Essay: Infantile hemangioma (IH) – use of oral Propranolol

Focused Clinical Question:
In patients ages six weeks to five years old with an infantile hemangioma (IH), does treatment with oral Propranolol decrease the redness and rate of growth of the hemangioma in comparison with the patients who receive a placebo treatment?
Summary of search, “Best Evidence” Appraised, and Key Findings
• The literature was searched for clinical trials or systematic reviews (SR) of randomized control trials (RCT) with level 2a evidence or higher to compare the use of oral propranolol with a placebo.
• Four studies were used:
o Two RCT studies were found, which met criteria for small-scale high quality RCT studies.
o One Retrospective Cohort Study
o One Systematic Review
• All studies showed the oral administration of  propranolol is a safe and effective alternative to waiting for the hemangioma to involute without intervention.
• All studies demonstrated the treatment of mild to moderate infantile hemangiomas increases healing time.
• All studies confirm the use of oral propranolol as an appropriate treatment option for mild to moderate infantile hemangiomas, but did not demonstrate if said treatment was more or less effective statistically than surgical resection/ laser removal for severe hemangiomas in patients with PHACE syndrome.
• All studies confirm oral propranolol as the standard of care for the treatment of  pediatric patients presenting with mild to moderate infantile hemangiomas, but there is a limited evidence base to support this conclusion as a large number of alternative treatments have not been evaluated by randomized control trials.
Clinical Bottom Line
• There is moderate supportive evidence for the use of oral propranolol as a safe and effective treatment for mild to moderate Infantile Hemangiomas. Furthermore, research revealed the use of beta blockers as a more cost effective option when compared with surgery and the complications that can arise during recovery of the skin condition without medical intervention.
Strength of Recommendation
• Level B evidence exists and supports the use of oral propranolol as a safe and effective treatment in the management of mild to moderate infantile hemangioma.
Search Strategy
Terms Used to Guide Search Strategy
• Patient/Client Group: Infant*, Pediatric*, Infantile Hemangioma*, IH, Haemangioma*
• Intervention: Oral Propranolol AND Propranolol AND Beta-Blocker AND Propranolol Oral Solution
• Comparison: Placebo AND No Treatment
• Outcome: Redness AND Size AND treatment of infantile hemangiomas AND Volume AND Safety
Sources of Evidence Searched
• PubMed
• Science Direct (Full Text Obtained from Elsevier)
• Cochrane Library
Inclusion and Exclusion Criteria
Inclusion Criteria:
• Limited to English language
• Limited to last 10 years (2008-2018)
• Limited to full text articles
• Limited to level 2 evidence or higher
• Infants ages 6 weeks to 5 years old with mild to moderate infantile hemangioma
• Treatment with oral propranolol solution
• Treatment with placebo solution
Exclusion Criteria:
• Topical Propranolol
• Timolol Maleate therapy
• Complicated or severe infantile hemangiomas
• Sham Radiation therapy
• Bleomycin Therapy
• High-Intensity Focused Ultrasound Therapy (HIFU)
Results of Search
Three relevant studies were found and categorized as shown in Table 1.1-3 Two additional studies were used4,5, but were not categorized, as one was a prospective study specifically focusing on ulcerated hemangiomas and the other was a retrospective cohort study with a small sampling size.
Best Evidence
The following studies were identified as the “best” evidence and selected for inclusion in the CAT (Table 2). Reasons for selecting these studies were because they were of level 2a evidence or higher, evaluated the treatment of infants ages 6 weeks to 5 years old with mild to moderate infantile hemangiomas with significant improvement as an outcome, and compared results of treatment with an oral placebo in order to evaluate the natural condition regression/progression.
Implications for Practice, Research and Future Evidence
Infantile hemangiomas are one of the most common childhood tumors.5 They often will regress on their own without intervention, but sometimes they proliferate and can affect the child’s ability to breath or obstruct their vision. These obstructions then can result in developmental delays. The randomized control trials and the retrospective cohort study demonstrated the use of oral propranolol as a safe and effective alternative to allowing spontaneous healing of the IH over time in order to prevent the occurrence of these complications .1-3,4 Current research suggests that the use of an oral propranolol is a safe method of intervention that allows patient’s recovery time to decrease when the patient does not suffer from pre-existing cardiac conditions 2,4 In the randomized control trial by Dr. Hogeling, patients were recruited in a single tertiary center after being recruited for the study by a primary care doctor or pediatrician, which has benefits including control over patient demographic and a unified photography protocol for treatment.2  Two children in this study did not respond as well as the others, for reasons unknown. One 5.5 month old child had a decreased response in comparison with other children and an 11 month old child developed an ulceration in the tumor that took two months to heal. Due to the small sample size, these two instances are significant.2 Larger multi-center trials, like the Leute- Lebreze reinforced this finding, as patients in the 35-90 day old age range saw increased healing in comparison to the 90-150 day old patients.4 This finding suggests that if the hemangioma is caught and treated during the initial proliferative phase, it is most likely to respond well to treatment with oral propranolol.2, 4
The implications for the clinical setting are restricted to the treatment of infantile hemangiomas in the early pediatric setting, as little research has been done on the treatment of late stage hemangiomas that persist in adolescents or adults.2,4 Two additional studies5,6compiled evidence from multiple studies and concluded that treatment with oral propranolol at 2mg/kg/day is an effective therapeutic dose, with less side effects than the 3mg/kg/day4,6. One weakness to the randomized control trials that was noted is the lack of long term follow-up for patients healing. In the retrospective cohort study, follow up was assessed at 96 weeks and it was determined that some patients would have benefited from continuous propranolol use as their hemangioma began growing again after discontinuation. 1
Areas of future related research may include the various other options for treatment that have been proven to be effective as well as the development of a better system of classification for Infantile Hemangiomas. All of the studies conducted at this point use vague terminology to describe healing as a result. This provides a level of uncertainty in the definition of “healing”  and does not address residual telangiectasis that can remain in some patients after treatment.4  Also, the treatment of Infantile Hemangioma with oral propranolol is not well studied for patients who suffer from PHACE Syndrome due to their underlying cardiac abnormalities. These patients are unfortunately those with the most severe expression of IH and would benefit from further research in regards to their treatment. This CAT should be repeated after another large randomized control trial has been conducted. It would be beneficial if a large sample size was analyzed at the 2mg/kg/day oral propranolol dosing, since this therapeutic level was not analyzed in the Leaute-Labreze study.2,4  This CAT would also be more clinically applicable if it included a comparison with another treatment such as laser removal or oral corticosteroids with the placebo as a control.