Propranolol

 

Propranolol’s Role in the Treatment of Infantile Hemangioma

By Karla Hall Executive Director NOVA

Infantile Hemangioma (IH) is the most common benign tumor of infancy and children.  It is commonly reported that up to 10% of children affected by (IH) require treatment.  Complications of IH lesions include visual obstruction, nasal obstruction, ulceration, bleeding, significant tissue distortion and heart-failure or other life threatening symptoms.  Treatment of Hemangioma includes medical management, laser and surgical options.  Glucocortico steroids have been the mainstay of medical treatment of complicated infantile hemangioma.  Interferon and Vincristine therapy have served as a second or third line in medical treatment.  Because of the efficacy and side effects of all three of these drugs new treatment modalities are needed.  In the spring of 2007 NOVA first brought to you the news that the beta-blocker propranolol had serendipitously been observed to accelerate the involution of infantile hemangioma.  The efficacy, dosing and duration of treatment along with the mechanism by which propranolol causes involution has been the subject of evaluation ever since.  Published reports demonstrate consistent and rapid therapeutic effects of propranolol with few noted complications.  The exact role propranolol has in the treatment of infantile hemangioma is still being investigated.  Large scale studies are underway at several centers.

 

            Propranolol is a well tolerated Beta-adrenergic receptor blocker that is commonly used for cardiac indications in young children and adults. (abnormal heart rate and abnormal heart rhythm)  It has been shown to be a relatively safe drug in the pediatric population. 1 In rare occurrences adverse effects of propranolol include slow heart rate, (bradycardia), low blood pressure, (hypotension), low blood sugar, (hypoglycemia), and bronchospasm.  Since it was first observed to halt growth and induce involution of infantile hemangioma oral propranolol has been used successfully in both retrospective and prospective studies.   However; there is little known about its safety for pre-term and low birth weight infants.  In some situations, such as patients with PHACE Syndrome the potential for serious complications exists.   The mechanism by which propranolol halts the growth of proliferating hemangioma and induces involution is still not fully understood, althoug it is thought to act as a vascoconstrictor, regulating angiogenic pathways thus inducing apoptosis of the vascularized enotheilial cells.    Propranolol is considered safe, causing few side effects in patients.  Aalthough there are cases of hypoglycemia, hypotension, diarrehea, relux, cold extremities, bronch9ospasm and hyperkalemia being described in the literature and clinics. 10 

            Infantile Hemangioma occurs more often in females then males at a rate of 5:1.  They are move commonly seen in pre-term and low birth weight infants.    The types of IH (segmental vs non-segmental), location, the size/depth of a hemangioma and the age at onset of treatment have been show to affect the response to treatments.  (IH) are known to present with complications including obstruction of vision, nasal obstruction, ulceration with and without bleeding, significant tissue distortion, pain, and heart failure.   These complicated and endangering hemangiomas have been the subject of debate of the most effective means of treatment.  Large segmental hemangioma are more likely to develop complications that include life- threatening bleeds and are associated with structural anomalies of the brain, cerebral and cardiac vessels, (PHACE Syndrome) 2

 

            Currently there are numerous reports in the literature demonstrating that the oral administration of 2 – 3mg/kg/day of propranolol have a rapid and consistent therapeutic effect on (IH). 3   It is also shown that the drug is well tolerated in the pediatric population with few adverse effects being noted.  In one study 44 patients were pre-screened by an experienced cardiovascular clinician.  EKG, Echo, blood pressure and heart rate were monitored throughout the initial dosing.  39 of the pre-screened patients were administered 2 to 3 mg/kg/day divided into 3 daily doses.  5 of the 44 were briefly admitted to the hospital for complications of heart failure, airway obstruction or social reasons.  There were no occurrences of hypotension, bradycardia, or heart failure in the remaining 89% of the patients (39).  4 Another report demonstrates that propranolol rapidly halted the proliferation of (IH) in 100% of patients (n=31) with a significant regression in 87% (n=31). 5   The treatment was well tolerated by all patients with little side effects noted.  In a retrospective study of 71 infants with IH treated with oral propranolol the response was similar regardless of sex, age at onset of treatment, type of IH, location, size/ depth or if ulceration was present.  Very few side effects were noted with 10 of 71 patients reported to have agitated sleep.  6   A reporting of 15 infants aged 3 weeks to 8.5 months underwent propranolol treatment for proliferating hemangioma with complications.  The minimal dosage required to achieve accelerated involution was 1.5 mg/kg/day – 2.0 mg/kg/day in divided doses until the 12 months of age or complete involution was noted.  Rebound growth was noted in 1 infant when the dose was withdrawn at 7/5 months of age.  Treatment was reinstituted.  No other rebound growth was observed in other patients.  No complications were noted.  7 The ability of propranolol to accelerate the involution of (IH) with minimal side effects being noted lessens the severity and duration of complicated hemangioma.  Concern still exists for adverse effects in patients with diagnosed PHACE. 

 

            Despite the published accounts of the efficacy of propranolol for the treatment of (IH), the safety of its use in pre-term or low birth weight infants is of concern.  At this time only one study was noted to have been completed on the safety and efficacy of propranolol in this population.  This limited size study demonstrated hemangioma regression with no adverse side effects in all patients after 2 months of treatment. 8 Further studies in this population of patients are needed.

Propranolol is rising to be a first line, single agent therapy for Infantile Hemangioma.  While reports in the literature continue to show dramatic efficacy with few side effects, the limited number of patients studied still gives rise for caution in its use. One report has gone so far has to state that, “long term steroid therapy is no longer indicated, propranolol can be used as a first line single agent therapy.” 9 However; other studies used in this literature summary are still calling for larger scale studies to confirm the safety and efficacy of propranolol  and to establish the exact role propranolol with play in the management of infantile hemangioma in the future.  It is important that patients be pre-screened by  experienced cardiovascular clinicians and closely monitored during treatment.  NOVA advocates that if a child is put on propranolol that they be followed by a vascular anomalies center or physician experienced in the management of vascular anomalies.  A plan of care that specifically outlines the evaluations needed prior to the use of propranolol and a documented consent process is advisable. 

** In patients diagnosed with PHACE syndrome care must be taken to assess the patient, blood pressure should be monitored.  An evaluation by a cardiologist is advised.***

 

 

1 Artman M, Grayson M, boerth RC. Propranolol in Children: Safety – Toxicity.  Pediatrics 1982; 70; 30-31

 2.  Sidbury R., Update on vascular tumors of infancy.  Current Opinion Pediatrics; 2010 Aug; 22(4); 432-437

 3 Sans Veronique, Dumas Eric, Berge Jerome, et. al. Propranolol for Severe Infantile Hemangiomas: Follow up Report. Pediatrics 2009; 124:e423-e431

 4. Cushing SL, Boucek RJ, Manning SC, Sidbury R, Perkins JA, Initial experience with a multidisciplinary strategy for initiation of propranolol therapy for infantile hemangioma. Otolaryngol Head Neck Surg, 2011 Jan; 122(1):78-84

 5.  Holmes WJ, Mishra A, Gorst C Liew SH,  Propranolol as a first line treatment of rapidly proliferating Infantile Hemangioma.  J of Plastic Reconstructive Surgery, 2011 April; 64 (4) 445-51

 6.  Bagazgoitia L, torrelo A, Gutierrez JC, et. al. Propranolol for Infantile Hemangioma. Pediatric Dermatology; 2011 March; 28 (2) 108-114

 7  Tan ST, Itinteang T, Leadbitter P, Low Dose Propranolol for Infantile Hemangioma.  J Plastic Reconstructive Aesthetic Surgery, 2011 March; 64 (3) 292-299.

 8.  Erbay A, Sanrialioqlu F, malbora B, Abbasoqiu A, et. al. Propranolol for infantile hemangiomas: a preliminary report on efficacy and safety in very low birth weight infants. Turk J Pediatrics; 2010 Sept-Oct; 52 (5); 450-456.

 9.  Leboulanger N, cox A, Garabedian EN, Denovelle F, Infantile hemangioma and beta-blockers in otolaryngology.  Eur Ann Otohinolaryngol Head Neck Disease 2011 April 15 (Epub ahead of print).

10. Sanchez-Carpintero, Ruis Rodrique R, Lopez-Gutierrez JC, Propranolol in the treatmetn of infantile hemangioma: clinical effectiveness risks and recommendations., Actas Demosifilogr, 2011 Jul18 (Epub ahead of print) (abstract)

NOVA PROVIDES THIS INFORMATION TO FAMILIES AS A RESOURCE. IT IS NOT INTENDED TO ENGAGE IN THE PRACTICE OF MEDICINE OR TO REPLACE THE PHYSICIAN. NOVA DOES NOT CLAIM TO HAVE MEDICAL KNOWLEDGE. NOVA DOES NOT ENDORSE ANY PARTICULAR PHYSICIAN, TREATING FACILITY OR TREATMENT PROTOCAL. IN ALL CASES NOVA AND ITS BOARD OF DIRECTORS RECOMMENDS THAT YOU SEEK THE OPINION OF A PHYSICIAN EXPERIENCED IN THE MANAGEMENT OF HEMANGIOMAS AND VASCULAR MALFORMATIONS. 

 Revised 8/8/2011

Copyright 2011 National Organization of Vascular Anomalies

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