The dynamics of endothelial changes in vivo following standardized skin injury.

BACKGROUND: Vascular changes, that is, functional and cellular endothelial changes, are of essential importance in healing. Alongside these vascular changes, inflammatory factors and hypoxia may play an important role in recovery. OBJECTIVES: To investigate the dynamics of functional and cellular endothelial changes and hypoxia in vivo following standardized skin damage caused by tape stripping. METHODS: Vascular changes (endothelial cell proliferation, vascular network size, vessel diameter) and hypoxia-inducible factor-1α were examined immunohistochemically using a CD31/Ki67 double staining and HIF-1α single staining. Cutaneous perfusion was evaluated using the Twente Optical Perfusion Camera (TOPCam). RESULTS: The initial phase is seen to be dominated by endothelial cell proliferation, HIF-1α expression, and vasodilatation. Cutaneous perfusion intensity is particularly increased in the first 16 hours. The late phase of recovery (after 72 hours) is characterized by a peak of expansion of the vascular network and a second peak of endothelial cell proliferation and HIF-1α expression. CONCLUSION: Endothelial cell proliferation and HIF-1α expression appear to be (strongly) related, having maximum levels at 16 hours and 72 hours. Angiogenesis and HIF-1α expression are not continuous processes, but rather occur intermittently.

Use of the Hemangioma Severity Scale to facilitate treatment decisions for infantile hemangiomas.

BACKGROUND: The Hemangioma Severity Scale (HSS) assesses the severity of an infantile hemangioma (IH). OBJECTIVE: First, to compare HSS scores between patients with IH for whom propranolol treatment was indicated at their first visit and those who were not treated. Second, to assess suitable cutoff values for the need for propranolol treatment. METHOD: All patients with IH who attended our tertiary referral center since 2008 and were 0 to 6 months of age at their first visit were included. They were divided into propranolol and no-propranolol groups on the basis of choice of treatment at their first visit. HSS scores were assessed, and median scores were compared. RESULTS: A total of 657 children (342 in the propranolol group) were included. The median HSS score (25th-75th percentile) in the propranolol group was 10 (range, 8-14) compared with 7 (range, 4-9) in the no-propranolol group (P < .001). Cutoff values of 6 or lower (no indication for treatment) and 11 or higher (indication for treatment) resulted in 94% sensitivity and 89% specificity, respectively. LIMITATIONS: HSS scoring was not completely blinded. CONCLUSION: The HSS with cutoff values of 6 or lower and 11 or higher could be used as a triage tool for propranolol treatment. Patient age, IH type, and parental preference may also contribute to treatment decisions.

Propranolol treatment of infantile hemangioma is not associated with psychological problems at 7 years of age.

BACKGROUND: Concern has been raised about the potential long-term effects of propranolol treatment for infantile hemangioma (IH). OBJECTIVES: We sought to assess psychologic (social, emotional, behavioral, and executive) functioning in children treated with propranolol for IH. METHODS: Twenty-seven patients with IH (6.1-7.6 years of age) treated with propranolol for ≥6 months during infancy, and without other developmental risk factors, were recruited. Parents completed the Behavior Rating Inventory of Executive Function, Social Emotional Questionnaire, Child Behavior Checklist, and Strengths and Difficulties Questionnaire. For each questionnaire, the number of patients with abnormal scores, based on established cutoff points, was calculated. RESULTS: Only 1 child (3.7%) scored outside the normal range. The Hemangioma Severity Scale did not correlate with psychologic problems in these patients. Longer treatment duration was found to correlate with less attention-deficit hyperactivity disorder (ADHD) characteristics (ρ = -0.476; P = .012) and better executive functioning (ρ = -0.466; P = .014). LIMITATIONS: Exclusion of children born at gestational age <36 weeks or small for gestational age, no reference group and relatively small study size. CONCLUSION: We found no increased risk for psychologic problems at age 7 in IH patients treated with propranolol.

Propranolol treatment of infantile hemangioma (IH) is not associated with developmental risk or growth impairment at age 4 years.

BACKGROUND: Long-term adverse effects of propranolol treatment for infantile hemangioma (IH) in young children have been suggested. OBJECTIVE: To compare growth and development in children treated with propranolol for IH with nontreated healthy controls. METHODS: Eighty two (73%) children with IH aged 43 to 51 months treated with propranolol for 6 months or longer, and without other developmental risk factors, were recruited (cases) and matched with 4 twin counterparts and 78 children from a community-based cohort (control subjects). Parents completed the 48-months Ages and Stages Questionnaire (ASQ). Percentages of children with abnormal ASQ results were compared using χ(2) analyses. Mean ASQ scores and growth were compared using Mann-Whitney U tests. RESULTS: Six (7.3%) cases had abnormal ASQ results, compared with 10 (12.2%) controls (P = .292). Mean ASQ total score (25th-75th percentile) was 52.9 (50.8-57.0) for cases and 51.9 (49.0-56.0) for controls (P = .383). Height and weight of cases and controls were comparable. LIMITATIONS: A parent-completed screening instrument was used. The exclusion of children born at gestational age less than 36 weeks and/or children born small for gestational age partly limits generalizability. CONCLUSION: We found no increased developmental risk or growth impairment at age 4 years in patients with IH treated with propranolol.

Parental experiences with propranolol versus oral corticosteroids for complicated infantile hemangioma, a retrospective questionnaire study.

BACKGROUND: Infantile hemangiomas (IHs) are common and mostly emerge in the head-neck area. Recently, propranolol has been replacing oral corticosteroids (OCS) as the main treatment modality. OBJECTIVES: The aim of this study was to explore the impact of treatment, contentment with treatment outcome and quality of life for families and patients with cervicofacial IHs, treated with propranolol versus OCS. MATERIALS AND METHODS: This study was performed using questionnaires administered by a phone interview. Parents of 16 patients with a cervicofacial IH treated by OCS and 16 patients with an IH of similar localization and overall severity treated with propranolol were interviewed. The questions concerned the impact of treatment at different time periods and the contentment with treatment results. Parents were also asked to give a quality of life (QoL) score (1 to 10) for different time-points. RESULTS: Parents from the OCS group seemed to feel significantly more worried during treatment. Moreover, parents from the propranolol group perceived less negative impact on normal life issues, including work and vaccination of their child. During and after treatment, the parents of propranolol-treated IH patients gave significantly higher QoL scores. CONCLUSION: Propranolol seems to change the impact of IHs, their treatment and the quality of life. Propranolol treatment interferes less with normal issues in daily life, compared to OCS. These findings underline propranolol as the first choice treatment for life- or function-threatening IHs.

Propranolol treatment in life-threatening airway hemangiomas: a case series and review of literature.

OBJECTIVES: Infantile hemangiomas (IHs) in the airway may be potentially life-threatening during the proliferative phase. Available treatments like oral corticosteroids (OCS) and chemotherapeutic agents usually showed variable responses and serious side effects. Propranolol is a new and promising treatment option. METHODS: A case series of five IH patients with airway involvement is presented, supplemented with a review of literature. Propranolol treatment (2.0-3.0mg/kg/day) was initiated between 3 weeks and 6 months of age. Three cases were treated with propranolol monotherapy, 2 cases with OCS primarily and propranolol secondarily, in which treatment with OCS could be reduced rapidly. RESULTS: In our case series a dramatic, fast response was observed in all cases, with a permanent effect after discontinuation in four cases. In one patient a relapse of airway problems occurred two months after discontinuation of propranolol at 16 months of age; this resolved after re-start of propranolol. Review of literature together with these five cases showed 81 patients with airway IHs treated with propranolol. Propranolol was effective in 90% of the cases and seven patients were classified as non-responders. Eight IHs relapsed while weaning of propranolol or after discontinuation; dose adjustment or restart was effective in most cases but one patient appeared resistant to therapy. CONCLUSIONS: Propranolol seems to be a rapidly effective and safe treatment strategy for most IHs obstructing the airway. Because of the fast and important effects of propranolol, randomized controlled trials are hardly justifiable for this specific, relatively rare but, acute treatment indication. Despite the efficacy of propranolol, close monitoring of the patients with an airway IH is required, considering the risk of relapse of symptoms during or after treatment and the reported resistance to propranolol in at least 9% of the published cases. The dose and duration of treatment should be high and long enough to prevent relapse. Further research should focus on the optimal treatment protocol; the actual percentage of non-responders and also the mechanism of resistance to propranolol is unknown and needs to be illuminated.

Kaposiform hemangioendothelioma with Kasabach-Merritt syndrome: a new indication for propranolol treatment.

Kaposiform hemangioendothelioma is a rare vascular tumor in children. Especially, in association with the Kasabach-Merritt Phenomenon it can be life threatening. The management of these patients is very difficult and an aggressive treatment regime is required. Several multimodality and chemotherapeutic regimens have been described but with variable success and many side effects. We present a 6-week-old boy with Kaposiform hemangioendothelioma and Kasabach-Merritt Phenomenon. Ongoing propranolol treatment with only 4 initial courses of vincristine resulted in a remission that lasted at least 1 year.

Propranolol, a very promising treatment for ulceration in infantile hemangiomas: a study of 20 cases with matched historical controls.

BACKGROUND: Ulceration is a common but poorly understood complication of infantile hemangiomas (IH) that is difficult to control. OBJECTIVE: To investigate the possible role of monotherapy with propranolol for ulcerating IH. METHODS: Propranolol was given to 20 patients with IH, who suffered from ulceration at the start of treatment (mean age at onset of treatment, 3.5 months; standard error of the mean: 0.4). After cardiac screening, propranolol was administered in a progressive schedule to 2 to 2.5 mg/kg per day, divided in 3 doses. Blood pressure, heart rate, and fasting glucose levels were monitored during the first 3 days in hospital and, in the absence of complications, treatment was continued at home until the age of approximately 1 year. The 20 propranolol-treated patients were matched to patients from a historical control group, seen before the 'propranolol era'. These matches were randomly made by using clinical pictures based on type, location and size of the IH, extent of ulceration, and age at the start of ulceration. RESULTS: The time to complete healing from the onset of ulceration was significantly shorter for the propranolol-treated patients, compared with the control group (8.7 vs 22.4 weeks; t test: P < .015). In the propranolol group, a tendency to shorter ulceration duration was seen in patients starting propranolol at an earlier stage of disease. LIMITATIONS: The study was limited by the partially retrospective design and the small number of patients. CONCLUSION: Propranolol reduces the duration of ulceration in IH and seems to be more effective when started in an early phase. We propose propranolol as the treatment of first choice for ulcerating IH.