treatments for infantile hemangioma.[100]

Airway infantile hemangioma lesions are rare. A meta-analysis of 61 patients reported the following results:[101]

Airway infantile hemangioma lesions are rare. A meta-analysis of 61 patients reported the following results:[101]

There was a trend in decreased treatment failure with increased dosing strategies, which is consistent with the use of higher doses of propranolol in these patients (3 mg/kg per day).

Airway infantile hemangioma lesions are rare. A meta-analysis of 61 patients reported the following results:[101]

The analysis also suggested that the concurrent use of steroids and propranolol may have reduced efficacy in patients with segmental airway hemangiomas, but prior treatment with steroids had no deleterious effect.

Airway infantile hemangioma lesions are rare. A meta-analysis of 61 patients reported the following results:[101]

Additional prospective studies are needed to validate these findings.

Airway infantile hemangioma lesions are rare. A meta-analysis of 61 patients reported the following results:[101]

Diffuse (segmental) hemangiomas of the airway are very rare, and their clinical behavior is different from that of isolated airway lesions.

Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]The pretreatment evaluation (inpatient or outpatient) includes the following:

Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]The pretreatment evaluation (inpatient or outpatient) includes the following:

Infant aged 4 weeks or younger (corrected for gestational age).

Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]The pretreatment evaluation (inpatient or outpatient) includes the following:

Infant of any age with inadequate social support.

Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]The pretreatment evaluation (inpatient or outpatient) includes the following:

Infant of any age with comorbid conditions affecting the cardiovascular or respiratory system, including symptomatic airway infantile hemangiomas.

Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]The pretreatment evaluation (inpatient or outpatient) includes the following:

Infant of any age with conditions affecting blood glucose maintenance.

Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]The pretreatment evaluation (inpatient or outpatient) includes the following:

History, with focus on cardiovascular and respiratory abnormalities (e.g., poor feeding, dyspnea, tachypnea, diaphoresis, wheezing, heart murmur) and family history of heart block or arrhythmia.

Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]The pretreatment evaluation (inpatient or outpatient) includes the following:

Physical examination, including cardiac and pulmonary assessment and measurement of heart rate.

Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]The pretreatment evaluation (inpatient or outpatient) includes the following:

No need for echocardiogram or electrocardiogram for standard-risk patients. Two studies found no contraindication to beta-blocker therapy in 6.5% to 25% of patients who had electrocardiogram abnormalities.[106,107] Electrocardiogram should be considered in children with heart rate lower than normal for age and history of arrhythmia or arrhythmia detected during examination.

Initiation of treatment: Guidance from consensus panels suggested that treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. They suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:[103]The pretreatment evaluation (inpatient or outpatient) includes the following:

Family history of congenital heart disease or maternal history of connective tissue disease.

Dosing: According to the consensus panels, the dosing used is generally 1 mg/kg per day to 3 mg/kg per day divided into two or three doses. The starting dose varies depending on risk factors and location of initiation. Outpatients and inpatients are initially started at a dose of 0.5 mg/kg per day to 1 mg/kg per day and increased over time.[104-106] A retrospective review of initial dosing indicates a starting dose of 2 mg/kg may also be well tolerated. This initial dosing could decrease the need for up-titration and more frequent clinic visits, although prospective studies are needed.[108] Initially, dosing of three times per day is recommended for infants younger than 5 weeks and for patients with PHACE syndrome.[47,103]

Monitoring: Monitoring varies depending on the institution. However, oral propranolol peaks at 1 to 3 hours after administration and most centers measure heart rate and blood pressure 1 and 2 hours after each dose with initiation and then when the dose is increased by at least 0.5 mg/kg per day. Parent and patient education includes when to withhold the medication, signs of hypoglycemia, feeding necessity through the night, and when to call the physician with issues, such as illness, that may interfere with oral intake or lead to dehydration or respiratory problems.A large retrospective multicenter study assessed the safety of outpatient administration of propranolol and evaluated the need for monitoring. In this study, 783 patients with 1,148 office visits were evaluated. No symptomatic bradycardia or hypotension was noted. Blood pressure evaluation was unreliable. The results suggested that outpatient evaluation may not be necessary for standard-risk patients with infantile hemangiomas.[109]

Contraindications: Propranolol treatment is contraindicated in infants and children with the following:[103-105]

Contraindications: Propranolol treatment is contraindicated in infants and children with the following:[103-105]

Sinus bradycardia.

Contraindications: Propranolol treatment is contraindicated in infants and children with the following:[103-105]

Hypotension.

Contraindications: Propranolol treatment is contraindicated in infants and children with the following:[103-105]

Heart block greater than first degree.

Contraindications: Propranolol treatment is contraindicated in infants and children with the following:[103-105]

Heart failure.

Contraindications: Propranolol treatment is contraindicated in infants and children with the following:[103-105]

Asthma.

Contraindications: Propranolol treatment is contraindicated in infants and children with the following:[103-105]

Hypersensitivity.

Contraindications: Propranolol treatment is contraindicated in infants and children with the following:[103-105]

PHACE syndrome. PHACE syndrome with CNS arterial disease and/or coarctation of the aorta may be a relative contraindication. A retrospective multi-institutional study that investigated the safety of propranolol therapy for patients with PHACE syndrome identified 76 infants, including 12 patients who were at high risk of having a stroke.[110] The incidence of adverse events in these patients was similar to the incidence in 726 infants who received oral propranolol therapy for hemangioma but did not meet the criteria for PHACE syndrome. A decision to treat should be made in consultation with neurology/neurosurgery and cardiology.

Adverse effects of propranolol include the following:[111]These complications have been reported in several studies, and severe complications have been rare.[111,113] The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.A retrospective review of 1,260 children with infantile hemangiomas who were treated with propranolol identified 26 patients (2.1%) with side effects that required discontinuation of propranolol.[114] Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 patients received atenolol and 3 patients received prednisolone as second-line therapy. In the multivariate analysis, only younger age (95% confidence interval [CI], 1.201–2.793; P = .009) and lower body weight (95% CI, 1.036–1.972; P = .014) were associated with intolerable side effects.

Adverse effects of propranolol include the following:[111]These complications have been reported in several studies, and severe complications have been rare.[111,113] The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.A retrospective review of 1,260 children with infantile hemangiomas who were treated with propranolol identified 26 patients (2.1%) with side effects that required discontinuation of propranolol.[114] Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 patients received atenolol and 3 patients received prednisolone as second-line therapy. In the multivariate analysis, only younger age (95% confidence interval [CI], 1.201–2.793; P = .009) and lower body weight (95% CI, 1.036–1.972; P = .014) were associated with intolerable side effects.

Hypoglycemia.One study in Japan monitored hypoglycemia in infants with infantile hemangiomas who started treatment with propranolol.[112] After treatment with propranolol, the incidences of severe hypoglycemia and hypoglycemic convulsions were approximately 0.54% and 0.35%, respectively. The incidence of hypoglycemic convulsions appeared to be higher in Japan than in Western countries. Severe hypoglycemia was common in infants younger than 1 year when propranolol was used for 6 months or longer. Severe hypoglycemia often developed from 5:00 AM to 9:00 AM, and it was frequently associated with prolonged periods of fasting, poor feeding, or poor physical conditions.

Adverse effects of propranolol include the following:[111]These complications have been reported in several studies, and severe complications have been rare.[111,113] The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.A retrospective review of 1,260 children with infantile hemangiomas who were treated with propranolol identified 26 patients (2.1%) with side effects that required discontinuation of propranolol.[114] Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 patients received atenolol and 3 patients received prednisolone as second-line therapy. In the multivariate analysis, only younger age (95% confidence interval [CI], 1.201–2.793; P = .009) and lower body weight (95% CI, 1.036–1.972; P = .014) were associated with intolerable side effects.

Hypotension.

Adverse effects of propranolol include the following:[111]These complications have been reported in several studies, and severe complications have been rare.[111,113] The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.A retrospective review of 1,260 children with infantile hemangiomas who were treated with propranolol identified 26 patients (2.1%) with side effects that required discontinuation of propranolol.[114] Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 patients received atenolol and 3 patients received prednisolone as second-line therapy. In the multivariate analysis, only younger age (95% confidence interval [CI], 1.201–2.793; P = .009) and lower body weight (95% CI, 1.036–1.972; P = .014) were associated with intolerable side effects.

Bradycardia.

Adverse effects of propranolol include the following:[111]These complications have been reported in several studies, and severe complications have been rare.[111,113] The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.A retrospective review of 1,260 children with infantile hemangiomas who were treated with propranolol identified 26 patients (2.1%) with side effects that required discontinuation of propranolol.[114] Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 patients received atenolol and 3 patients received prednisolone as second-line therapy. In the multivariate analysis, only younger age (95% confidence interval [CI], 1.201–2.793; P = .009) and lower body weight (95% CI, 1.036–1.972; P = .014) were associated with intolerable side effects.

Sleep disturbance.

Adverse effects of propranolol include the following:[111]These complications have been reported in several studies, and severe complications have been rare.[111,113] The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.A retrospective review of 1,260 children with infantile hemangiomas who were treated with propranolol identified 26 patients (2.1%) with side effects that required discontinuation of propranolol.[114] Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 patients received atenolol and 3 patients received prednisolone as second-line therapy. In the multivariate analysis, only younger age (95% confidence interval [CI], 1.201–2.793; P = .009) and lower body weight (95% CI, 1.036–1.972; P = .014) were associated with intolerable side effects.

Diarrhea/constipation.

Adverse effects of propranolol include the following:[111]These complications have been reported in several studies, and severe complications have been rare.[111,113] The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.A retrospective review of 1,260 children with infantile hemangiomas who were treated with propranolol identified 26 patients (2.1%) with side effects that required discontinuation of propranolol.[114] Severe sleep disturbance was the most common reason for propranolol cessation, accounting for 65.4% of cases. In total, 23 patients received atenolol and 3 patients received prednisolone as second-line therapy. In the multivariate analysis, only younger age (95% confidence interval [CI], 1.201–2.793; P = .009) and lower body weight (95% CI, 1.036–1.972; P = .014) were associated with intolerable side effects.

Cold extremities.

Duration of treatment: There are no consensus guidelines for the treatment duration of propranolol. In a prospective, multi-institutional study that assessed efficacy and safety of propranolol in high-risk patients, the administration of propranolol for a minimum of 6 months, up to a maximum of age 12 months, increased treatment success; dosing of propranolol was 3 mg/kg per day. Treatment results were sustained for up to 3 months after discontinuation of therapy. Efficacy and safety of propranolol in this study were similar to those reported in other studies.[115]

Rebound growth after propranolol therapy: Rebound refers to the growth of infantile hemangiomas after propranolol cessation. A multi-institutional, retrospective review of 997 patients with infantile hemangiomas found a rebound rate of 25.3% in 912 patients with adequate data. On univariate analysis, the factors associated with rebound included discontinuation of treatment before age 9 months, female sex, location on the head or neck, segmental pattern, and deep or mixed skin involvement. On multivariate analysis, only deep infantile hemangiomas and female sex were significantly related.[116] A single-center retrospective review examined 198 patients with infantile hemangioma who underwent oral propranolol therapy. The study reported 35 patients (18%) with rebound growth 1 to 3 months after discontinuation of propranolol treatment. Of the 35 patients, 23 were re-treated with propranolol for up to 3 months. All patients had good responses.[117][Level of evidence C3]

Late growth of infantile hemangiomas: Hemangioma growth can occur in patients older than 3 years, and growth as late as age 8.5 years has been reported. Associated risk factors include segmental morphology, large hemangiomas, PHACE syndrome, and deep cutaneous and subcutaneous lesions in the head and neck.[118,119]