Discussion
This study documented a wide variation in the treatment of infantile hemangiomas. A consistent theme is that each patient and each IH are unique. The clinical practice guidelines are based on available data, and on expert opinions in the absence of data. With the publication of additional high quality studies and the widespread use of beta blockers for the management of IH, updated clinical practice guidelines may be indicated.
Ongoing studies continue to demonstrate the safety and efficacy of propranolol as well as other beta-blockers including atenolol,18,19 nadolol,20 and topical timolol.21 Most studies have used a goal dose of 2 – 3 mg/kg/day of propranolol.15 Three mg/kg/day is superior to 1 mg/kg/day,9 but little data exist comparing 2 mg/kg/day to 3 mg/kg/day.22 In fact, doses of 2.5 – 3 mg/kg/day may increase toxicity without added benefit.12,23,24 Early initiation of propranolol (before 10 – 12 weeks of age) improves outcomes compared to an older age of initiation.25,26 Current literature suggests that propranolol is effective and well tolerated in infants younger than five weeks corrected gestational age.27 Depending on response, most experts recommend continuing propranolol until age 12 months, and sometimes longer.15,28 The CPG recommends a baseline echocardiogram for patients with PHACE syndrome, but does not address the indications of an echocardiogram for other patients.15 Obtaining a baseline electrocardiogram is rarely helpful in otherwise well infants.29 Five or more cutaneous IH is associated with IH of the liver, and it has been recommended that such patients undergo ultrasound of the liver.30 However, at least one study found that liver ultrasound rarely affects clinical management, and that it may be safely omitted in the absence of concerning signs or symptoms such as lethargy or poor feeding.31
The FDA’s recommendation for monitoring patients is currently based on a clinical trial which had strict criteria and oversight, including intermittently monitoring heart rate and blood pressure for two hours after the first dose and when increasing the dose.9For propranolol, peak plasma concentrations occur 1 – 4 hours after a dose. Consumption of protein-rich foods increases the bioavailability by about 50% with no change in time to peak concentration.32 At least one large study suggests that at home initiation and dose escalation may be safely done.33 In addition, guidelines from Britain, Australia, and North America state that in children without risk factors, outpatient initiation without monitoring may be safely done with initial doses of 1 mg/kg/day.34-36 At home initiation and dose escalation, including by telehealth encounters, became more common for non-high risk patients during the COVID-19 pandemic.34 When therapy has been completed, some clinicians may discontinue propranolol abruptly,36although it has been suggested that it be tapered (for example, over two to four weeks), to potentially lower the risk of rebound growth.28,37 Despite evidence that most patients can be safely started on propranolol at home, many practitioners continue to monitor patients in the clinic or in the hospital when initiating or increasing the dose of propranolol, and some still get routine cardiac assessments and lab work.
Areas identified for future research and discussion include the optimal dose of propranolol (including for ulcerated IH, which may respond better to a lower initial dose (≤1 mg/kg/day) of propranolol38), the optimal duration of therapy, which patients truly benefit from ultrasound of the liver, how patients should be monitored, how often to see patients in follow-up, which patients should get additional work up (such as an echocardiogram), and how propranolol should best be discontinued (tapered or stopped abruptly).
Limitations of this study include a small sample size which is heavily biased towards PHOs and pediatric cardiologists. Few dermatologists and other providers responded, which could impact results since dermatologists, particularly the Hemangioma Investigators Group (https://www.hemangiomaeducation.org/) have been leaders in the treatment of infantile hemangiomas. Thus, analysis of variations in practice between specialties could not be reliably performed. Published guidelines suggest that dermatologists are more comfortable with outpatient initiation and dose escalation of beta blockers.34-36
In conclusion, this study demonstrates wide practice variations in managing infantile hemangiomas. Further research is indicated to address these variations and develop additional/updated evidence-based guidelines.
Acknowledgements: The authors thank Christine Rodgers and Janet Tooze for assistance with the REDCap survery.