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Education & Practice Online First, published on November 15, 2013 as 10.1136/archdischild-2013-305027 GUIDELINE REVIEW
Propranolol for infantile haemangiomas: review of report of a consensus conference Lauren Biesbroeck,1 Heather A Brandling-Bennett2 1
Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington, USA 2 Division of Dermatology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, Washington, USA Correspondence to Dr Heather A Brandling-Bennett, Division of Dermatology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, 4800 Sand Point Way NE, M/S OC.9.835, Seattle, WA 98105, USA; heather.brandlingbennett@ seattlechildrens.org Received 6 August 2013 Revised 16 October 2013 Accepted 27 October 2013
INTRODUCTION Infantile haemangiomas (IHs) are common benign vascular tumours of infancy, most of which do not require treatment. Complications for which treatment is indicated include impairment of vital function by ocular or airway involvement, potential to cause significant disfigurement, and ulceration. Case reports, case series and anecdotal experience since 2008 have established that propranolol is a rapidly effective and generally welltolerated treatment for IHs in comparison with previously available therapies such as corticosteroids, vincristine and interferon.1–4 Recently published recommendations provide a provisional set of best practices meant to standardise the approach to the use of propranolol for IHs (see box 1). INFORMATION ABOUT CURRENT RECOMMENDATIONS In January 2013, a multispecialty group sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases published consensus recommendations entitled: ‘Initiation and use of propranolol for infantile hemangioma: Report of a consensus conference.’5 The goal of the conference was ‘to develop a standardised, consensus-derived set of best practices for the use of propranolol in infants with infantile hemangioma.’ In all, 28 participants from five specialties (including paediatrics, dermatology, otolaryngology, cardiology, haematology/ oncology) and 12 US institutions
To cite: Biesbroeck L, Brandling-Bennett HA. Arch Dis Child Educ Pract Ed Published Online First: [ please include Day Month Year] doi:10.1136/archdischild2013-305027
Box 1
Resources
▸ http://pediatrics.aappublications.org/ content/131/1/128 Link to full guideline
participated in the conference. These participants reviewed the available literature on propranolol use for IH and developed consensus protocols. PREVIOUS GUIDELINE There are no previous guidelines published regarding the use of propranolol for IH. CONTROVERSIAL AND KEY ISSUES THAT THE RECOMMENDATIONS ADDRESS ▸ Consider treatment of IH with propranolol when the following are present: ulceration, impairment of vital function (ocular compromise or airway obstruction) or risk of permanent disfigurement. ▸ Box 2 delineates recommendations for pretreatment evaluation. ▸ Contraindications for the use of propranolol include: cardiogenic shock, sinus bradycardia, hypotension, heart block (greater than first degree), heart failure, asthma and hypersensitivity to propranolol. ▸ All infants with large facial haemangiomas should be thoroughly evaluated for PHACE syndrome (see box 3). This workup should include MRI/MRA of head and neck, as
Box 2
Pretreatment evaluation
▸ Thorough history and physical examination, with emphasis on cardiac and pulmonary systems. ▸ ECG if one or more of the following: – Heart rate is below normal for age. – Patient or family history of congenital heart disease or arrhythmias. – Maternal history of connective tissue disease. – Arrhythmia detected on exam. ▸ Echocardiogram is only necessary if exam findings are abnormal.
Biesbroeck L, et al. Arch Dis Child Educ Pract Ed 2013;0:1–3. doi:10.1136/archdischild-2013-305027 1 Copyright Article author (or their employer) 2013. Produced by BMJ Publishing Group Ltd under licence.
Downloaded from ep.bmj.com on August 20, 2014 - Published by group.bmj.com
Guideline review Box 3
PHACE syndrome
Box 4 Clinical bottom line
▸ P: Posterior fossa abnormalities, such as Dandy– Walker malformation, cerebellar hypoplasia or other structural abnormalities. ▸ H: Haemangioma, typically segmental facial haemangioma >5 cm in diameter. ▸ A: Arterial abnormalities, typically stenotic, dysplastic, hypoplastic, aberrant, or non-visualised cerebral or cervical vessels. ▸ C: Cardiac abnormalities, including coarctation of the aorta, ventricular or atrial septal defects. ▸ E: Eye abnormalities, such as hypoplastic optic nerve or vascular anomalies of the retina.
▸
▸
▸
▸
well as cardiac imaging including the aortic arch. Patients with long-segment arterial narrowing or absence of major cerebral/cervical vessels without collateral circulation, particularly when there are also cardiac and aortic arch abnormalities, are at the highest risk for ischaemic stoke, and this risk may increase with propranolol use. Target propranolol dose is 1–3 mg/kg/day, divided in three daily doses at least 6 h apart. The target dose should be reached by escalating from a low starting dose of 1 mg/kg/day. The 20 mg/5 mL or similar formulation of propranolol is preferred to avoid confusion since small volumes are typically required. Consider inpatient hospitalisation for initiation of propranolol in the following settings: Infants ≤8 weeks of gestationally-corrected age, inadequate social support, or comorbidities affecting respiratory system, cardiovascular system or glucose maintenance. Routine hospitalisation of all patients is not required. Cardiac monitoring with propranolol initiation should include heart rate and blood pressure recordings at baseline and 1 and 2 h after initial dose. This should be repeated with any significant increase in dose (>0.5 mg/ kg/day). Bradycardia may be the most reliable monitor for toxicity. Data do not support use of holter monitoring. Hypoglycaemia is a potential serious complication. Prevention of hypoglycaemia includes education of parents, avoidance of prolonged fasts and holding propranolol during illnesses, especially if oral intake is decreased. Data do not support the use of routine blood glucose screening.
UNDERLYING EVIDENCE BASE/METHODOLOGY These recommendations were proposed by a multidisciplinary team at a consensus conference after review of the literature regarding propranolol use in IH and other paediatric indications. They also reviewed data from a 2011 survey of established prescribing practices. Since current literature is mostly retrospective or anecdotal in nature, the recommendations are largely based on clinical experience and expert opinion (box 4).
2
▸ Treatment of infantile haemangioma (IH) is indicated in the presence of: impairment of vital function such as ocular or airway involvement, potential to cause significant disfigurement, and ulceration. ▸ Propranolol is a rapidly effective and generally welltolerated treatment for IHs.1–4 ▸ Recently published recommendations provide a provisional set of best practices meant to standardise the approach to use of propranolol for IH. ▸ More research is necessary in order to refine these guidelines.
WHAT DO I NEED TO KNOW?
▸ What should I stop doing? – Stop checking routine serum glucose levels. – Stop obtaining pretreatment echocardiogram on a routine basis without abnormal clinical findings. – Stop routinely hospitalising most patients for initiation of treatment. ▸ What should I ensure I have started doing? – Recognise that patients with PHACE syndrome are at higher risk for stroke and manage them in conjunction with neurology. – Monitor heart rate and blood pressure at baseline and 1 and 2 h after administering the first dose of propranolol. Repeat this with any significant dose increase (>0.5 mg/kg/day). ▸ What can I continue to do as before? – Perform detailed pretreatment history and physical examination, with emphasis on cardiovascular and respiratory systems. – Titrate up from low dose to a target dose of 1–3 mg/kg/ day in three daily divided doses. Use the 20 mg/5 mL formulation of propranolol. – Avoid prolonged fasts in patients on propranolol and stop the medication during intercurrent illnesses, especially when there is decreased oral intake.
UNRESOLVED CONTROVERSIES There was no consensus regarding routine ECG screening prior to initiation of propranolol. There is little evidence regarding the safety of propranolol in patients with PHACE syndrome and the risk to benefit ratio in this scenario is not well established.6 More research is necessary to determine whether initiation of propranolol in the outpatient setting will be safe even for younger infants or those with medical comorbidities. Additionally, more data will be needed to define the optimal treatment dose and duration. Contributors HAB-B and LB: conception and design, manuscript draft and revision. HAB-B: final approval. Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
Biesbroeck L, et al. Arch Dis Child Educ Pract Ed 2013;0:1–3. doi:10.1136/archdischild-2013-305027
Downloaded from ep.bmj.com on August 20, 2014 - Published by group.bmj.com
Guideline review REFERENCES 1 Hermans DJ, Bauland CG, Zweegers J, et al. Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions. Br J Dermatol 2013;168:837–43. 2 Gan LQ, Ni SL, Tan Q, et al. A retrospective study of propranolol therapy in 109 infants with infantile hemangioma. Pediatr Dermatol 2013 2013;30:270–2. 3 Hogeling M, Adams S, Wargon O. A randomized controlled trial of propranolol for infantile hemangiomas. Pediatrics 2011;128:e259–66.
4 Schupp CJ, Kleber JB, Günther P, et al. Propranolol therapy in 55 infants with infantile hemangioma: dosage, duration, adverse effects, and outcome. Pediatr Dermatol 2011;28:640–4. 5 Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics 2013;131:128–40. 6 Metry D, Frieden IJ, Hess C, et al. Propranolol use in PHACE syndrome with cervical and intracranial arterial anomalies: collective experience in 32 infants. Pediatr Dermatol 2013;30:71–89.
Biesbroeck L, et al. Arch Dis Child Educ Pract Ed 2013;0:1–3. doi:10.1136/archdischild-2013-305027
3
Downloaded from ep.bmj.com on August 20, 2014 - Published by group.bmj.com
Propranolol for infantile haemangiomas: review of report of a consensus conference Lauren Biesbroeck and Heather A Brandling-Bennett Arch Dis Child Educ Pract Ed published online November 15, 2013
doi: 10.1136/archdischild-2013-305027
Updated information and services can be found at: http://ep.bmj.com/content/early/2013/11/15/archdischild-2013-305027.full.html
These include:
References
This article cites 6 articles, 2 of which can be accessed free at: http://ep.bmj.com/content/early/2013/11/15/archdischild-2013-305027.full.html#ref-list-1
P
Education & Practice Online First, published on November 15, 2013 as 10.1136/archdischild-2013-305027 GUIDELINE REVIEW
Propranolol for infantile haemangiomas: review of report of a consensus conference Lauren Biesbroeck,1 Heather A Brandling-Bennett2 1
Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington, USA 2 Division of Dermatology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, Washington, USA Correspondence to Dr Heather A Brandling-Bennett, Division of Dermatology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, 4800 Sand Point Way NE, M/S OC.9.835, Seattle, WA 98105, USA; heather.brandlingbennett@ seattlechildrens.org Received 6 August 2013 Revised 16 October 2013 Accepted 27 October 2013
INTRODUCTION Infantile haemangiomas (IHs) are common benign vascular tumours of infancy, most of which do not require treatment. Complications for which treatment is indicated include impairment of vital function by ocular or airway involvement, potential to cause significant disfigurement, and ulceration. Case reports, case series and anecdotal experience since 2008 have established that propranolol is a rapidly effective and generally welltolerated treatment for IHs in comparison with previously available therapies such as corticosteroids, vincristine and interferon.1–4 Recently published recommendations provide a provisional set of best practices meant to standardise the approach to the use of propranolol for IHs (see box 1). INFORMATION ABOUT CURRENT RECOMMENDATIONS In January 2013, a multispecialty group sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases published consensus recommendations entitled: ‘Initiation and use of propranolol for infantile hemangioma: Report of a consensus conference.’5 The goal of the conference was ‘to develop a standardised, consensus-derived set of best practices for the use of propranolol in infants with infantile hemangioma.’ In all, 28 participants from five specialties (including paediatrics, dermatology, otolaryngology, cardiology, haematology/ oncology) and 12 US institutions
To cite: Biesbroeck L, Brandling-Bennett HA. Arch Dis Child Educ Pract Ed Published Online First: [ please include Day Month Year] doi:10.1136/archdischild2013-305027
Box 1
Resources
▸ http://pediatrics.aappublications.org/ content/131/1/128 Link to full guideline
participated in the conference. These participants reviewed the available literature on propranolol use for IH and developed consensus protocols. PREVIOUS GUIDELINE There are no previous guidelines published regarding the use of propranolol for IH. CONTROVERSIAL AND KEY ISSUES THAT THE RECOMMENDATIONS ADDRESS ▸ Consider treatment of IH with propranolol when the following are present: ulceration, impairment of vital function (ocular compromise or airway obstruction) or risk of permanent disfigurement. ▸ Box 2 delineates recommendations for pretreatment evaluation. ▸ Contraindications for the use of propranolol include: cardiogenic shock, sinus bradycardia, hypotension, heart block (greater than first degree), heart failure, asthma and hypersensitivity to propranolol. ▸ All infants with large facial haemangiomas should be thoroughly evaluated for PHACE syndrome (see box 3). This workup should include MRI/MRA of head and neck, as
Box 2
Pretreatment evaluation
▸ Thorough history and physical examination, with emphasis on cardiac and pulmonary systems. ▸ ECG if one or more of the following: – Heart rate is below normal for age. – Patient or family history of congenital heart disease or arrhythmias. – Maternal history of connective tissue disease. – Arrhythmia detected on exam. ▸ Echocardiogram is only necessary if exam findings are abnormal.
Biesbroeck L, et al. Arch Dis Child Educ Pract Ed 2013;0:1–3. doi:10.1136/archdischild-2013-305027 1 Copyright Article author (or their employer) 2013. Produced by BMJ Publishing Group Ltd under licence.
Downloaded from ep.bmj.com on August 20, 2014 - Published by group.bmj.com
Guideline review Box 3
PHACE syndrome
Box 4 Clinical bottom line
▸ P: Posterior fossa abnormalities, such as Dandy– Walker malformation, cerebellar hypoplasia or other structural abnormalities. ▸ H: Haemangioma, typically segmental facial haemangioma >5 cm in diameter. ▸ A: Arterial abnormalities, typically stenotic, dysplastic, hypoplastic, aberrant, or non-visualised cerebral or cervical vessels. ▸ C: Cardiac abnormalities, including coarctation of the aorta, ventricular or atrial septal defects. ▸ E: Eye abnormalities, such as hypoplastic optic nerve or vascular anomalies of the retina.
▸
▸
▸
▸
well as cardiac imaging including the aortic arch. Patients with long-segment arterial narrowing or absence of major cerebral/cervical vessels without collateral circulation, particularly when there are also cardiac and aortic arch abnormalities, are at the highest risk for ischaemic stoke, and this risk may increase with propranolol use. Target propranolol dose is 1–3 mg/kg/day, divided in three daily doses at least 6 h apart. The target dose should be reached by escalating from a low starting dose of 1 mg/kg/day. The 20 mg/5 mL or similar formulation of propranolol is preferred to avoid confusion since small volumes are typically required. Consider inpatient hospitalisation for initiation of propranolol in the following settings: Infants ≤8 weeks of gestationally-corrected age, inadequate social support, or comorbidities affecting respiratory system, cardiovascular system or glucose maintenance. Routine hospitalisation of all patients is not required. Cardiac monitoring with propranolol initiation should include heart rate and blood pressure recordings at baseline and 1 and 2 h after initial dose. This should be repeated with any significant increase in dose (>0.5 mg/ kg/day). Bradycardia may be the most reliable monitor for toxicity. Data do not support use of holter monitoring. Hypoglycaemia is a potential serious complication. Prevention of hypoglycaemia includes education of parents, avoidance of prolonged fasts and holding propranolol during illnesses, especially if oral intake is decreased. Data do not support the use of routine blood glucose screening.
UNDERLYING EVIDENCE BASE/METHODOLOGY These recommendations were proposed by a multidisciplinary team at a consensus conference after review of the literature regarding propranolol use in IH and other paediatric indications. They also reviewed data from a 2011 survey of established prescribing practices. Since current literature is mostly retrospective or anecdotal in nature, the recommendations are largely based on clinical experience and expert opinion (box 4).
2
▸ Treatment of infantile haemangioma (IH) is indicated in the presence of: impairment of vital function such as ocular or airway involvement, potential to cause significant disfigurement, and ulceration. ▸ Propranolol is a rapidly effective and generally welltolerated treatment for IHs.1–4 ▸ Recently published recommendations provide a provisional set of best practices meant to standardise the approach to use of propranolol for IH. ▸ More research is necessary in order to refine these guidelines.
WHAT DO I NEED TO KNOW?
▸ What should I stop doing? – Stop checking routine serum glucose levels. – Stop obtaining pretreatment echocardiogram on a routine basis without abnormal clinical findings. – Stop routinely hospitalising most patients for initiation of treatment. ▸ What should I ensure I have started doing? – Recognise that patients with PHACE syndrome are at higher risk for stroke and manage them in conjunction with neurology. – Monitor heart rate and blood pressure at baseline and 1 and 2 h after administering the first dose of propranolol. Repeat this with any significant dose increase (>0.5 mg/kg/day). ▸ What can I continue to do as before? – Perform detailed pretreatment history and physical examination, with emphasis on cardiovascular and respiratory systems. – Titrate up from low dose to a target dose of 1–3 mg/kg/ day in three daily divided doses. Use the 20 mg/5 mL formulation of propranolol. – Avoid prolonged fasts in patients on propranolol and stop the medication during intercurrent illnesses, especially when there is decreased oral intake.
UNRESOLVED CONTROVERSIES There was no consensus regarding routine ECG screening prior to initiation of propranolol. There is little evidence regarding the safety of propranolol in patients with PHACE syndrome and the risk to benefit ratio in this scenario is not well established.6 More research is necessary to determine whether initiation of propranolol in the outpatient setting will be safe even for younger infants or those with medical comorbidities. Additionally, more data will be needed to define the optimal treatment dose and duration. Contributors HAB-B and LB: conception and design, manuscript draft and revision. HAB-B: final approval. Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
Biesbroeck L, et al. Arch Dis Child Educ Pract Ed 2013;0:1–3. doi:10.1136/archdischild-2013-305027
Downloaded from ep.bmj.com on August 20, 2014 - Published by group.bmj.com
Guideline review REFERENCES 1 Hermans DJ, Bauland CG, Zweegers J, et al. Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions. Br J Dermatol 2013;168:837–43. 2 Gan LQ, Ni SL, Tan Q, et al. A retrospective study of propranolol therapy in 109 infants with infantile hemangioma. Pediatr Dermatol 2013 2013;30:270–2. 3 Hogeling M, Adams S, Wargon O. A randomized controlled trial of propranolol for infantile hemangiomas. Pediatrics 2011;128:e259–66.
4 Schupp CJ, Kleber JB, Günther P, et al. Propranolol therapy in 55 infants with infantile hemangioma: dosage, duration, adverse effects, and outcome. Pediatr Dermatol 2011;28:640–4. 5 Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics 2013;131:128–40. 6 Metry D, Frieden IJ, Hess C, et al. Propranolol use in PHACE syndrome with cervical and intracranial arterial anomalies: collective experience in 32 infants. Pediatr Dermatol 2013;30:71–89.
Biesbroeck L, et al. Arch Dis Child Educ Pract Ed 2013;0:1–3. doi:10.1136/archdischild-2013-305027
3
Downloaded from ep.bmj.com on August 20, 2014 - Published by group.bmj.com
Propranolol for infantile haemangiomas: review of report of a consensus conference Lauren Biesbroeck and Heather A Brandling-Bennett Arch Dis Child Educ Pract Ed published online November 15, 2013
doi: 10.1136/archdischild-2013-305027
Updated information and services can be found at: http://ep.bmj.com/content/early/2013/11/15/archdischild-2013-305027.full.html
These include:
References
This article cites 6 articles, 2 of which can be accessed free at: http://ep.bmj.com/content/early/2013/11/15/archdischild-2013-305027.full.html#ref-list-1
P
