How should propranolol be initiated for infantile hemangiomas: Inpatient versus outpatient?

How should propranolol be initiated for infants with infantile hemangiomas warranting treatment? Infantile hemangiomas (IH) show a characteristic growth pattern of proliferation and eventual involution during the first decade of life, and may be isolated lesions or part of a constellation of findings such as “PHACEs” (posterior fossa abnormalities, hemangioma, arterial lesions, cardiac and eye anomalies). Two-thirds of IH occur in the head and neck, and otolaryngologists are frequently asked to manage such lesions. While partial or complete involution is the expected natural outcome, 12% of IH require therapy1 during infancy to hasten involution. There is no FDA-approved treatment of IH, and management is largely based on expert opinion and observational studies. Propranolol's efficacy in treating IH1 has virtually supplanted the traditional use of corticosteroids, largely due to the side effects associated with prolonged corticosteroid therapy. In support of this paradigm shift, preliminary results of the only prospective, randomized controlled study comparing propranolol to prednisolone2 show similar efficacy but significantly fewer serious adverse events (AEs) from propranolol (unpublished data). Recognizing that propranolol is not FDA approved for any pediatric indication, this article reviews the current practice of use for IH, focusing on pretreatment screening, outpatient versus inpatient initiation, dosing, use in PHACEs, and monitoring for AEs. Propranolol is a nonselective beta-adrenergic antagonist with a favorable safety profile for use in the pediatric population akin to that in adults. Menezes noted an 18% incidence of AEs upon review of all series reporting ≥10 patients with IH who were treated with propranolol.2 AEs reported in another review of 1,175 patients with IH include sleep disturbances (3.7%), asymptomatic or unspecified hypotension (2.8%), somnolence (2.2%), cool or mottled extremities (1.7%), pulmonary symptoms including wheezing (1.4%), asymptomatic or unspecified bradycardia (0.9%), hypoglycemia (0.9%), gastroesophageal reflux or gastrointestinal upset (0.7%), symptomatic hypotension (0.3%), and symptomatic bradycardia (0.1%) (Table 1).3 While AEs are generally not life-threatening, the most concerning are those affecting blood glucose and the cardiac system. Much debate exists regarding whether propranolol for IH should be initiated on an inpatient basis or on an outpatient monitored basis. Proponents of outpatient initiation cite propranolol's long track record of safe use in patients with cardiac indications, while inpatient proponents caution that such data cannot be extrapolated to patients with IH. In a review of over 50 infants with IH admitted for propranolol therapy, all had at least one low systolic or diastolic blood pressure (BP) recording and two-thirds had at least one simultaneous low systolic and diastolic BP measure, with 14% having concomitant bradycardia.4 Despite the high frequency of events, all were asymptomatic and none warranted a change in medication dosing. Propranolol's greatest effect on BP occurs with the initial dose and peaks 2 hours after an oral dose, which serves as a valuable guideline for monitoring. Hypoglycemia is a well-recognized AE that is dose independent, and if severe may induce seizure activity. The mechanism is thought secondary to beta blockade of glucose mobilization during fasting states, and reports are nearly always associated with concomitant infection and/or poor oral intake.2 Beta blockade may induce bronchoconstriction, particularly during respiratory illnesses.2 The lack of consensus regarding pretreatment workup, initiation, and dosing of propranolol for IH led to a multidisciplinary consensus conference to review all data and establish best practice guidelines. (NIH-NIAMS-1R34AR060881). The team of 28 experts from dermatology, otolaryngology, cardiology, hematology, oncology, and biostatistics collectively treated over 1,000 patients at 12 institutions. The resulting best practice guidelines are conservative and based on current levels of evidence, largely level 3 observational studies. Propranolol hydrochloride, 20 mg/5 ml, at a target dose of 2 mg/kg/day (range: 1–3 mg/kg/day) administered as 0.66 mg/kg TID with a minimum of 6 hours between doses is recommended and should only be prescribed by physicians experienced in monitoring infant vital signs and knowledgeable about propranolol's potential AEs. A thorough history should identify contraindications to therapy, including cardiogenic shock, sinus bradycardia, hypotension, greater than first-degree heart block, heart failure, bronchial asthma, and hypersensitivity to propranolol. History of poor feeding, dyspnea, tachypnea, diaphoresis, respiratory illnesses with wheezing, heart murmur, or family history of arrhythmia should warrant exploration for contraindications to treatment. The prescribing physician should complete, or document, a recent normal cardiovascular and pulmonary examination. • Heart rate (HR) below age adjusted norm. < 70 beats per minute for newborns (< 1 month of age). For inpatients, propranolol is initiated at 0.33 mg/kg orally three times daily (TID); and BP and HR are checked 1 and 2 hours after each administration. If three doses are tolerated, propranolol is increased to the target of 0.66 mg/kg TID (2 mg/kg/day) with similar BP and HR monitoring. Once the target dose is tolerated for at least 2 hours, the patient is discharged. If dose initiation or escalation is not tolerated, the dose is reduced and gradually increased until tolerated.2 Outpatient initiation should be performed with cardiovascular monitoring for at least 2 hours after the first dose and after each escalation to capture peak changes in HR and BP. Propranolol is initiated at 0.33 mg/kg, and BP and HR check are checked at 1 and 2 hours. If the initial dose is tolerated, the patient may be discharged on 0.33 mg/kg TID, with a minimum of 6 hours between doses. Once 0.33 mg/kg TID is tolerated for 3 to 7 days, the dose can be increased to 0.5 mg/kg TID with BP and HR checks at 1 and 2 hours after the first dose. After 3 to 7 days, the dose may be similarly increased to target dose of 0.66 mg/kg TID with BP and HR checks at 1 and 2 hours after the first dose.2 Transient decrease in BP may cause stroke in infants with PHACEs if severe intracranial arteriopathy is present so magnetic resonance imaging/magnetic resonance angiogram (MRI/MRA) of the head and aortic arch is recommended before initiation of propranolol.5 If findings are abnormal, neurology consultation is indicated to assess the risk of propranolol initiation. If potential benefits appear to outweigh the risks of initiation, propranolol should be initiated in close consultation with cardiology and as an inpatient, slowly titrating the propranolol dose to the lowest possible dose necessary to achieve an effect.3 Caretaker counseling is paramount to recognize signs of side effects including hypotension, bradycardia, hypoglycemia, and wheezing, to ensure 6 hours minimum between doses, to underscore need for regular feedings, and to hold propranolol if oral intake is diminished.2 Current evidence supports that propranolol is safe to use for otherwise healthy infants with IH with appropriate screening, cautious dosing, and thorough caretaker education following the above-mentioned guidelines. Outpatient monitored initiation may be considered for infants over 48 weeks postconceptual age, with adequate social support and without relevant comorbid cardiac, pulmonary, or blood glucose conditions. For other infants, including those with PHACES, inpatient initiation is advised. Level IIb: Reference #4. Level III: Reference #1, 2, 3, 5.