Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents.

BACKGROUND: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH. OBJECTIVE: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents. METHODS: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children's outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents' outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). RESULTS: Data of 105 children (36 propranolol, 69 atenolol; 6.0-11.8 years) were analyzed. Mental health outcomes did not differ between both ß-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. CONCLUSION: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant's ß-blocker treatment.

Rare complication - skin atrophy - after systemic conservative therapy of infantile hemangioma.

BACKGROUND: Hemangiomas, also called infantile hemangiomas (IH) or hemangiomas of infancy are the most frequently seen benign vascular tumors of infancy. Different types of hemangiomas are described in the literature. The current approach is to assess the risk and, if needed, first line treatment is to initiate systemic propranolol. CASE PRESENTATION: A 3-month-old Caucasian female patient was brought as an outpatient. The main complaint was an infantile hemangioma in the facial area, which as per the parents' story appeared within a week of birth like a small reddish line and it rapidly grew. Systemic propranolol was proposed as a first-line treatment and the adverse effects were explained. The parents, afraid of the side effects, wanted to explore other possibilities such as topical timolol, however, since it had no effect, propranolol was initiated in the end. Hemangioma was completely reduced in size; however, a skin defect was detected. As per the dermatologist's counsel, topical cream was initiated. The skin defect was reduced but not fully healed. The child is still being monitored periodically. CONCLUSION: After successful treatment of hemangioma, we identified a skin defect, which was very similar to steroid-induced skin atrophy. However, we cannot attribute this to a single factor. The only thing that can be concluded is that the subject needs a thorough studying, since rate of infantile hemangioma is high, and pediatricians need a clear management strategy of how to approach skin atrophy after successfully treating the hemangioma itself.

Critical role of Aquaporin-1 and telocytes in infantile hemangioma response to propranolol beta blockade.

Propranolol, a nonselective ß-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.

Long-Term Results of Oral Propranolol Treatment Protocol for Periocular Infantile Hemangioma: Should There Be Any Contraindication?

PURPOSE: The authors report long-term results of the oral propranolol treatment protocol for periocular infantile hemangioma regardless of conventional indications. METHODS: This is a retrospective study (2008-2018) on children with propranolol treatment protocol for periocular infantile hemangioma and last follow-up (FU) of ≥4 months after treatment and age of >24 months. After systemic evaluation, it was started with 0.5 and increased by 0.5 every 3 days to reach 2 mg/kg/day. If there was no good response, it would be gradually increased up to 3 mg/kg/day. Tapering (0.5 mg/kg/day every 4 weeks) was started when patients were on treatment for ≥6 months and ≥12 months old and there was no change in the infantile hemangioma size for ≥3 months. Rebound growth was based on the parents' report and would be treated by increasing the dose to at least 2 mg/kg/day for 3 months. FU was either in-person or via social media. Change in periocular infantile hemangioma size on the photos was scored by 3 masked observers (visual analog scale) and presented as excellent (≥50% reduction), good (1%-49%), fair (no change), and failure (enlarged). RESULTS: Forty-three patients were included. Orbital involvement was in 49%, ptosis in 58%, and risk of amblyopia in 63%. Mean treatment, tapering, and FU duration were 37, 13, and 74 months, respectively. Mean age at presentation, start of propranolol treatment protocol, tapering, stop, and last FU were 1.5, 5, 29, 42, and 78 months, respectively. Twenty-seven patients received 2, seven 2.5, and nine 3 mg/kg/day. Mean visual analog scale significantly increased from 43% (FU1) to 92% (last FU) when 97.6% of patients showed an excellent response. The remaining skin lesions were observed in 35%. No side effect was reported. CONCLUSIONS: Long-term results of the propranolol treatment protocol for periocular infantile hemangioma showed an excellent response in 97.6% of patients with no side effects. A residual skin lesion was observed in 1/3 of the patient.

Clinical efficacy and safety of two different hematoporphyrin monomethyl ether-mediated photodynamic therapy regimen in Chinese children with port-wine stain.

Hematoporphyrin monomethyl ether-photodynamic therapy (HMME-PDT) has achieved encouraging clinical outcomes in adult port-wine stain (PWS). Optimal treatment option for children with PWS was minimal. To compare whether the clinical effectiveness of HMME-PDT with the 5-min (fast) administration treatment regimen (FATR) was better than the 20-min (slow) administration treatment regimen (SATR) for PWS of children in vivo and in vitro. Thirty-four children with PWS were divided into two groups including FATR and SATR. The two groups received three times HMME-PDT, respectively. Treatment efficacy and safety were evaluated in vivo and in vitro. Erythema index (EI) was used to evaluate the clinical outcomes. Both FATR and SATR were effective and safe in children with PWS after HMME-PDT. There were significance differences between the two groups in reductions of EI after the second treatment (p < 0.001) and the third treatment (p < 0.001) with HMME-PDT. The serum HMME concentration reach the peak level at short time compare with SATR group. A significance increased superoxide levels were observed in FATR group compare to SATR groups in vitro (p < 0.05). Our study suggested that HMME-PDT was effective and safe for children with PWS, the therapy regimen with FATR was better in clinical efficacy than that of the SATR.

Incidence and clinical factors associated with ulceration in infantile hemangiomas.

BACKGROUND: Ulceration is an important complication in infantile hemangiomas (IHs). Prior to the use of ß-blockers, the estimated incidence of this complication in a referral population was between 15% and 30%. The incidence and factors associated with ulceration have not been systematically studied since the emergence of ß-blocker therapy. OBJECTIVE: Examine the incidence and clinical predictors for ulceration in IHs. METHODS: Retrospective study at tertiary referral centers. RESULTS: Compared with a previous large pre-propranolol cohort study, ulceration occurred at a significantly lower incidence of 11.4%. Clinical factors associated with ulceration included partial segmental morphology, location in the diaper area, and size greater than 5 cm. Higher risk of ulceration in Black patients was observed, suggesting barriers to care including delayed diagnosis and referral to specialty care. LIMITATIONS: Retrospective design at tertiary referral centers. CONCLUSION: Compared with reports before the use of ß-blockers became widespread, the incidence of ulceration in IHs has decreased. However, it continues to be a relatively frequent complication of IH.

Foam Sclerotherapy in the Treatment of Hemangiomas and Venous Malformations.

BACKGROUND: Sclerotherapy has achieved great success in treating most venous malformation (VM) lesions. OBJECTIVE: To compare the effects of foam sclerotherapy on infantile hemangioma and pyogenic granuloma (PG). In addition, we analyzed the data and outcomes of foam sclerotherapy for the VM. MATERIALS AND METHODS: Thirty-nine patients with hemangiomas and 83 patients with VMs were treated, and clinical outcomes, resolution, and complication rates were compared. Sclerotherapy data from the VM group were also analyzed. RESULTS: The average age of the patients and the distribution and tissue involvement of lesions among the 3 groups were significantly different ( p < .001). The average amount of sclerosing foam administered per session in VMs was significantly higher than that in the other 2 groups ( p < .0001) (whereas that in the PG group was lower than that in the infantile hemangioma group [ p < .0001]). However, the overall therapeutic efficacy and side effects in the 3 groups were not significantly different. For VMs, the frequency of ultrasound guided foam sclerotherapy and use of 3% polidocanol increased from superficial to deep lesions, whereas the use of 1% POL decreased ( p < .0001). CONCLUSION: Infantile hemangioma and PG treatments presented good results and minor adverse reactions comparable with those of VMs.

Early initiation of treatment with oral propranolol for infantile hemangioma improves success rate.

BACKGROUND/OBJECTIVES: Early referral and treatment of infantile hemangioma (IH) is a major challenge for treatment success. However, there is a lack of data supporting a specific threshold for initiating treatment with oral propranolol. The aim of this analysis was to find factors, such as age at treatment initiation, leading to a higher success rate with oral propranolol treatment. METHODS: Based on data from the pivotal phase 2-3 clinical trial of oral propranolol in IH, we used Generalized Additive Model (GAM) charts with Generalized Linear Models (GLM), then a rule discovery algorithm, to identify sub-groups presenting a high probability of occurrence of the predefined outcome (i.e., success [complete or nearly complete resolution of the target hemangioma] at 6 months of treatment). RESULTS: Our analyses identified that patients who started oral propranolol 3 mg/kg/day before the age of 10 weeks had a success rate of 86%, higher than the 60% success rate for all patients that received the same regimen commencing after 10 weeks of age. CONCLUSIONS: Treatment initiation before 10 weeks of age was associated with a significantly higher rate of treatment success with oral propranolol 3 mg/kg/day. Infants with IH requiring treatment should be referred to an expert center and treated as soon as possible.

A case of large airway and orbital hemangiomas with facial capillary malformation.

Infantile hemangiomas (IHs) are the most common pediatric vascular tumors, although their genetic etiology is largely unknown. Congenital capillary malformations (CMs) are associated with known somatic pathogenic variants, including GNAQ, GNA11, PIK3CA, and PIK3R1. Co-occurrence of a facial CM such as port wine stain and IH is not associated with any recognized vascular anomaly syndromes and rarely reported in the literature. We describe a case of a 5-week-old female patient with a large facial CM and extensive IHs of the lower lip, airway, and orbit who presented with airway compromise and responded to propranolol therapy.

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.

Propranolol inhibits the angiogenic capacity of hemangioma endothelia via blocking ß-adrenoceptor in mast cell.

BACKGROUND: Propranolol, a non-selective blocker of the ß-adrenoceptor (AR), is a first-line treatment for infantile hemangioma (IH). Mast cells have been implicated in the pathophysiology of propranolol-treated hemangioma. However, the function of mast cells remains unclear. METHODS: HMC-1s (Human mast cell line) having been treated with propranolol for 24 h were centrifuged, washed with PBS twice, and maintained in cell culture medium for another 24 h. The supernatants with propranolol which were named as propranolol-treated HMC-1s supernatants were obtained. The expression of cytokines and mediators was examined among HMC-1s dealt with propranolol. HemECs (hemangioma endothelial cells) were co-cultured with propranolol-treated HMC-1s supernatants, and their proliferation and apoptosis were investigated. The autophagic-related protein was examined in HemECs using immunoblot. RESULTS: In propranolol-treated HMC-1s, the expressions of ADRB1 (ß1-AR) and ADRB2 (ß2-AR) were reduced by 70% and 60%, respectively, and that of cytokines and mediators were reduced. The proliferation was decreased, but apoptosis and autophagy were induced in HemECs treated with propranolol-treated HMC-1s supernatants. However, propranolol can work well in shRNA-ADRB1 or shRNA-ADRB2 transfected HMC-1s. CONCLUSIONS: Propranolol inhibit the proliferation of HemECs and promote their apoptosis and autophagy through acting on both ß1 and ß2 adrenoceptor in mast cell. IMPACT: Treated with propranolol, ß1, and ß2 adrenoceptor on human mast cell expression was reduced significantly. After hemangioma endothelial cell treated with the supernatants from propranolol-treated human mast cell, its proliferation was decreased, but apoptosis and autophagy were significantly induced. Propranolol can work well in shRNA-ADRB1 or shRNA-ADRB2 transfected HMC-1s. Mast cells may have a role in the action of propranolol in infantile hemangioma through both ß1 and ß2 adrenoceptors to inhibit the angiogenic capacity of hemangioma endothelial cells.

Mediastinal infantile hemangioma with spinal canal extension and extensive gastrointestinal involvement complicated by respiratory failure.

Infantile hemangioma is the most common soft tissue tumor of infancy. Extensive organ involvement is rare. This report describes an infant with biopsy confirmed infantile hemangioma with diffuse organ involvement causing anemia and failure to thrive. Treatment was initiated with propranolol and led to initial improvement; however, course was complicated by several episodes of respiratory failure secondary to pulmonary edema. Propranolol therapy was interrupted for several months while patient was maintained on a diuretic regimen and treated with vincristine and high-dose corticosteroids. Patient was transitioned back to propranolol and is clinically thriving with objective improvement on radiographic imaging.

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.

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 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.

Efficacy of intravenous propranolol for life-threatening diffuse neonatal hemangiomatosis.

Oral propranolol is recommended as the first-line agent for infantile hemangioma requiring systemic treatment. Life-threatening complications such as obstructive infantile hemangioma of the airway or infantile hepatic hemangioma associated with high-output congestive heart failure are major indications for the consideration of early treatment. We present the case of an infant with life-threatening diffuse neonatal hemangiomatosis, including airway obstruction due to subglottic hemangioma, heart failure due to multiple hepatic hemangiomas with portohepatic venous shunts, and severe anemia due to continuous gastrointestinal bleeding, in which treatment with intravenous propranolol proved successful.

Safety of propranolol for infantile hemangioma in infants less than five weeks corrected age.

BACKGROUND/OBJECTIVES: Propranolol is used to treat problematic infantile hemangiomas (IHs), but its safety in infants <5 weeks corrected age has not been established. The objective of this study was to assess the safety and efficacy of propranolol for treatment of IH in infants <5 weeks corrected age, or 45 weeks corrected gestational age (CGA). METHODS: We performed a single institution, retrospective review of patients treated with propranolol prior to the age of 6 months between 2017 and 2021. Patient characteristics, location of hemangioma(s), weight at initiation of treatment, dosing information, side effects, response, and duration of treatment were documented. RESULTS: Of 200 patients with IH treated with propranolol, 24 started treatment prior to 45 weeks CGA. Mean CGA at initiation of treatment was 42 weeks. Sixty-seven percent were female and 75% were white, non-Hispanic. Mean duration of treatment was 255 days. Twenty-two patients (92%) had clear benefit from treatment at a dose of 1-3 mg/kg/day. The most common side effects were sleep disturbance (21%), irritability (17%), and cool hands/feet (13%). There were no serious adverse events. CONCLUSIONS: In this cohort of 24 patients with corrected age <5 weeks (CGA <45 weeks), propranolol was safe and effective for the treatment of infantile hemangiomas. Larger, prospective studies are indicated to investigate propranolol in this age group.

Worsening ulceration of infantile hemangioma after initiation or escalation of propranolol.

For infantile hemangiomas (IH) requiring treatment, including those in high-risk locations or in the setting of ulceration, oral propranolol is first-line therapy. Here, we present three cases of infantile hemangioma with worsening ulceration following initiation or escalation of oral propranolol at standard doses.

Propranolol therapy for hemangiomas in infants with neonatal abstinence syndrome may produce intolerable side effects.

We report three infants with infantile hemangioma who experienced severe agitation and diarrhea following propranolol administration. Propranolol, a non-selective ß-adrenergic receptor blocker, is the first-line treatment for infantile hemangiomas. All three infants were exposed to opioids in utero and experienced neonatal abstinence syndrome at birth. We hypothesize that chronic opioid exposure in utero may cause protracted upregulation of ß2-adrenergic receptors in the central nervous system, resulting in increased susceptibility to adverse reactions to propranolol.

Application of topical betaxolol to cure superficial infantile hemangioma: A pilot study.

BACKGROUND: Beta-blockers have gradually become an attractive option for the treatment of infantile hemangiomas. Topical application is preferred to oral administration because of their potential systemic adverse effects. The aim of this study is to investigate the effect of betaxolol in treating superficial infantile hemangioma. METHODS: Seventy-four infants admitted to the First Affiliated Hospital of Xinjiang Medical University from 2018 to 2019 were observed and recorded. Variables such as color, size, tension, and thickness were recorded monthly and evaluated using visual analog scales. Multi-factor analysis of variance with repeated measurements and the non-parametric Kruskal-Wallis H test were used to compare clinical effectiveness across the different groups. RESULTS: After 6 months of treatment, 33.78% (25/74) showed excellent results, 55.41% (41/74) had good responses, 8.11% (6/74) had moderate responses, and 2.70% (2/74) had poor responses. Local discomfort and systemic complications were not found. There was no significant difference in gender and location of occurrence among groups (p > 0.05), and the effect of topical application of betaxolol was optimum in the children aged 0-3 months (p = 0.002). None of three age groups had statistically significant difference in heart rate and blood pressure after accepting treatment (1 month, p = 0.618; 4 months, p = 0.138; 6 months, p = 0.757). CONCLUSIONS: Our study showed that topical administration of betaxolol was effective and well tolerated for superficial infantile hemangiomas, particularly in the early proliferative stage. However, its safety and efficacy need further research.