Nancy M. Bauman

Initiation and Use of Propranolol for Infantile Hemangioma: Report of a Consensus Conference

Infantile hemangiomas (IHs) are common neoplasms composed of proliferating endothelial-like cells. Despite the relative frequency of IH and the potential severity of complications, there are currently no uniform guidelines for treatment. Although propranolol has rapidly been adopted, there is significant uncertainty and divergence of opinion regarding safety monitoring, dose escalation, and its use in PHACE syndrome (PHACE = posterior fossa, hemangioma, arterial lesions, cardiac abnormalities, eye abnormalities; a cutaneous neurovascular syndrome characterized by large, segmental hemangiomas of the head and neck along with congenital anomalies of the brain, heart, eyes and/or chest wall). A consensus conference was held on December 9, 2011. The multidisciplinary team reviewed existing data on the pharmacologic properties of propranolol and all published reports pertaining to the use of propranolol in pediatric patients. Workgroups were assigned specific topics to propose protocols on the following subjects: contraindications, special populations, pretreatment evaluation, dose escalation, and monitoring. Consensus protocols were recorded during the meeting and refined after the meeting. When appropriate, protocol clarifications and revision were made and agreed upon by the group via teleconference. Because of the absence of high-quality clinical research data, evidence-based recommendations are not possible at present. However, the team agreed on a number of recommendations that arose from a review of existing evidence, including when to treat complicated IH; contraindications and pretreatment evaluation protocols; propranolol use in PHACE syndrome; formulation, target dose, and frequency of propranolol; initiation of propranolol in infants; cardiovascular monitoring; ongoing monitoring; and prevention of hypoglycemia. Where there was considerable controversy, the more conservative approach was selected. We acknowledge that the recommendations are conservative in nature and anticipate that they will be revised as more data are made available.

Management of pediatric orbital cellulitis and abscess.

Purpose of reviewOrbital cellulitis and abscess formation in pediatric patients usually arises as a complication of acute sinusitis and if untreated may cause visual loss or life-threatening intracranial complications. This review describes the current evaluation and management of this condition. Recent findingsComputed tomography with contrast remains the optimal imaging study for orbital inflammation. Orbital inflammation is still classified by Chandlers original description as preseptal or postseptal and nearly all cases of preseptal cellulitis are managed with oral antibiotics. Most cases of postseptal cellulitis are managed with intravenous antibiotics, although surgical therapy is required for some abscesses, particularly large ones. Patients under 9 years respond to medical management more frequently than older patients but recent studies confirm that even children over 9 with small or moderate-sized abscesses and normal vision deserve a medical trial before surgical intervention. Medial subperiosteal abscesses that fail medical therapy are usually drained endoscopically, whereas lateral or intraconal abscesses require an open procedure. SummaryPeriorbital complications of sinusitis in pediatric patients often respond to medical therapy but may require surgical intervention to prevent serious complications. Continuous in-house evaluation of patients is necessary to observe for progression of symptoms and to optimize outcome.

Management of pediatric orbital cellulitis in patients with radiographic findings of subperiosteal abscess

Objective: Controversies remain regarding the management of orbital cellulitis (OC). The objective of this study was to examine the outcomes of patients admitted to our institution for orbital cellulitis during a 7-year period. Study Design: Case series with chart review. Setting: Tertiary referral pediatric hospital. Subjects and Methods: Charts of 465 consecutive OC admissions were reviewed for presentation, imaging, medical and surgical treatment, and outcome. Results: Of these patients, 189 were treated in the emergency room and 276 were admitted. CT scan was performed on 240 patients. Subperiosteal abscess (SPA) was noted in 68 patients. Of these, 47 were treated medically and 21 had surgery. Surgical patients were older (8.3 vs 6.2 years, P = 0.039), had larger abscesses (>10 mm, P < 0.001), required a longer admission (10.2 vs 6.6 days, P < 0.001), and had higher temperatures on admission (38.0°C vs 37.3°C, P = 0.03). Conclusion: The majority of small SPAs as diagnosed on CT scans in younger children can be successfully treated medically. Surgery, however, should be considered for a worsening clinical examination. Our findings confirm those of previous reports on this clinical entity.

Propranolol vs prednisolone for symptomatic proliferating infantile hemangiomas: A randomized clinical trial

IMPORTANCE While propranolol is touted as superior to prednisolone for treating infantile hemangiomas (IH), a randomized clinical trial (RCT) comparing the outcome and tolerability of these medications for symptomatic, proliferating IH has not been reported. OBJECTIVES To determine if oral propranolol is more efficacious and better tolerated than prednisolone in treating symptomatic, proliferating IH and to determine the feasibility of conducting a multi-institutional, RCT comparing efficacy and tolerability of both medications. DESIGN, SETTING, AND PARTICIPANTS Phase 2, investigator-blinded, multi-institutional RCT conducted in 3 academic vascular anomalies clinics on 19 of 44 eligible infants aged between 2 weeks and 6 months. All participating patients had symptomatic proliferating IH treated between September 1, 2010, and August 1, 2012. INTERVENTIONS Treatment with oral propranolol vs prednisolone (2.0 mg/kg/d) until halted owing to toxic effects or clinical response. MAIN OUTCOMES AND MEASURES Primary outcome was change in IH size after 4 months of therapy. Secondary outcomes were response rate and frequency and severity of adverse events (AEs). RESULTS The primary outcome showed no difference in lesion size or affected skin area after 4 months of therapy: 41% and 1.32 mm2 for prednisolone vs 64% and 0.55 mm2 for propranolol (P = .12 for lesion size, and P = .56 for affected skin area). Longitudinal analyses showed a faster response in total lesion outer dimension with prednisolone (P = .03), but this advantage over time was not noted when central clearing and outer dimension were included in the analysis (P = .91). The overall frequency of AEs was similar (44 for prednisolone vs 32 for propranolol) (P = .84), but prednisolone-treated participants had more grade 3 severe AEs (11 vs 1) (P = .01), particularly growth retardation resulting in size and weight below the fifth percentile. Early study withdrawal owing to AEs occurred in 6 (75%) of 8 patients in the prednisolone group but 0 of 11 propranolol-treated participants. The mean duration of therapy was shorter for prednisolone (141 vs 265 days), reflecting the higher rate of early withdrawals. CONCLUSIONS AND RELEVANCE Both medications show similar efficacy for reducing the area of symptomatic, proliferating IH. Although prednisolone showed a faster response rate, propranolol was better tolerated with significantly fewer severe AEs. Propranolol should be the first line of therapy for symptomatic IH unless contraindicated or unless future studies demonstrate severe AEs from propranolol. Recruiting participants for a phase 3 RCT would be difficult owing to safety profiles measured here and emerging trends favoring propranolol. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00967226.

Standardized Outcome and Reporting Measures in Pediatric Head and Neck Lymphatic Malformations

Objective To develop general and site-specific treatment effect and outcome measures to standardize the reporting of head and neck lymphatic malformation (HNLM) treatments. Study Design Consensus statement/expert opinion. Setting Multiple tertiary academic institutions. Subjects and Methods The modified Delphi method is an iterative process of collecting expert opinions, refining opinions through discussion and feedback, statistically aggregating opinions, and using these aggregates to generate consensus opinion in the absence of other data. The modified Delphi method was used by a multi-institutional group of otolaryngology and interventional radiology experts in the field of vascular anomalies to formulate a list of recommended reporting outcomes for the study and treatment of head and neck lymphatic malformations. Results Through 3 rounds of iteration, 10 expert panelists refined 98 proposed outcome measures and 9 outcome categories to a final consensus set of 50 recommended outcome measures in 3 global categories (general, demographics, and treatment complications) and 5 site-specific categories (orbit, oral cavity, pharynx, larynx, and neck). Conclusions We propose the first consensus set of standardized reporting measures for clinical and treatment outcomes in studies of HNLMs. Consistent outcome measures across future studies will facilitate comparison of treatment options and allow systematic review. We hope that these guidelines facilitate the design and reporting of subsequent HNLM studies.

Cardiovascular and blood glucose parameters in infants during propranolol initiation for treatment of symptomatic infantile hemangiomas.

Objectives: We sought to determine the effect of propranolol on cardiovascular and blood glucose parameters in infants with symptomatic infantile hemangiomas who were hospitalized for initiation of treatment, and to analyze adverse effects of propranolol throughout the course of inpatient and outpatient treatment. Methods: A retrospective cohort analysis was performed on 50 infants (age less than 12 months) with symptomatic infantile hemangiomas who were hospitalized for propranolol initiation between 2008 and 2012. Demographic data and disease characteristics were recorded. Systolic and diastolic blood pressures, heart rate, blood glucose values, and adverse events recorded during hospitalization were analyzed. An additional cohort of 200 consecutively treated children was also assessed for adverse events associated with outpatient propranolol use. Results: The median age among the inpatient cohort was 3.4 months (range, 0.8 to 12.0 months). Infants older than 6 months were more likely to exhibit bradycardia than were younger infants (p < 0.001). Hypotensive and/or bradycardic periods were infrequent and were not associated with observable clinical symptoms. The mean systolic and diastolic blood pressures and the mean heart rate decreased significantly from day 1 of hospitalization to day 2 (p = 0.004; p = 0.008; p < 0.001), but not from day 2 to day 3, when the propranolol dose was increased to target. Hypoglycemia was rare (0.3% incidence.) Among the 250 outpatients, 2 infants developed lethargy and hypoglycemia during a viral illness and recovered without sequelae. One infant experienced recurrent bronchospasm with viral illnesses and required concomitant bronchodilator therapy. Conclusions: Frequent deviations from normal ranges of blood pressure and heart rate occur upon initiation of propranolol, but are clinically asymptomatic. These findings support that outpatient initiation of propranolol in healthy, normotensive infants appears to be a relatively safe alternative to inpatient initiation. Hypoglycemia is rare, but can occur throughout the treatment period; parent counseling is of paramount importance.

Unexpected pathologies in pediatric parotid lesions: Management paradigms revisited

OBJECTIVES To present case vignettes of unusual pediatric parotid pathologies and discuss management paradigms in the context of these lesions. STUDY DESIGN Retrospective case series. SETTING Free-standing, academic tertiary care pediatric hospital. METHODS All patients over the past 18 months undergoing parotidectomy for a parotid mass were reviewed (N=5). RESULTS Ages ranged from 17 months to 16 years. All presented with a remarkably similar clinical course, consisting of a persistent parotid mass for more than 3 months which was usually painless. Most (4/5 patients) had been treated with antibiotics prior to Otolaryngology consultation. Fine-needle aspiration (FNA) was performed on 3 patients and was diagnostic in one. Complete excision of the mass was performed in each child through a parotidectomy approach (3 total, 2 lateral lobe). The final pathology showed metastatic neuroblastoma (17 months old), undifferentiated primitive sarcoma (22 months old), mucoepidermoid carcinoma (11 years old), nodular fasciitis (12 years old), and hyperplastic lymph node (16 years old). The patient with neuroblastoma died from complications of bone marrow transplant. CONCLUSIONS The differential diagnosis for a persistent pediatric parotid mass is expansive and differs from that found in the adult population. As this series highlights, in many cases, it is impossible to discern the pathology, or rule out malignancy, based upon the clinical course, imaging, or FNA results. Surgical excision remains the standard for management of these patients and is both diagnostic and therapeutic. Our anecdotal case series highlights the importance of having a low threshold for parotidectomy in these children.

Propranolol-Mediated Attenuation of MMP-9 Excretion in Infants With Hemangiomas

IMPORTANCE Infantile hemangiomas (IHs) vary substantially in localization and extent of tissue involvement, but IH biological progression is remarkably unique and predictable. Propranolol is an effective treatment for symptomatic IH, but its mechanism of action remains unknown and understudied. OBJECTIVE To compare excreted proteins in infants with IH being treated with propranolol vs prednisolone. DESIGN, SETTING, AND PARTICIPANTS Exploratory urine proteomics profiling of patients with IH from July 2010 to September 2012 at a tertiary pediatric hospital. Participants were infants with IH treated at our institution who were participating in a blinded, randomized trial comparing prednisolone vs propranolol. They ranged in age from 14 days to 15 months at enrollment. Exclusion criteria included a history of diabetes mellitus, asthma, and/or cardiovascular disease including hypertension or hypotension. Urine samples were longitudinally collected from all participants. Specimens were desalted, concentrated, and gel fractionated, and the protein content was identified using liquid chromatography tandem mass spectrometry. Western blot analyses and enzyme-linked immunosorbent assays (ELISAs) were performed to validate mass spectrometry findings. INTERVENTION Treatment with propranolol or prednisolone administered starting before the age of 6 months. MAIN OUTCOMES AND MEASURES Proteins present in urine samples and change in urinary levels of proteins over time. RESULTS Samples were obtained from 3 patients treated with prednisolone, 3 patients treated with propranolol, and 5 untreated controls with IH. More than 1000 urinary proteins were identified by proteomics. Patients treated with propranolol demonstrated attenuation of excreted matrix metalloproteinase 9 (MMP-9) in urine over the proliferative phase of the condition compared with prednisolone-treated patients. These findings were validated with Western blot analysis and quantified with ELISA, which confirmed mean urinary MMP-9 levels in the first year of life to be significantly lower in propranolol-treated patients with IH compared with prednisolone-treated patients with IH (0.118 vs 0.501 ng/mL; P = .03) or with nontreated patients with IH (0.118 vs 3.69 ng/mL; P = .02). CONCLUSIONS AND RELEVANCE Propranolol treatment decreases urinary excretion of MMP-9 in patients with IH. Matrix metalloproteinase 9 may be a biomarker for IH propranolol responsiveness, and its signaling pathways may represent the molecular target of this drug.

How should propranolol be initiated for infantile hemangiomas: inpatient versus outpatient?

BACKGROUND Infantile hemangiomas (IH) show a characteristic growth pattern of proliferation and eventual involution during the first decade of life, and may be isolated lesions or part of a constellation of findings such as “PHACEs” (posterior fossa abnormalities, hemangioma, arterial lesions, cardiac and eye anomalies). Two-thirds of IH occur in the head and neck, and otolaryngologists are frequently asked to manage such lesions. While partial or complete involution is the expected natural outcome, 12% of IH require therapy during infancy to hasten involution. There is no FDA-approved treatment of IH, and management is largely based on expert opinion and observational studies. Propranolol’s efficacy in treating IH has virtually supplanted the traditional use of corticosteroids, largely due to the side effects associated with prolonged corticosteroid therapy. In support of this paradigm shift, preliminary results of the only prospective, randomized controlled study comparing propranolol to prednisolone show similar efficacy but significantly fewer serious adverse events (AEs) from propranolol (unpublished data). Recognizing that propranolol is not FDA approved for any pediatric indication, this article reviews the current practice of use for IH, focusing on pretreatment screening, outpatient versus inpatient initiation, dosing, use in PHACEs, and monitoring for AEs. LITERATURE REVIEW Propranolol is a nonselective beta-adrenergic antagonist with a favorable safety profile for use in the pediatric population akin to that in adults. Menezes noted an 18% incidence of AEs upon review of all series reporting 10 patients with IH who were treated with propranolol. AEs reported in another review of 1,175 patients with IH include sleep disturbances (3.7%), asymptomatic or unspecified hypotension (2.8%), somnolence (2.2%), cool or mottled extremities (1.7%), pulmonary symptoms including wheezing (1.4%), asymptomatic or unspecified bradycardia (0.9%), hypoglycemia (0.9%), gastroesophageal reflux or gastrointestinal upset (0.7%), symptomatic hypotension (0.3%), and symptomatic bradycardia (0.1%) (Table 1). While AEs are generally not life-threatening, the most concerning are those affecting blood glucose and the cardiac system. Much debate exists regarding whether propranolol for IH should be initiated on an inpatient basis or on an outpatient monitored basis. Proponents of outpatient initiation cite propranolol’s long track record of safe use in patients with cardiac indications, while inpatient proponents caution that such data cannot be extrapolated to patients with IH. In a review of over 50 infants with IH admitted for propranolol therapy, all had at least one low systolic or diastolic blood pressure (BP) recording and two-thirds had at least one simultaneous low systolic and diastolic BP measure, with 14% having concomitant bradycardia. Despite the high frequency of events, all were asymptomatic and none warranted a change in medication dosing. Propranolol’s greatest effect on BP occurs with the initial dose and peaks 2 hours after an oral dose, which serves as a valuable guideline for monitoring. Hypoglycemia is a well-recognized AE that is dose independent, and if severe may induce seizure activity. The mechanism is thought secondary to beta blockade of glucose mobilization during fasting states, and reports are nearly always associated with concomitant infection and/ or poor oral intake. Beta blockade may induce bronchoconstriction, particularly during respiratory illnesses. The lack of consensus regarding pretreatment workup, initiation, and dosing of propranolol for IH led to a multidisciplinary consensus conference to review all data and establish best practice guidelines. (NIHNIAMS-1R34AR060881). The team of 28 experts from From the Division of Otolaryngology (N.J.P.); and the Division of Otolaryngology, Children’s National Medical Center (N.M.B.), George Washington University, Washington, DC, U.S.A. Editor’s Note: This Manuscript was accepted for publication on July 25, 2013. Dr. Bauman receives National Institutes of Health (NIH) salary support for study of this topic (ClinicalTrials.gov identifiers: NCT00967226, NICHD, 5R21HD062959). The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Nancy M. Bauman, MD, FACS, FAAP, Children’s National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010. E-mail: nbauman@cnmc.org

Social Impact of Facial Infantile Hemangiomas in Preteen Children

IMPORTANCE Involuted infantile facial hemangiomas (IHs) may adversely affect the social skills of children. OBJECTIVE To assess the social impact of involuted facial IHs, with or without prior treatment, in preteen children. DESIGN, SETTING, AND PARTICIPANTS An observational, cross-sectional study of social anxiety and skills in preteen children with facial IHs diagnosed during infancy. The study took place in an academic institution and a community dermatology practice between January 1, 2013, and July 30, 2014. Records on 236 children with IHs located in a cosmetically sensitive area were identified; of those, 144 potential participants (parents) were reached by telephone and mailed study packets. Thirty completed questionnaires were returned. Data analysis was performed from August 1, 2014, to September 7, 2015. INTERVENTIONS The questionnaires included the following psychiatric scales: (1) Social Anxiety Scale for Children-Revised (SASC-R), completed by parents and children, including the domains of Fear of Negative Evaluation and Social Avoidance/Distress in New Situations (SAD-New) (higher scores indicate greater social anxiety), and (2) Social Competency Inventory (SCI), completed by parents, including the domains of Prosocial Behavior and Social Initiative (lower scores indicate poorer social competency). MAIN OUTCOMES AND MEASURES Demographics, clinical details, and survey responses were collected. Analysis was conducted using t tests to compare scores for each survey domain with established normative data and between sex as well as between treatment vs nontreatment groups. RESULTS Of the 144 potential participants, 30 (21%) responded. The mean age of the preteen subjects was 10.0 years (range, 5.4-12.9 years) with a 2:1 female to male ratio. Twenty-five children (83%) had a single IH, and the remaining 5 participants (17%) had multiple IHs, with at least 1 IH in a cosmetically sensitive area. The periocular region was the most common site of the IH (10 [33%]), followed by the nose (6 [20%]), cheek (5 [17%]), forehead (4 [13%]), lip or perioral region (4 [13%]), and ear (1 [3%]). Eighteen children (60%) had received treatment for their IH. With results reported as mean (SD), the SASC-R test showed that social anxiety of the children was not increased over normative data; however, those who did not receive IH treatment had significantly greater anxiety for new situations compared with those who received treatment (SAD-New: 15.5 [5.1] vs 11.5 [3.8]; P = .02). Results of the SCI scale indicated that the Prosocial Orientation domain score for the children was similar to normative data (3.96 [0.48] vs 3.89 [0.55], P = .50). Social Initiative domain scores were significantly poorer in children who did not receive treatment vs those who received treatment (3.45 [0.43] vs 4.03 [0.55]; P = .006). CONCLUSIONS AND RELEVANCE Preteen children with involuted, untreated facial IHs have higher Social Anxiety domain scores in new situations and decreased Social Initiative domain scores compared with children who receive treatment for facial IH. Although this study is limited by a small sample size, it raises important considerations for whether early treatment of facial IHs in cosmetically sensitive areas has a beneficial effect on social skills in preteens.