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Figure 1. Teams consulted as part of the protocol before initiation of propranolol hydrochloride therapy (response to “Which of the following providers do you routinely consult as part of workup for propranolol treatment?”).

Figure 1. Teams consulted as part of the protocol before initiation of propranolol hydrochloride therapy (response to “Which of the following providers do you routinely consult as part of workup for propranolol treatment?”).

Figure 2. Monitoring protocols after initiation of propranolol hydrochloride therapy (response to “Which of the following do you routinely monitor after initiation propranolol therapy?”).

Figure 2. Monitoring protocols after initiation of propranolol hydrochloride therapy (response to “Which of the following do you routinely monitor after initiation propranolol therapy?”).

Figure 3. Admission rates after initiation of propranolol hydrochloride therapy (response to “Approximately what percentage of patients do you admit to the hospital for propranolol initiation?”). One survey was incomplete, resulting in 14 respondents.

Figure 3. Admission rates after initiation of propranolol hydrochloride therapy (response to “Approximately what percentage of patients do you admit to the hospital for propranolol initiation?”). One survey was incomplete, resulting in 14 respondents.

Figure 4. Days to the first follow-up visit after initiation of propranolol hydrochloride therapy (response to “How many days after initiating propranolol do your patients typically return for follow-up with either you or another provider?”). One survey was incomplete, resulting in 14 respondents.

Figure 4. Days to the first follow-up visit after initiation of propranolol hydrochloride therapy (response to “How many days after initiating propranolol do your patients typically return for follow-up with either you or another provider?”). One survey was incomplete, resulting in 14 respondents.

Figure 5. Maximum trial time allowed for patients to respond to propranolol hydrochloride therapy (response to “How long would you wait before stopping propranolol treatment if there is no clinical response?”). One survey was incomplete, resulting in 14 respondents.

Figure 5. Maximum trial time allowed for patients to respond to propranolol hydrochloride therapy (response to “How long would you wait before stopping propranolol treatment if there is no clinical response?”). One survey was incomplete, resulting in 14 respondents.

Table. Participating Institutions
Table. Participating Institutions
1.
Perkins JA, Duke W, Chen E, Manning S. Emerging concepts in airway infantile hemangioma assessment and management.  Otolaryngol Head Neck Surg. 2009;141(2):207-212PubMedArticle
2.
Tan ST, Itinteang T, Leadbitter P. Low-dose propranolol for multiple hepatic and cutaneous hemangiomas with deranged liver function.  Pediatrics. 2011;127(3):e772-e776ArticlePubMedArticle
3.
Sciveres M, Marrone G, Pipitone S,  et al.  Successful first-line treatment with propranolol of multifocal infantile hepatic hemangioma with high flow cardiac overload.  J Pediatr Gastroenterol Nutr. 2011;53(6):693-695PubMed
4.
Kim LH, Hogeling M, Wargon O, Jiwane A, Adams S. Propranolol: useful therapeutic agent for the treatment of ulcerated infantile hemangiomas.  J Pediatr Surg. 2011;46(4):759-763PubMedArticle
5.
Fabian ID, Ben-Zion I, Samuel C, Spierer A. Reduction in astigmatism using propranolol as first-line therapy for periocular capillary hemangioma.  Am J Ophthalmol. 2011;151(1):53-58PubMedArticle
6.
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;358(24):2649-2651PubMedArticle
7.
Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action.  Br J Dermatol. 2010;163(2):269-274PubMedArticle
8.
Itinteang T, Brasch HD, Tan ST, Day DJ. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution.  J Plast Reconstr Aesthet Surg. 2011;64(6):759-765PubMedArticle
9.
Cushing SL, Boucek RJ, Manning SC, Sidbury R, Perkins JA. Initial experience with a multidisciplinary strategy for initiation of propranolol therapy for infantile hemangiomas.  Otolaryngol Head Neck Surg. 2011;144(1):78-84PubMedArticle
10.
Dyme JL, Thampan A, Han EJ, Nyirenda TL, Kotb ME, Shin HT. Propranolol for infantile haemangiomas: initiating treatment on an outpatient basis [published online December 14, 2011].  Cardiol YoungArticlePubMed
11.
Goswamy J, Rothera MP, Bruce IA. Failure of propranolol in the treatment of childhood haemangiomas of the head and neck.  J Laryngol Otol. 2011;125(11):1164-1172PubMedArticle
12.
Bernabeu-Wittel J, Pereyra-Rodriguez JJ, Mantrana-Bermejo ME, Fernàndez-Pineda I, de Agustin JC, Conejo-Mir J. Propranolol for the treatment of severe hemangiomas of infancy: results from a series of 28 patients.  Actas Dermosifiliogr. 2011;102(7):510-516Article
13.
Buckmiller L, Dyamenahalli U, Richter GT. Propranolol for airway hemangiomas: case report of novel treatment.  Laryngoscope. 2009;119(10):2051-2054PubMedArticle
14.
Buckmiller LM, Munson PD, Dyamenahalli U, Dai Y, Richter GT. Propranolol for infantile hemangiomas: early experience at a tertiary vascular anomalies center.  Laryngoscope. 2010;120(4):676-681PubMedArticle
15.
Janmohamed SR, Madern GC, de Laat PC, Oranje AP. Haemangioma of infancy: two case reports with an overdose of propranolol.  Case Rep Dermatol. 2011;3(1):18-21PubMedArticle
16.
Breur JM, de Graaf M, Breugem CC, Pasmans SG. Hypoglycemia as a result of propranolol during treatment of infantile hemangioma: a case report.  Pediatr Dermatol. 2011;28(2):169-171PubMedArticle
17.
Zvulunov A, McCuaig C, Frieden IJ,  et al.  Oral propranolol therapy for infantile hemangiomas beyond the proliferation phase: a multicenter retrospective study.  Pediatr Dermatol. 2011;28(2):94-98PubMedArticle
Original Article
February 2013

Propranolol Use for Infantile HemangiomasAmerican Society of Pediatric Otolaryngology Vascular Anomalies Task Force Practice Patterns

Author Affiliations

Author Affiliations: Departments of Otolaryngology–Head and Neck Surgery, Seattle Children's Hospital, University of Washington, Seattle (Drs Parikh, Manning, and Perkins), Children's Hospital of the King's Daughters, Eastern Virginia Medical School, Norfolk (Dr Darrow), and University of Arkansas for Medical Sciences, Little Rock (Dr Richter); and Division of Otolaryngology–Head and Neck Surgery, University of Utah, Salt Lake City (Dr Grimmer).

JAMA Otolaryngol Head Neck Surg. 2013;139(2):153-156. doi:10.1001/jamaoto.2013.1218
Abstract

Importance This study provides multi-institutional practice guidelines for the initiation of propranolol hydrochloride treatment of routine infantile hemangiomas.

Objective To provide information on current propranolol treatment practices for infantile hemangiomas among a cohort of pediatric otolaryngologists.

Design and Setting A survey for initiation of propranolol therapy was created by the American Society of Pediatric Otolaryngology Vascular Anomalies Task Force Subcommittee. After an initial pilot of the survey by 4 task force members, the survey was modified and then distributed by e-mail. Results were transferred to spreadsheet format and analyzed.

Participants All 51 members of the task force.

Results A total of 18 respondents from 15 institutions submitted completed surveys. Data from respondents at the same institution were aggregated and/or averaged to minimize regional bias. Fourteen of 15 responding institutions (93%) treat patients with infantile hemangioma as part of a multidisciplinary vascular anomalies team. Ten institutions (67%) routinely consult cardiology before initiation of propranolol therapy. The median propranolol hydrochloride initiation dosage is 2.00 (mean [SD], 1.65 [0.64]; range, 0.45-2.50) mg/kg/d. Postinitiation monitoring for propranolol therapy includes blood pressure (15 of 15 respondents [100%]), serum glucose levels (7 of 15 [47%]), and pulse oximetry (2 of 15 [13%]). Only 2 institutions routinely admit all patients for initiation of propranolol therapy. Typical duration of therapy ranges from 4 to 8 (5 of 15 [33%]) or 8 to 12 months (10 of 15 [67%]), and cessation of therapy in most cases is based on the clinical response (7 of 14 [50%]) or the age of the patient (6 of 14 [43%]).

Conclusions and Relevance Propranolol is a commonly used medication for the treatment of infantile hemangiomas among otolaryngologists in the Vascular Anomalies Task Force. Propranolol therapy is commonly initiated in the outpatient setting and continued for as long as 12 months.

Infantile hemangiomas (IHs) are benign vascular endothelial tumors that have a typical proliferative phase during infancy followed by an involution phase of variable duration.1 Complications of IH depend on the IH location and can be serious. These complications include airway compromise, vision loss, ulceration, heart failure, and death.25

In 2008, Léauté-Labrèze et al6 described a series of 11 children with cervicofacial IH whose lesions were observed to respond to propranolol hydrochloride. Since that landmark description, propranolol has gained rapid popularity as the treatment of choice for IH. Léauté-Labrèze et al6 described using a propranolol hydrochloride dosage of 2.00 mg/kg/d in 3 divided doses. They also suggested that the mechanism of response was through downregulation of endothelial growth factors. Several proposed mechanisms of action include downregulation of angiogenesis, apoptosis of angiogenesis cell signaling, and vasoconstriction.7,8 The exact mechanism of action remains unknown.

Although propranolol has become widely popular as a medical therapy for IH, no consensus exists on indications, initiation workup, dosing, or safety. One report of a strategy for propranolol therapy initiation exists, which was multidisciplinary and largely outpatient based.9 In this report, all patients underwent a cardiology evaluation but were admitted for initiation only if they had known airway compromise, cardiac dysfunction, or predisposition to neurological compromise. Other reports of outpatient propranolol management have also been published.10

The optimal dosing, timing, and duration of treatment remain unknown. Some reports have described rebound growth of hemangiomas after stopping propranolol therapy.11 Furthermore, reported response rates have ranged from 50% to 88%.1214

The safety profile of propranolol is largely based on pediatric experience for cardiovascular disease. As a nonselective β-blocker, the drug has the potential to cause bradycardia, bronchospasm, and/or hypotension.15 In addition, a risk of hypoglycemia exists, although the exact mechanism of action is not known.16

In 2001, a group of American Society of Pediatric Otolaryngology (ASPO) members formed the ASPO Vascular Anomalies Task Force. This group of otolaryngologists from the United States and Canada meets twice a year to share experiences and discuss personal outcomes using different treatment modalities for vascular anomalies. Since 2008, propranolol has gained widespread acceptance within this group as an off-label therapeutic modality for IH. However, at a recent meeting of the task force, no strong consensus resulted regarding the principles for initiation and maintenance of propranolol therapy. We undertook the present survey of the task force members to gain insight into current propranolol therapy protocols among pediatric otolaryngologists.

METHODS

Study data were collected and managed using REDCap (Research Electronic Data Capture) tools hosted at a single institution. The REDCap system is a secure, web-based application designed to support data capture for research studies. It is hosted by Vanderbilt University (more information is available at http://www.project-redcap.org/). The tools provide (1) an intuitive interface for validated data entry, (2) audit trails for tracking data manipulation and export procedures, (3) automated export procedures for seamless data downloads to common statistical packages, and (4) procedures for importing data from external sources. Four task force members at 4 different institutions performed the initial pilot survey. Comments and suggestions were incorporated into a second revised survey that was sent to all task force members. Final survey data were exported to a spreadsheet (Excel; Microsoft Corp) from the REDCap software. Data were analyzed with descriptive statistics. Data from the same institutions were averaged to avoid institutional bias.

RESULTS

Of the 51 task force members, a total of 18 respondents from 15 institutions submitted completed surveys (Table). Data from respondents at the same institutions were averaged so as to minimize regional bias, leaving 15 respondents for analysis. Fourteen respondents submitted complete surveys, and 1 respondent submitted a partial survey. Fourteen of the 15 institutions (93%) treat patients with IH as part of a multidisciplinary vascular anomalies team. Cardiology consultation is routinely sought in 10 of the 15 institutions (67%) before initiation of propranolol therapy (Figure 1). An electrocardiogram is obtained at 14 of the 15 institutions (93%) before commencing propranolol therapy. The median propranolol initiation dose is 2.00 (mean [SD], 1.65 [0.64]; range 0.45-2.50) mg/kg/d. Dosing intervals of propranolol are 2 times a day (7 of 15 respondents [47%]) or 3 times a day (8 of 15 [53%]). Postinitiation monitoring includes blood pressure (15 of 15 [100%]), serum glucose levels (7 of 15 [47%]), and pulse oximetry (2 of 15 [13%]) (Figure 2). Only 2 institutions routinely admit 100% of their patients for monitoring, whereas rates of admission vary among the other institutions (Figure 3). Typical duration of therapy ranges from 4 to 8 months (5 of 15 [33%]) or 8 to 12 months (10 of 15 [67%]) and rarely represented the main factor used to decide to stop therapy (1 of 14 [7%]; 1 survey was incomplete). Typical cessation of therapy is based on the clinical response (7 of 14 [50%]) or the age of thepatient (6 of 14 [43%]). The first outpatient follow-up visit ranges from 3 to 30 days with a median of 7 days (Figure 4). The dosage reported as usually effective ranges from 2.00 mg/kg/d by 12 respondents to 2.50 and 3.00 mg/kg/d by 1 respondent each. The maximum dosage respondents are willing to administer are 2.00 (3 respondents), 2.50 (1 respondent), 3.00 (7 respondents), 4.00 (2 respondents), and 6.00 (1 respondent) mg/kg/d. The duration of propranolol therapy allowed for IH regression before the patient is deemed a nonresponder ranges from 2 to 12 weeks (Figure 5).

COMMENT

Among members of the ASPO Vascular Anomalies Task Force, propranolol has emerged as a common agent for IH treatment. Precise therapeutic indications, dosing, outcome measures, and the safety profile are yet to be determined. We initiated this survey to gain an understanding of the current treatment algorithms used by otolaryngologists treating IH. Although not designed to be a clinical practice guideline, this study acquaints interested clinicians with the variety of current treatment philosophies.

Propranolol therapy may be initiated on an inpatient or an outpatient basis. Our survey suggests that most centers (13 of 15) treat selected patients with uncomplicated disease courses on an outpatient basis. Only 2 of the 15 centers admit all patients for initiation of propranolol therapy. Although not specifically addressed in this study, many clinicians consider admission for infants younger than 2 months (or premature infants [<48 weeks after conception]), those with cardiovascular or respiratory comorbidities, those with disorders of glucose maintenance, and those whose caregivers may be unable to provide the necessary monitoring and support at home.

In this study, all 15 centers monitor blood pressure after the initiation of propranolol therapy, whereas fewer than half monitor blood glucose levels, electrocardiography, or pulse oximetry. Although we did not study respondents' preferred time to initiate monitoring after starting propranolol therapy, many clinicians advocate giving the first outpatient dose and any dose increases in a setting in which heart rate and blood pressure may be checked 1 to 2 hours after administration. Adverse effects, such as bradycardia and hypotension, are usually apparent after the initial dose, and we remain unclear on whether admission provides timelier and safer treatment of these adverse effects.

From this survey, we discovered that most of the responding institutions initiate propranolol hydrochloride therapy at a dosage of 2.00 mg/kg/d as initially described by Léauté-Labrèze et al.6 The ideal dosing interval remains unknown, but all study responders administer doses 2 or 3 times a day. Although the plasma half-life of propranolol is approximately 4 to 6 hours, its duration of action is 6 to 12 hours depending on the dose.

Although most IHs have completed 80% of their growth before the patient is 6 months of age, the proliferative growth phase may continue through the first year of life.17 As a result, some responders base the duration of therapy on patient age, whereas others use the patient's clinical response. In addition, although systemic corticosteroid therapy is thought to be effective only during active proliferation of the hemangiomas, propranolol might be effective in other phases of the hemangioma growth cycle also. Termination of propranolol therapy may be appropriate once the proliferative phase is thought to be complete, with careful observation for evidence of additional growth. Because of the potential for rebound growth, tapering of therapy may be advisable. Our study could not establish whether the response to propranolol is dose-dependent.

As the primary strength of this study, we report the first survey of propranolol therapy initiation practices among otolaryngologists with a special interest in IH. Although the study is strictly descriptive, understanding current treatment practices across North America within a single specialty is of value. With a lack of control or statistical analysis, this study has an inherent weakness with regard to power and statistically based conclusions. In addition, our study had a low response rate that may be attributed to avoidance of redundant responses from the same institution, noncompletion of the survey by members who treat vascular anomalies other than hemangiomas, and/or disinterest in survey studies. As a whole, however, this survey allows us to conclude that propranolol is being used as the primary systemic therapy for IH within a narrow range for dose and frequency of therapy and that most institutions initiate such therapy on an outpatient basis for most of their patients.

In conclusion, propranolol is commonly used as medical therapy for the treatment of IHs among otolaryngologists in the ASPO Vascular Anomalies Task Force. To our knowledge, this is the first survey of the initiation of propranolol treatment practices for the management of IHs.

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Article Information

Correspondence: Sanjay R. Parikh, MD, Department of Otolaryngology–Head and Neck Surgery, Seattle Children's Hospital, 4800 Sand Point Way NE, W-7729, Seattle, WA 98105 (sanjay.parikh@seattlechildrens.org).

Submitted for Publication: May 16, 2012; final revision received August 13, 2012; accepted October 19, 2012.

Author Contributions: Drs Parikh, Richter, and Perkins had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Parikh, Darrow, Grimmer, Manning, and Perkins. Acquisition of data: Parikh, Grimmer, and Richter. Analysis and interpretation of data: Parikh, Manning, Richter, and Perkins. Drafting of the manuscript: Parikh and Richter. Critical revision of the manuscript for important intellectual content: Parikh, Darrow, Grimmer, Manning, and Perkins. Statistical analysis: Parikh and Richter. Administrative, technical, and material support: Manning and Richter. Study supervision: Manning and Perkins.

Conflict of Interest Disclosures: None reported.

Previous Presentation: This study was presented at the 2012 Annual Meeting of the American Society for Pediatric Otolaryngology; April 22, 2012; San Diego, California.

REFERENCES
1.
Perkins JA, Duke W, Chen E, Manning S. Emerging concepts in airway infantile hemangioma assessment and management.  Otolaryngol Head Neck Surg. 2009;141(2):207-212PubMedArticle
2.
Tan ST, Itinteang T, Leadbitter P. Low-dose propranolol for multiple hepatic and cutaneous hemangiomas with deranged liver function.  Pediatrics. 2011;127(3):e772-e776ArticlePubMedArticle
3.
Sciveres M, Marrone G, Pipitone S,  et al.  Successful first-line treatment with propranolol of multifocal infantile hepatic hemangioma with high flow cardiac overload.  J Pediatr Gastroenterol Nutr. 2011;53(6):693-695PubMed
4.
Kim LH, Hogeling M, Wargon O, Jiwane A, Adams S. Propranolol: useful therapeutic agent for the treatment of ulcerated infantile hemangiomas.  J Pediatr Surg. 2011;46(4):759-763PubMedArticle
5.
Fabian ID, Ben-Zion I, Samuel C, Spierer A. Reduction in astigmatism using propranolol as first-line therapy for periocular capillary hemangioma.  Am J Ophthalmol. 2011;151(1):53-58PubMedArticle
6.
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;358(24):2649-2651PubMedArticle
7.
Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action.  Br J Dermatol. 2010;163(2):269-274PubMedArticle
8.
Itinteang T, Brasch HD, Tan ST, Day DJ. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution.  J Plast Reconstr Aesthet Surg. 2011;64(6):759-765PubMedArticle
9.
Cushing SL, Boucek RJ, Manning SC, Sidbury R, Perkins JA. Initial experience with a multidisciplinary strategy for initiation of propranolol therapy for infantile hemangiomas.  Otolaryngol Head Neck Surg. 2011;144(1):78-84PubMedArticle
10.
Dyme JL, Thampan A, Han EJ, Nyirenda TL, Kotb ME, Shin HT. Propranolol for infantile haemangiomas: initiating treatment on an outpatient basis [published online December 14, 2011].  Cardiol YoungArticlePubMed
11.
Goswamy J, Rothera MP, Bruce IA. Failure of propranolol in the treatment of childhood haemangiomas of the head and neck.  J Laryngol Otol. 2011;125(11):1164-1172PubMedArticle
12.
Bernabeu-Wittel J, Pereyra-Rodriguez JJ, Mantrana-Bermejo ME, Fernàndez-Pineda I, de Agustin JC, Conejo-Mir J. Propranolol for the treatment of severe hemangiomas of infancy: results from a series of 28 patients.  Actas Dermosifiliogr. 2011;102(7):510-516Article
13.
Buckmiller L, Dyamenahalli U, Richter GT. Propranolol for airway hemangiomas: case report of novel treatment.  Laryngoscope. 2009;119(10):2051-2054PubMedArticle
14.
Buckmiller LM, Munson PD, Dyamenahalli U, Dai Y, Richter GT. Propranolol for infantile hemangiomas: early experience at a tertiary vascular anomalies center.  Laryngoscope. 2010;120(4):676-681PubMedArticle
15.
Janmohamed SR, Madern GC, de Laat PC, Oranje AP. Haemangioma of infancy: two case reports with an overdose of propranolol.  Case Rep Dermatol. 2011;3(1):18-21PubMedArticle
16.
Breur JM, de Graaf M, Breugem CC, Pasmans SG. Hypoglycemia as a result of propranolol during treatment of infantile hemangioma: a case report.  Pediatr Dermatol. 2011;28(2):169-171PubMedArticle
17.
Zvulunov A, McCuaig C, Frieden IJ,  et al.  Oral propranolol therapy for infantile hemangiomas beyond the proliferation phase: a multicenter retrospective study.  Pediatr Dermatol. 2011;28(2):94-98PubMedArticle
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