Propranolol for infantile hemangiomas: Start to finish

By Warren R. Heymann, MD, FAAD
March 26, 2025
Vol. 7, No. 12

“We have observed that propranolol can inhibit the growth of these [infantile capillary] hemangiomas.” (1) In my career, I cannot think of any statement that led to such a swift, dramatic paradigm shift in management more than this observation by Léauté-Labrèze et al. in 2008. Although propranolol is now considered the primary treatment for infantile hemangiomas (IH) requiring therapeutic intervention, questions remain about its mechanisms of action, dosing initiation, and discontinuation. This commentary addresses new literature about these considerations, exclusive of other therapies that may be indicated in the event of propranolol failure or contraindication (selective beta-blockers [atenolol], topical beta-blockers [timolol], corticosteroids, sirolimus, laser, or surgery).

IH is the most common pediatric vascular tumor, with a reported incidence rate of 2-10%. IH have been linked to a low birth weight, multiple pregnancies, progesterone treatment, prematurity, female gender, white ethnicity, and family history. IH usually appears during the first few weeks of life and follows characteristic stages of proliferation and involution. Their clinical appearance depends on their depth and distribution. Classification comprises superficial, mixed, and deep IH as well as IH with minimal or arrested growth. Multifocal IH (>5) are more likely to be associated with infantile hepatic hemangiomas. Large facial IHs warrant investigation for PHACE syndrome (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects or aortic coarctation, and eye anomalies). Lumbar IH warrant investigation for the LUMBAR syndrome (lower body IH and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformity, anorectal malformations, arterial anomalies, and renal anomalies ). Complications of IH include ulceration (with possible secondary infection by Streptococci, Staphylococci, Klebsiella, and others), obstruction or functional impairment, hypothyroidism, and cosmetic sequelae. (2,3,4)

IH pathogenesis is poorly understood but is believed to represent an aberrant response of pluripotent stem cells to stimuli such as hypoxia and the renin-angiotensin system, activation of the RAS pathway, and enhanced VEGF expression. (2,3)

Xiang et al. state, “Propranolol is a nonselective β-blocker that is frequently used in clinical practice, and mechanistic studies on the treatment of proliferative IH have previously explored its effects on vasoconstriction, inhibition of angiogenesis, and induction of apoptosis. In terms of angiogenesis, propranolol also inhibited HemEC [hemangioma endothelial cell] migration and tubulogenesis. Treatment of IH with propranolol affects the intracellular state and the extracellular environment. Interventions targeting the intracellular state mainly influence cellular autophagy, glucose metabolism and lipid metabolism, and interventions targeting the extracellular environment mainly stabilize the fragile vasculature and eliminate inflammation.” Propranolol comprises a racemic mixture of R(+) and S(-) enantiomers. Studies demonstrate that the R(+) enantiomer inhibits the differentiation of hemangioma stem cells into endothelial cells by interfering with the transactivation of the SOX18 target gene. Only the S(-) stereoisomer has a blocking effect on β-adrenergic receptors. (5) Seebauer et al. suggest that the R (+) enantiomers of beta-blockers could be repurposed to increase the efficiency of current IH treatment and decrease associated side effects. (6)

Potential adverse effects of beta-blockers include hypotension, bradycardia, hypoglycemia, bronchospasm, sleep disturbances, diarrhea, and hyperkalemia. These can be managed by careful monitoring during initial administration and appropriate parental counseling. (7)

The site for initiation of propranolol (outpatient versus inpatient) is evolving as more evidence accumulates that cardiovascular and other acute toxicities occur rarely. (8) Kwak et al. performed cardiac evaluations (electrocardiography, Holter monitoring, chest X-ray, and echocardiography) on 64 patients with IH treated with oral propranolol before 2 years of age. None of the 64 patients experienced severe adverse side effects during propranolol treatment. There were no statistically significant differences in echocardiographic function and electrocardiographic data after treatment. The authors concluded that propranolol treatment ≥6 months was effective and safe without significant cardiac toxicity in the treatment of patients with IH. (9)

Serbaratnam et al. assert, “In-office cardiovascular monitoring after initial propranolol dosing or dose escalation has not demonstrated benefit in healthy infants, born at term, with normal birth weight, older than 45 weeks postconception and with established feeding, weight gain, and adequate social support. In these patients, propranolol can be commenced at 1 mg/kg/day on an outpatient basis without monitoring and increased after 1 day or 1 week to an optimal dose of 2 mg/kg/day, unless a lower dose is clinically effective. If the IH is not responding adequately, the dose of propranolol can be increased to 3 mg/kg/day.” (10) The Food and Drug Administration approves the use of propranolol hydrochloride oral solution (Hemangeol, 4.28 mg/mL) for IH and recommends starting at an initial dose of 0.6 mg/kg twice daily before escalating to a maintenance dose of 1.7 mg/kg twice daily after 2 weeks. Huang et al. retrospectively analyzed 244 IH patients treated with propranolol - 123 were initiated at the 1 mg/kg/day dose and 121 at the 2 mg/kg/day dose. There was no significant difference in the incidence of adverse events between the two groups (p = .057). Additionally, among patients initiated at 2 mg/kg/day, there were no significant differences in the incidence of age-related or weight-related adverse events for those younger than 2 months or those in the 1st or 2nd quartile for weight (p = .53). Assuming that the regimen for accelerated propranolol initial dosing (RAPID) are confirmed, the authors conclude that “revisions to the current standardized protocol may be considered to enhance the efficiency, workflow, and cost-effectiveness of providing treatment for infantile hemangiomas.” (11)

When is it optimal to discontinue propranolol for IH? Propranolol has a > 90% efficacy rate for IH, although up to 30% of lesions may relapse upon termination of therapy, especially if treatment is discontinued early. In a prospective study of 150 IH patients (with 173 lesions), Wang et al. determined that the optimal time for withdrawing propranolol was when the patients were older than 13 months, and the lesions maintained maximum regression for 3 months. (12)

Witnessing a revolutionary therapy blossom based on a serendipitous observation has been exhilarating. As more data accrue, propranolol treatment for IH will be further refined.

Point to Remember: Propranolol is first-line therapy for patients with infantile hemangiomas that warrant therapeutic intervention. Studies suggest that starting at the targeted dose and maintaining therapy until age 13 months and 3 months after the lesion has regressed may be appropriate management guidelines.

Our expert’s viewpoint

Patrick McMahon, MD, FAAD
Associate Professor of Medicine Cooper Medical School of Rowan University

I was fortunate enough to have begun my dermatology residency July 1, 2008, only days after the case report detailing the impact of propranolol on infantile hemangiomas. The pediatric dermatologists where I was training at the University of California-San Francisco were abuzz about this case report heard ‘round the world. (1) Having such an effective option for these potentially disfiguring tumors that had previously been treated by systemic steroids, vincristine, and surgery has been revolutionary. It has also been interesting to be a pediatric dermatologist as we have adopted this systemic beta-blocker treatment in a way that was safe and measured.

I recall the early days of propranolol initiation when every patient was admitted to the inpatient pediatric unit for monitoring of blood pressures, heart rates, and blood sugars before and after initial doses and with dose escalations. These admissions were at least 48 hours and required a protocoled approach that involved an EKG on every patient, management by the general pediatric team and, sometimes, cardiology input. Over time, with the advent of an FDA-approved version of propranolol that included clinical trials, academic endeavors including retrospective reviews of safety data, and expert consensus opinions, our field has migrated toward outpatient initiation with much less monitoring. While I still screen for risk factors including bradycardia and heart block by asking about a maternal history of lupus and inherited arrythmias, I no longer keep patients in the office for 1-2 hours to recheck heart rates or blood pressure after initiation. We have streamlined this initiation significantly and, yet, I still take the time to stress the importance of accurate dosing. I will show every patient’s parent or guardian exactly how much to draw up per dose. I express the importance of giving the medicine after feeding to limit risk for hypoglycemia and avoid accidental double dosing due to having too many “cooks in the kitchen.” I make sure that someone is the “quarterback” of the propranolol treatment to avoid errors. Regarding neonates who need to begin treatment sooner than the on-label lower age limit of 5 weeks post due date (an age that needs correcting for premature infants), my practice is still to admit them to the hospital.

The portion of this report that got me most excited for the future was the mention of the R (+) and S (-) enantiomers. (6) The concept of having a therapy with the anti-proliferative effects of propranolol without the beta-blocking impact is extremely enticing and may eventually allow us to initiate a treatment safely in even younger populations without an inpatient stay. I am grateful to those in our field who have dedicated so much time and research to optimizing this treatment for all of the young babies and families impacted by infantile hemangiomas. I look forward to continuing to be a part of the evolving treatment approach as we further tailor treatments for this population.

1. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008 Jun 12;358(24):2649-51. doi: 10.1056/NEJMc0708819. PMID: 18550886.

2. Rodríguez Bandera AI, Sebaratnam DF, Wargon O, Wong LF. Infantile hemangioma. Part 1: Epidemiology, pathogenesis, clinical presentation and assessment. J Am Acad Dermatol. 2021 Dec;85(6):1379-1392. doi: 10.1016/j.jaad.2021.08.019. Epub 2021 Aug 19. PMID: 34419524.

3. Sharma A, Gupta M, Mahajan R. Infantile hemangiomas: a dermatologist's perspective. Eur J Pediatr. 2024 Jul 25. doi: 10.1007/s00431-024-05655-8. Epub ahead of print. PMID: 39052139.

4. Abtahi-Naeini B, Pourmahdi-Boroujeni M, Alipour N, Sattari H, Pourmoghaddas Z. Klebsiella pneumoniae-infected hemorrhagic ulcerative infantile hemangioma: A rare complication. Clin Case Rep. 2024 Jul 4;12(7):e9149. doi: 10.1002/ccr3.9149. PMID: 38966289; PMCID: PMC11222967.

5. Xiang S, Gong X, Qiu T, Zhou J, Yang K, Lan Y, Zhang Z, Ji Y. Insights into the mechanisms of angiogenesis in infantile hemangioma. Biomed Pharmacother. 2024 Jul 25;178:117181. doi: 10.1016/j.biopha.2024.117181. Epub ahead of print. PMID: 39059349.

6. Seebauer CT, Graus MS, Huang L, McCann A, Wylie-Sears J, Fontaine F, Karnezis T, Zurakowski D, Staffa SJ, Meunier F, Mulliken JB, Bischoff J, Francois M. Non-beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma. J Clin Invest. 2022 Feb 1;132(3):e151109. doi: 10.1172/JCI151109. PMID: 34874911; PMCID: PMC8803322.

7. Koka K, Patel BC. Capillary Infantile Hemangiomas. 2023 May 23. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 30855837.

8. Krowchuk DP, Frieden IJ, Mancini AJ, Darrow DH, Blei F, Greene AK, Annam A, Baker CN, Frommelt PC, Hodak A, Pate BM, Pelletier JL, Sandrock D, Weinberg ST, Whelan MA; SUBCOMMITTEE ON THE MANAGEMENT OF INFANTILE HEMANGIOMAS. Clinical Practice Guideline for the Management of Infantile Hemangiomas. Pediatrics. 2019 Jan;143(1):e20183475. doi: 10.1542/peds.2018-3475. PMID: 30584062.

9. Kwak JH, Yang A, Jung HL, Kim HJ, Kim DS, Shim JY, Shim JW. Cardiac Evaluation before and after Oral Propranolol Treatment for Infantile Hemangiomas. J Clin Med. 2024 Jun 5;13(11):3332. doi: 10.3390/jcm13113332. PMID: 38893043; PMCID: PMC11172932.

10. Sebaratnam DF, Rodríguez Bandera AL, Wong LF, Wargon O. Infantile hemangioma. Part 2: Management. J Am Acad Dermatol. 2021 Dec;85(6):1395-1404. doi: 10.1016/j.jaad.2021.08.020. Epub 2021 Aug 19. PMID: 34419523.

11. Huang CY, Perman MJ, Yan AC. Regimen for accelerated propranolol initial dosing (RAPID). Pediatr Dermatol. 2024 Jul-Aug;41(4):621-627. doi: 10.1111/pde.15623. Epub 2024 Apr 17. PMID: 38631683.

12. Wang L, Wang W, Zhou Z, Li J, Li Z, Lv R, Xu G, Bi J, Huo R. Exploration of the optimal time to discontinue propranolol treatment in infantile hemangiomas: A prospective study. J Am Acad Dermatol. 2024 Apr;90(4):783-789. doi: 10.1016/j.jaad.2023.12.034. Epub 2023 Dec 29. PMID: 38159645.

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