Hemangiomas Treated with Propranolol: Do the Rewards Outweigh the Risks? Kathryn M. Haider, M.D. Daniel E. Neely, M.D. David A. Plager, M.D.
ABSTRACT Recent reports of propranolol for the treatment of hemangiomas have led many physicians to question the best treatment strategy for children with vision-threatening hemangiomas. Although propranolol has potential side effects, including hypoglycemia and hypotension, early studies suggest it is more efficacious than systemic corticosteroids with a lower incidence of adverse side effects.
INTRODUCTION Infantile hemangiomas are the most common orbital tumors in infancy, with nearly 80% of all hemangiomas occurring in the head and neck. Although they are benign vascular hamartomas, they have the potential to cause permanent visual impairment. Recent reports of propranolol for the treatment of hemangiomas have From the Glick Eye Institute, Indianapolis, Indiana. Requests for reprints should be addressed to: Kathryn M. Haider, M.D., Glick Eye Institute, 1160 West Michigan #220, Indiana University, Indianapolis, IN 46202; e-mail: [email protected] Presented as part of a Symposium of the Joint Meeting of the American Orthoptic Council, the American Association of Certified Orthoptists, and the American Academy of Ophthalmology, Chicago, Illinois, November 11, 2012.
led many physicians to question the best treatment strategy for children with hemangiomas. Most infantile hemangiomas do not need treatment because they will eventually regress. Periocular hemangiomas can cause occlusional amblyopia, induced astigmatism, anisometropia, painful ulceration, or significant facial disfigurement. As ophthalmologists, we treat vision-threatening hemangiomas because long after the hemangiomas regress, the lasting effects of amblyopia and vision loss can remain. HEMANGIOMAS Periorbital hemangiomas have three classic presentations: superficial, subcutaneous, and orbital. Superficial lesions first appear as flat, red “birthmarks” that
© 2013 Board of Regents of the University of Wisconsin System, American Orthoptic Journal, Volume 63, 2013, ISSN 0065-955X, E-ISSN 1553-4448
2
HAIDER
can grow to become elevated, “strawberry” red, and shiny. As they regress, the color deepens to a dull red. Subcutaneous hemangiomas often appear bluish, purple in color, and may enlarge with valsalva. They typically feel soft. Orbital hemangiomas may be associated with both superficial or subcutaneous involvement or may present with isolated proptosis. Radiographical imaging can help delineate the extent of a hemangioma, especially when there is suspected orbital involvement. Prior to 2008, treatment options included oral corticosteroids, systemic therapy, topical corticosteroids, injectable corticosteroids, surgical excision, and chemotherapy. Oral corticosteroids have been the mainstay treatment for large hemangiomas that were not better treated with local therapy. Systemic therapy is generally effective, but also has a host of side effects, including adrenal suppression, growth retardation, cushingoid appearance, gastrointestinal intolerance, infections, and delays in routine immunizations. Topical corticosteroids can work for very superficial hemangiomas, but they are not ideal for very large or deep lesions. Injectable corticosteroids are best used with discrete subcutaneous lesions. An injection can show rapid improvement, typically within 2 to 4 weeks. This approach is logistically difficult for very large, orbital lesions or mainly superficial lesions. Potential side effects include systemic absorption, subcutaneous white deposits, fat atrophy, and central retinal artery occlusion.1, 2 While the first three effects most often resolve with time, the most feared complication is the central artery occlusion because it can result in permanent and complete vision loss. This complication is likely rare, but the true incidence is unknown. Surgical excision is an excellent option for subcutaneous, well-circumscribed lesions, but is not an ideal choice for superficial or orbital tumors. 3, 4 Chemotherapeutic agents are
American Orthoptic Journal
the last line of treatment and are associated with signifi cant systemic side effects. PROPRANOLOL TREATMENT Léauté-Labrèze et al. first reported their serendipitous discovery of propranolol as a treatment for infantile hemangiomas in 2008.5 They describe a boy with a nasal capillary hemangioma who was initially treated with systemic steroids but developed obstructive hypertropic myocardiopathy. The child was subsequently placed on propranolol. A second boy had a plaque-like infantile hemangioma affecting the right face as well as a mass that compressed his trachea and esophagus. His initial treatment also included systemic steroids, but he was started on propranolol due to increased cardiac output. Both children had impressive and rapid resolution of the hemangiomas as well as their secondary complications. Since this first report in 2008, there has been an explosion in the literature on this topic. Anecdotally, anyone who has used this medication for the treatment of infantile hemangiomas has likely seen its dramatic and rapid effect on halting the progression and sometimes marked regression of hemangiomas. But what do we really know about this systemic drug we are giving to very young children? Propranolol is a nonselective beta blocker that was first introduced in the 1960s. It has effects on the heart, lungs, and gluconeogenesis. It has many uses including treatment of arrhythmias, migraines, and congenital heart disease. Side effects tend to be mild, including hypotension, bradycardia, hypoglycemia, bronchospasm, sleep disturbance, gastrointestinal disturbance, and rash. In 2003, Love and Sikka reported that “not one documented case of death or serious cardiovascular morbidity as a direct result of beta-blocker exposure is to be found in
3
SYMPOSIUM: CONTROVERSIES
English-language review for children under 6 years of age.”6 Armed with this knowledge, we published a case series in 2010 outlining our protocol for propranolol therapy on an outpatient basis.7 Briefly, it consisted of baseline vital signs and EKG. If normal, we proceeded with propranolol as an outpatient. Dosing started at 0.5 mg/ kilograms/day divided three times a day and increased to 2.0 mg/kilograms/day divided three times a day. Families were counseled on the signs and symptoms of hypotension and hypoglycemia including lethargy, restlessness, decreased heart rate, cool clammy skin, delayed capillary refill, and decreased appetite. Patients are monitored by their pediatrician after each increase in dose. We evaluated patients every 2 to 3 weeks initially and then every 3 to 8 weeks subsequently. The youngest child started was 3 weeks of age and the oldest was 12 months. The results were excellent. Ten of 17 patients had a greater than 50% reduction in size. Six of 17 had “good” results defined as less than 50% reduction in size. One patient had “fair” results defined as no progression although no reduction in size. No patients had progression or intolerable side effects. We were not alone in our experience. In 2011, Cornish and Reddy published a systematic review of the use of propranolol in the management of periocular capillary hemangiomas.8 There were nineteen case reports or case series all describing the success of using propranolol. Unfortunately, the largest case series included only eighteen patients and each paper had variable age of presentation, dose, and duration of treatment. A larger case series was published by Price et al. in 2011.9 They reviewed 110 patients treated with one of three treatment modalities: oral corticosteroids, propranolol without corticosteroids, and propranolol with previous corticosteroids. When defining success as greater than 75% im-
4
provement, there was a clear benefit of using propranolol (82%) with or without corticosteroids as compared to corticosteroids (29%) alone. They also reviewed side effects and cost. Adverse effects of propranolol were reported at 1%, while for corticosteroids were 100%. The cost of propranolol treatment was $205 as compared to $400 with corticosteroids. A randomized, double-blind, placebocontrolled, parallel-group trial of propranolol for infantile hemangiomas was published by Hogeling et al. in 2011.10 They reported on thirty-nine patients. Patients treated with propranolol had a significant reduction in mean volume when compared to placebo (14 vs. 60 %, respectively). In addition, there were no reports of hypotension, bradycardia, or hypoglycemia. But side effects can happen. The first report of complications related to propranolol therapy for hemangiomas was in 2009. Lawley et al. reported on an 8-week-old girl started on 2 mg/kilogram/day divided twice daily for a periocular hemangioma that was not responsive to corticosteroids.11 After her second dose, she developed lethargy and cold hands and feet. She was taken to the emergency room where her pulse was found to be 87 and her systolic blood pressure was 60. Her vital signs and symptoms normalized in two hours without specific intervention. They also describe a former 35-week premature infant who was placed on 2 mg/kilogram/day divided three times a day of propranolol for a diagnosis of disseminated hemangiomatosis. On routine laboratory evaluation, she was found to have a blood glucose level of 48. Propranolol was continued because the patient was asymptomatic and was growing well at the 50th percentile. Holland et al. reported three additional cases of hypoglycemia and reviewed published case reports of children receiving propranolol and having hypoglycemia.12 The vast majority of patients had a propanolol dose greater than 4 mg/kilogram/
Volume 63, 2013
HAIDER
day with episodes of hypoglycemia often associated with prolonged fasting or poor oral intake, although there were rare exceptions.
3.
4.
CONCLUSION The question we were posed was: do the rewards outweigh the risks? In our opinion, they do. Early studies suggest the propranolol may be more effective than systemic corticosteroids, although larger prospective studies are needed and not all children respond equally. The risks of hypoglycemia and hypotension are real, although the incidence is low. Parents and providers need to be aware of this potential complication and then compare that risk with the potential complications of the alternative treatment, systemic corticosteroids. Our results suggest propranolol has replaced systemic corticosteroids for treatments of hemangiomas. But systemic treatment is not always needed. Observation, topical corticosteroids, injectable corticosteroids, and resection still play a role. As health care providers, we are still charged with finding the best treatment for our individual patients.
5.
6.
7.
8.
9.
10.
11.
12.
REFERENCES 1. Ruttum MS, Abrams GW, Harris GJ, Ellis MK: Bilateral retinal embolization associated with intralesional corticosteroid injection for capillary hemangioma of infancy. J Pediatric Ophthalmol Strabismus 1993; 30:4-7. 2. Egbert JE, Schwartz GS, Walsh AW: Diagnosis and treatment of ophthalmic artery occlusion during an intralesional injection of corticosteroid
American Orthoptic Journal
into an eyelid capillary hemangioma. Am J Ophthalmol 1996; 121:638-642. Walker RS, Custer PL, Nerad JA: Surgical excision of periorbital capillary hemangiomas. Ophthalmology 1994; 101:1333-1340. Plager DA, Snyder SK: Resolution of astigmatism after surgical resection of capillary hemangiomas in infants. Ophthalmology 1997; 104:1102-1106. 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; 358:2649-2651. Love JN, Sikka N: Are 1-2 tablets dangerous? Beta blocker exposure in toddlers. J Emerg Med 2004; 26:309-314. Haider KM, Plager DA, Neely DE, Eikenberry J, Haggstrom A: Outpatient treatment of periocular infantile hemangiomas with oral propranolol. J AAPOS 2010; 14:251-256. Spiteri Cornish K, Reddy AR: The use of propranolol in the management of periocular capillary hemangioma: A systematic review. Eye 2011; 25:1277-1283. Price CJ, Lattouf C, Baum B, McLeod M, Schachner LA, Duarte AM, Connelly EA: Propranolol vs. corticosteroids for infantile hemangiomas: A multicenter retrospective analysis. Arch Dermatol 2011; 147:1371-1376. Hogeling M, Adams S, Wargon O: A randomized controlled trial of propranolol for infantile hemangiomas. Pediatrics 2011; 128:e259-266. Lawley LP, Siegfried E, Todd JL: Propranolol treatment for hemangioma of infancy: Risks and recommendations. Pediatr Dermatol 2009; 26:610-614. Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA: Hypoglycemia in children taking propranolol for the treatment of infantile hemangioma. Arch Dermatol 2010; 146:775-778.
Key words: infantile hemangioma, capillary hemangioma, periocular hemangioma, propranolol, amblyopia, anisometropia, hypoglycemia
5
ABSTRACT Recent reports of propranolol for the treatment of hemangiomas have led many physicians to question the best treatment strategy for children with vision-threatening hemangiomas. Although propranolol has potential side effects, including hypoglycemia and hypotension, early studies suggest it is more efficacious than systemic corticosteroids with a lower incidence of adverse side effects.
INTRODUCTION Infantile hemangiomas are the most common orbital tumors in infancy, with nearly 80% of all hemangiomas occurring in the head and neck. Although they are benign vascular hamartomas, they have the potential to cause permanent visual impairment. Recent reports of propranolol for the treatment of hemangiomas have From the Glick Eye Institute, Indianapolis, Indiana. Requests for reprints should be addressed to: Kathryn M. Haider, M.D., Glick Eye Institute, 1160 West Michigan #220, Indiana University, Indianapolis, IN 46202; e-mail: [email protected] Presented as part of a Symposium of the Joint Meeting of the American Orthoptic Council, the American Association of Certified Orthoptists, and the American Academy of Ophthalmology, Chicago, Illinois, November 11, 2012.
led many physicians to question the best treatment strategy for children with hemangiomas. Most infantile hemangiomas do not need treatment because they will eventually regress. Periocular hemangiomas can cause occlusional amblyopia, induced astigmatism, anisometropia, painful ulceration, or significant facial disfigurement. As ophthalmologists, we treat vision-threatening hemangiomas because long after the hemangiomas regress, the lasting effects of amblyopia and vision loss can remain. HEMANGIOMAS Periorbital hemangiomas have three classic presentations: superficial, subcutaneous, and orbital. Superficial lesions first appear as flat, red “birthmarks” that
© 2013 Board of Regents of the University of Wisconsin System, American Orthoptic Journal, Volume 63, 2013, ISSN 0065-955X, E-ISSN 1553-4448
2
HAIDER
can grow to become elevated, “strawberry” red, and shiny. As they regress, the color deepens to a dull red. Subcutaneous hemangiomas often appear bluish, purple in color, and may enlarge with valsalva. They typically feel soft. Orbital hemangiomas may be associated with both superficial or subcutaneous involvement or may present with isolated proptosis. Radiographical imaging can help delineate the extent of a hemangioma, especially when there is suspected orbital involvement. Prior to 2008, treatment options included oral corticosteroids, systemic therapy, topical corticosteroids, injectable corticosteroids, surgical excision, and chemotherapy. Oral corticosteroids have been the mainstay treatment for large hemangiomas that were not better treated with local therapy. Systemic therapy is generally effective, but also has a host of side effects, including adrenal suppression, growth retardation, cushingoid appearance, gastrointestinal intolerance, infections, and delays in routine immunizations. Topical corticosteroids can work for very superficial hemangiomas, but they are not ideal for very large or deep lesions. Injectable corticosteroids are best used with discrete subcutaneous lesions. An injection can show rapid improvement, typically within 2 to 4 weeks. This approach is logistically difficult for very large, orbital lesions or mainly superficial lesions. Potential side effects include systemic absorption, subcutaneous white deposits, fat atrophy, and central retinal artery occlusion.1, 2 While the first three effects most often resolve with time, the most feared complication is the central artery occlusion because it can result in permanent and complete vision loss. This complication is likely rare, but the true incidence is unknown. Surgical excision is an excellent option for subcutaneous, well-circumscribed lesions, but is not an ideal choice for superficial or orbital tumors. 3, 4 Chemotherapeutic agents are
American Orthoptic Journal
the last line of treatment and are associated with signifi cant systemic side effects. PROPRANOLOL TREATMENT Léauté-Labrèze et al. first reported their serendipitous discovery of propranolol as a treatment for infantile hemangiomas in 2008.5 They describe a boy with a nasal capillary hemangioma who was initially treated with systemic steroids but developed obstructive hypertropic myocardiopathy. The child was subsequently placed on propranolol. A second boy had a plaque-like infantile hemangioma affecting the right face as well as a mass that compressed his trachea and esophagus. His initial treatment also included systemic steroids, but he was started on propranolol due to increased cardiac output. Both children had impressive and rapid resolution of the hemangiomas as well as their secondary complications. Since this first report in 2008, there has been an explosion in the literature on this topic. Anecdotally, anyone who has used this medication for the treatment of infantile hemangiomas has likely seen its dramatic and rapid effect on halting the progression and sometimes marked regression of hemangiomas. But what do we really know about this systemic drug we are giving to very young children? Propranolol is a nonselective beta blocker that was first introduced in the 1960s. It has effects on the heart, lungs, and gluconeogenesis. It has many uses including treatment of arrhythmias, migraines, and congenital heart disease. Side effects tend to be mild, including hypotension, bradycardia, hypoglycemia, bronchospasm, sleep disturbance, gastrointestinal disturbance, and rash. In 2003, Love and Sikka reported that “not one documented case of death or serious cardiovascular morbidity as a direct result of beta-blocker exposure is to be found in
3
SYMPOSIUM: CONTROVERSIES
English-language review for children under 6 years of age.”6 Armed with this knowledge, we published a case series in 2010 outlining our protocol for propranolol therapy on an outpatient basis.7 Briefly, it consisted of baseline vital signs and EKG. If normal, we proceeded with propranolol as an outpatient. Dosing started at 0.5 mg/ kilograms/day divided three times a day and increased to 2.0 mg/kilograms/day divided three times a day. Families were counseled on the signs and symptoms of hypotension and hypoglycemia including lethargy, restlessness, decreased heart rate, cool clammy skin, delayed capillary refill, and decreased appetite. Patients are monitored by their pediatrician after each increase in dose. We evaluated patients every 2 to 3 weeks initially and then every 3 to 8 weeks subsequently. The youngest child started was 3 weeks of age and the oldest was 12 months. The results were excellent. Ten of 17 patients had a greater than 50% reduction in size. Six of 17 had “good” results defined as less than 50% reduction in size. One patient had “fair” results defined as no progression although no reduction in size. No patients had progression or intolerable side effects. We were not alone in our experience. In 2011, Cornish and Reddy published a systematic review of the use of propranolol in the management of periocular capillary hemangiomas.8 There were nineteen case reports or case series all describing the success of using propranolol. Unfortunately, the largest case series included only eighteen patients and each paper had variable age of presentation, dose, and duration of treatment. A larger case series was published by Price et al. in 2011.9 They reviewed 110 patients treated with one of three treatment modalities: oral corticosteroids, propranolol without corticosteroids, and propranolol with previous corticosteroids. When defining success as greater than 75% im-
4
provement, there was a clear benefit of using propranolol (82%) with or without corticosteroids as compared to corticosteroids (29%) alone. They also reviewed side effects and cost. Adverse effects of propranolol were reported at 1%, while for corticosteroids were 100%. The cost of propranolol treatment was $205 as compared to $400 with corticosteroids. A randomized, double-blind, placebocontrolled, parallel-group trial of propranolol for infantile hemangiomas was published by Hogeling et al. in 2011.10 They reported on thirty-nine patients. Patients treated with propranolol had a significant reduction in mean volume when compared to placebo (14 vs. 60 %, respectively). In addition, there were no reports of hypotension, bradycardia, or hypoglycemia. But side effects can happen. The first report of complications related to propranolol therapy for hemangiomas was in 2009. Lawley et al. reported on an 8-week-old girl started on 2 mg/kilogram/day divided twice daily for a periocular hemangioma that was not responsive to corticosteroids.11 After her second dose, she developed lethargy and cold hands and feet. She was taken to the emergency room where her pulse was found to be 87 and her systolic blood pressure was 60. Her vital signs and symptoms normalized in two hours without specific intervention. They also describe a former 35-week premature infant who was placed on 2 mg/kilogram/day divided three times a day of propranolol for a diagnosis of disseminated hemangiomatosis. On routine laboratory evaluation, she was found to have a blood glucose level of 48. Propranolol was continued because the patient was asymptomatic and was growing well at the 50th percentile. Holland et al. reported three additional cases of hypoglycemia and reviewed published case reports of children receiving propranolol and having hypoglycemia.12 The vast majority of patients had a propanolol dose greater than 4 mg/kilogram/
Volume 63, 2013
HAIDER
day with episodes of hypoglycemia often associated with prolonged fasting or poor oral intake, although there were rare exceptions.
3.
4.
CONCLUSION The question we were posed was: do the rewards outweigh the risks? In our opinion, they do. Early studies suggest the propranolol may be more effective than systemic corticosteroids, although larger prospective studies are needed and not all children respond equally. The risks of hypoglycemia and hypotension are real, although the incidence is low. Parents and providers need to be aware of this potential complication and then compare that risk with the potential complications of the alternative treatment, systemic corticosteroids. Our results suggest propranolol has replaced systemic corticosteroids for treatments of hemangiomas. But systemic treatment is not always needed. Observation, topical corticosteroids, injectable corticosteroids, and resection still play a role. As health care providers, we are still charged with finding the best treatment for our individual patients.
5.
6.
7.
8.
9.
10.
11.
12.
REFERENCES 1. Ruttum MS, Abrams GW, Harris GJ, Ellis MK: Bilateral retinal embolization associated with intralesional corticosteroid injection for capillary hemangioma of infancy. J Pediatric Ophthalmol Strabismus 1993; 30:4-7. 2. Egbert JE, Schwartz GS, Walsh AW: Diagnosis and treatment of ophthalmic artery occlusion during an intralesional injection of corticosteroid
American Orthoptic Journal
into an eyelid capillary hemangioma. Am J Ophthalmol 1996; 121:638-642. Walker RS, Custer PL, Nerad JA: Surgical excision of periorbital capillary hemangiomas. Ophthalmology 1994; 101:1333-1340. Plager DA, Snyder SK: Resolution of astigmatism after surgical resection of capillary hemangiomas in infants. Ophthalmology 1997; 104:1102-1106. 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; 358:2649-2651. Love JN, Sikka N: Are 1-2 tablets dangerous? Beta blocker exposure in toddlers. J Emerg Med 2004; 26:309-314. Haider KM, Plager DA, Neely DE, Eikenberry J, Haggstrom A: Outpatient treatment of periocular infantile hemangiomas with oral propranolol. J AAPOS 2010; 14:251-256. Spiteri Cornish K, Reddy AR: The use of propranolol in the management of periocular capillary hemangioma: A systematic review. Eye 2011; 25:1277-1283. Price CJ, Lattouf C, Baum B, McLeod M, Schachner LA, Duarte AM, Connelly EA: Propranolol vs. corticosteroids for infantile hemangiomas: A multicenter retrospective analysis. Arch Dermatol 2011; 147:1371-1376. Hogeling M, Adams S, Wargon O: A randomized controlled trial of propranolol for infantile hemangiomas. Pediatrics 2011; 128:e259-266. Lawley LP, Siegfried E, Todd JL: Propranolol treatment for hemangioma of infancy: Risks and recommendations. Pediatr Dermatol 2009; 26:610-614. Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA: Hypoglycemia in children taking propranolol for the treatment of infantile hemangioma. Arch Dermatol 2010; 146:775-778.
Key words: infantile hemangioma, capillary hemangioma, periocular hemangioma, propranolol, amblyopia, anisometropia, hypoglycemia
5
