Color Doppler Ultrasound Indices as Predictors of Propranolol Response in Infantile Hemangioma: A Prospective Study.

OBJECTIVE: To evaluate the utility of color Doppler ultrasonography in assessing infantile hemangioma response to treatment with oral propranolol. METHODS: A prospective study was conducted between January, 2016 and December, 2022, wherein children with symptomatic (ulceration, bleeding, pain and scarring) infantile hemangioma were given oral propranol (2 mg/kg per day in three divided doses) as outpatient therapy. The clinical response was assessed three months post-initiation of treatment (intermediate clinical response) and three months post-completion of treatment (final clinical response, FCR). The primary outcome measurement was a clinical and radiological response (resistivity index (RI), pulsatility index (PI) and peak systolic velocity) to treatment. The secondary outcomes assessed were the complications related to treatment. RESULTS: Out of 601 patients who were started on propranolol, 99 developed severe adverse effects and were excluded from analysis. At FCR assessment, out of 502 participants, 64.3% (n = 323) showed excellent response, 17.7% (n = 89) showed partial, and 17.9% (n = 90) were non-responders. A significant increase in RI and PI values was noted in all children following propranolol treatment for six months. An increase > 7.5% in RI could identify responders with 92% sensitivity, 91% specificity and area under the curve (AUC) of 0.963. An increase of > 11.5% in PI could identify responders with 86% sensitivity, 91% specificity and AUC of 0.896. Patients initially showing no response but later becoming excellent responders had significantly higher RI and PI values. CONCLUSIONS: Color Doppler ultrasonography is a valuable tool in predicting the treatment outcome of infantile hemangioma using propranolol.

Additive value of single intralesional bleomycin injection to propranolol in the management of proliferative infantile hemangioma.

BACKGROUND: /Objective: We aimed to evaluate whether additional intralesional bleomycin injections benefit children with proliferative infantile hemangiomas (IHs). METHODS: In this retrospective case-control study, we examined the medical records of 216 infants who were followed up for proliferative IH. Patients in group 1 were treated with propranolol orally at 2 mg/kg/day. Group 2 was treated with oral propranolol combined with intralesional bleomycin injections. RESULTS: We retrospectively reviewed 95 and 121 patients in groups 1 and 2, respectively. No significant differences were observed between both groups regarding visiting age, sex, lesion thickness, or risk site. The overall cure rates in groups 1 and 2 were 77.89% (74/95) and 84.30% (102/121), respectively. The overall distribution of the length of cure significantly differed between both groups (P = 0.035). From the survival analysis (P = 0.026), the median survival time was 198 days (95% confidence interval (CI) 174.46-221.54) for group 1 and 139 days (95% CI 114.58-163.42) for group 2. The effect of treatment modality (hazard ratio (HR) = 1.41, P = 0.031) and risk site on survival time (HR = .54, P < 0.001) was significant. CONCLUSION: No significant differences were observed in the resolution of proliferative IH; however, intralesional bleomycin injection with systemic propranolol for proliferative IH treatment may provide a more rapid resolution.

Oral atenolol compared to oral propranolol for infantile hemangioma. / Atenolol oral comparado con propranolol oral para hemangioma infantil.

Introduction: Infantile hemangioma is the most frequent benign vascular tumor in childhood, with an incidence of 3 to 10%. When patients require treatment, oral propranolol, a non-selective lipophilic beta-blocker, is usually considered the therapy of choice. However, its use has been associated with several adverse events related to its ß-2 action and its ability to cross the blood-brain barrier. Because of this, oral atenolol, a hydrophilic ß-1 receptor-selective beta-blocker, may represent a valid treatment alternative. Nonetheless, there is still controversy regarding the efficacy and safety of atenolol when compared with propranolol as monotherapy for this condition. Methods: We searched Epistemonikos, the largest database of systematic reviews in health science, which is maintained by screening multiple sources of information, including MEDLINE/PubMed, EMBASE, and Cochrane, among others. Data were extracted from the identified reviews, data from the primary studies were analyzed, a meta-analysis was performed, and a summary table of the results was prepared using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. Results: Nine systematic reviews were identified, including 10 primary studies and three randomized trials. The three randomized trials were included in the analysis of this investigation. Conclusion: The use of oral atenolol compared with oral propranolol as monotherapies may result in little or no difference in terms of likelihood of complete remission, decrease in Hemangioma Activity Score, likelihood of post-treatment relapse, and risk of adverse events and severe adverse events, in infantile hemangioma (low certainty of evidence).

Introducción: El hemangioma infantil corresponde al tumor vascular benigno más frecuente de la infancia, con una incidencia de 3 a 10%. Entre los pacientes que requieren tratamiento el uso oral de propranolol, un betabloqueador no selectivo de tipo lipofílico, es usualmente considerado como la terapia de elección. Sin embargo, su uso se ha asociado a diversos efectos adversos, relacionados con su acción ß-2, y a su capacidad de cruzar la barrera hematoencefálica. Debido a esto, el uso oral de atenolol, un betabloqueador selectivo de receptores ß-1, de tipo hidrofílico, podría representar una alternativa válida de tratamiento. Sin embargo, aún existe controversia en relación con la eficacia y seguridad del tratamiento con atenolol como monoterapia, en comparación con el uso de propranolol como monoterapia para esta condición. Métodos: Se realizó una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el tamizaje de múltiples fuentes de información, incluyendo MEDLINE/PubMed, EMBASE, Cochrane, entre otras. Se extrajeron los datos desde las revisiones identificadas, se analizaron los datos de los estudios primarios, se realizó un metanálisis y se preparó una tabla de resumen de los resultados utilizando el método GRADE. Resultados: Se identificaron nueve revisiones sistemáticas, que en conjunto incluyeron 10 estudios primarios y tres ensayos aleatorizados. Se incluyeron los tres ensayos aleatorizados en el análisis del presente trabajo. Conclusiones: El uso de atenolol oral como monoterapia, comparado con el uso de propranolol oral como monoterapia, podría resultar en poca o nula diferencia en cuanto a la probabilidad de remisión completa, la disminución del , la probabilidad de recaída posterior al tratamiento y el riesgo de presentar efectos adversos y efectos adversos severos, en el hemangioma infantil (certeza de la evidencia baja).

Cardiac side effects of propranolol in infants treated for infantile haemangiomas.

OBJECTIVES: This study aims to add proof to the safety profile of propranolol as first-line choice in treating infantile haemangiomas, in particular related to its cardiac side effects the main hindering reason for parents and physicians to start and comply with treatment. METHOD: This is a prospective observational and analytic study with a sample of 476 patients diagnosed with infantile haemangioma and treated with systemic propranolol during the time interval January 2011 to December 2021. We studied clinical propranolol adverse events experienced in hospital or outpatient and measured the impact of propranolol on blood pressure and heart rate. RESULTS: This study showed that symptomatic adverse events caused by propranolol were mild and severe adverse events were rare. The most common clinical side effects were paleness, sweating, reduced feeding, and agitation. Only in 28 (5.9%) cases these symptoms were severe enough to review treatment, 1.8% had severe respiratory symptoms, 2.7% experienced hypoglycaemia, and 1.2% had heart-related symptoms. Mean blood pressure reduction with treatment was statistically significant only after achieving the maintenance dose 2 mg/kg body weight. Blood pressure under the 5th percentile was registered in 2.9% of cases, but only four patients had symptomatic hypotension. While heart rate reduction was noticed with the first dose, only two experienced symptomatic bradycardia. CONCLUSION: We conclude that propranolol is not only an excellent drug in treating infantile haemangioma, but it has also a very safe profile, with mild side effects and very rare severe cardiac adverse events, easily overcome with treatment interruption.

Should Propranolol Remain the Gold Standard for Treatment of Infantile Hemangioma? A Systematic Review and Meta-Analysis of Propranolol Versus Atenolol.

BACKGROUND: Although propranolol has been established as the gold standard when treatment is sought for infantile hemangioma, concerns over its side effect profile have led to increasing usage of atenolol, a beta-1 selective blocker. METHODS: A systematic review of PubMed, Scopus, CINAHL, Google Scholar, and Cochrane was conducted following PRISMA guidelines using MeSH terms and keywords for the terms propranolol, atenolol, and infantile hemangioma, including alternative spellings. All randomized control trials (RCTs) or cohort studies directly comparing outcomes of hemangioma treatment with atenolol and propranolol were included. A meta-analysis with pooled mean differences, pooled odds ratios, and analysis of proportions was performed. RESULTS: A total of 669 participants in 7 studies (3 RCTs and 4 cohort) were included. Propranolol showed a significantly higher rate of complete response compared to atenolol (73.3% vs 85.4%, P = .0004). The pooled mean difference of 0.07 (95% CI -0.12, 0.27) in Hemangioma Activity Score (HAS) was not statistically significant. In terms of side effects, there were significantly more agitation and bronchial hyperreactivity events in the propranolol group (P = .0245 and P < .0001, respectively). Overall, there was a significantly greater number of adverse events in the propranolol group compared to the atenolol group (185 vs 117, P < .00001). The overall pooled odds ratio was 2.70 (95% CI 1.90, 3.84), indicating that there is 2.7 times higher odds of adverse events in the propranolol group. CONCLUSION: Propranolol treatment leads to a significantly higher rate of complete response than atenolol. However, its use must be weighed against its greater side effect profile.

Successful Late Treatment of Orbital Infantile Haemangiomas in Two Teenagers with Topical Transcutaneous Timolol Maleate 0.5% Alone.

We previously described the first successful treatment of deep periocular and, subsequently, orbital infantile haemangiomas (IH) with topical transcutaneous timolol maleate 0.5% (TM 0.5%) alone as the first-line treatment in the acute proliferative phase in infancy. It is not known whether orbital IH with persistent proptosis in later years, untreated in infancy, would still respond to TM 0.5% treatment as well. To our best knowledge, we here present the first reports of the successful late treatment of persistent orbital IH with topical timolol maleate 0.5% applied to the skin overlying the orbital IH in two teenagers. Case 1 was an 11-year-old girl with proptosis measuring 4 mm before and 7 mm after Valsalva manoeuvre that diminished to 1 mm after topical treatment. Case 2 was a 10-year-old girl with 2 mm (before) and 4 mm proptosis (after Valsalva) that decreased to 0 mm proptosis with topical treatment. The time to resolution was 19 months (case 1) and 13 months (case 2). The treatment dose was 3 drops of TM 0.5% applied an average of 1.94 (case 1) and two times daily (case 2). In comparison to proptosis, resolution of periorbital swelling required less treatment time. There was no recurrence of either proptosis or periorbital swelling 1 year after stopping treatment in either case. The findings indicate that beta-blockers are effective not just in the proliferative but also in the late involutional phase in older children. No adverse clinical effects were noted throughout treatment in either case. The presence of increased proptosis with a Valsalva manoeuvre predicts a significant persistent vascular compartment in the orbital IH and may thus serve as a simple predictive clinical sign of likely treatment success. We recommend that a trial with this well-tolerated treatment form is considered in persistent cases of orbital IH, especially in the presence of enhanced proptosis with a Valsalva manoeuvre.

Monitoring oral propranolol for infantile hemangiomata.

Treating infantile hemangiomas with oral propranolol may be initiated in accordance with various protocols some require hospitalization. However, different adverse events have been reported during treatment, thus it is of special importance to find a protocol which is both safe and feasible. We performed a retrospective cohort study of all cases of infantile hemangiomas treated with oral propranolol at our institute between January 2010 and February 2020. Pretreatment evaluation consisted of pediatric cardiologist evaluation including electrocardiography and echocardiography. The propranolol starting dosage was 0.5 mg/kg bid; 2 weeks later the dosage was escalated to 1 mg/kg bid. During the initiation and escalation visits, heart rate and blood pressure were measured before and every hour for a total of 3 h, and blood glucose level was measured within the first hour of treatment. A total of 131 children were treated during the study period. Scalp, facial and genital region infantile hemangiomas were more prevalent in regard to their relative body surface area. No symptomatic bradycardia, hypotension, hypoglycemia, or any other adverse events were documented; few patients had asymptomatic bradycardia and hypotension, which were more common in infants below 6-months of age. Only one patient had asymptomatic hypoglycemia, not requiring any intervention. Initiation and escalation of propranolol treatment for infantile hemangiomas proved to be safe, and without symptomatic adverse effects. However, considering the young age of the patients and the possible asymptomatic adverse reactions, we recommend the following simple protocol as presented, for pretreatment evaluation and short monitoring during treatment initiation and dose escalation.

Efficacy and safety of propranolol cream in infantile hemangioma: A prospective pilot study.

Infantile hemangioma (IH) is a common tumor in infants that gradually resolves and is often untreated. However, for cosmetic reasons, parents often opt for treatment. Oral propranolol, the first-line therapy for IH, is sometimes associated with several side effects, including hypotension, bradycardia, and hypoglycemia. No clinical studies on topical propranolol have been conducted using standardized procedures. We evaluated the efficacy and safety of topical propranolol in patients with IH. This multicenter, prospective pilot study was conducted from June 2019 to October 2020 and involved eight Japanese infants aged 35-150 days with proliferating IH. Patients were treated with 5% propranolol cream twice daily. We examined the efficacy rate based on central evaluation (complete or near-complete healing of the target hemangioma) at weeks 24 and 12, respectively, compared to baseline values. The efficacy rate at week 24 was 68.8% (95% confidence interval: 44.1-85.9%). The surface area, maximum diameter, and color intensity of the target IH decreased over time. Adverse event and drug-related adverse event rates were 87.5% and 0%, respectively. Propranolol cream may be effective and safe in Japanese patients with IH and may be considered a first-choice treatment for small and superficial IHs in cosmetically problematic areas.

Efficacy and Safety of Propranolol Gel for Infantile Hemangioma: A Randomized, Double-Blind Study.

We aimed to evaluate the efficacy and safety of propranolol gel at various concentrations with infantile hemangiomas after proliferative phases. We designed a single-center, randomized, double-blind, dose-dependent trial with placebo control and randomized patients to receive propranolol gel at 0, 1, or 5%, twice daily for 24 weeks. The primary efficacy endpoint was the percentage change in redness of the tumors. Safety endpoints were skin characteristics changes and systemic symptoms. We made two comparisons to evaluate the superiority of 1 and 5% propranolol gels against placebo for primary endpoint analysis and used the t-test to compare parents' satisfaction with these treatments. Initially, 19 patients were enrolled, but 8 were excluded from the analysis. We were underpowered to answer the question of efficacy. In the per-protocol set, we found similar results for the redness percentage change among the patients on placebo, 1 and 5% gel. However, the difference in redness before and after treatment suggested a slight decreasing trend of lesion's redness as the propranolol concentration increased. The difference in parents' satisfaction between the placebo and 5% propranolol gel groups was significant (p = 0.08). We observed no serious adverse events. We did not find an obvious dose-dependent effect for the propranolol gel treatment against infantile hemangiomas after the proliferative phase. However, external applications twice daily were less burdensome for parents and led to good compliances. It had a favorable safety profile in Japanese pediatric patients with infantile hemangiomas.