- Email: [email protected]
Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region
YIJOM-2649; No of Pages 5
Int. J. Oral Maxillofac. Surg. 2013; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2013.03.015, available online at http://www.sciencedirect.com
Clinical Paper Clinical Pathology
Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region
R. R. Sadykova,b, F. Podmellec, R. A. Sadykovb, K. R. Kasimovad, H. R. Metellmannc a
Department of General Surgery with Plastic Operations, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany; bTashkent Medical Academy, Tashkent, Uzbekistan; c Department of Maxillofacial and Plastic Surgery, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany; dOntario Cancer Institute, Biophysics & Bioimaging, Toronto, Ontario, Canada
R. R. Sadykov, F. Podmelle, R. A. Sadykov, K. R. Kasimova, H. R. Metellmann: Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region. Int. J. Oral Maxillofac. Surg. 2013; xxx: xxx–xxx. # 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. Propranolol has been used successfully in a limited number of children with infantile hemangiomas (IHs). This study describes the efficacy and adverse effects of propranolol in IH. Seventy-one infants with IHs were treated with oral propranolol, administered at a dose of 2 mg/kg/day, for at least 12 weeks. A photograph-based severity scoring assessment was performed by five observers to evaluate efficacy, utilizing a score of 10 as the original IHs before treatment and 0 as completely normal skin. The mean of the five independent measurements was used in the analysis. Propranolol was a rapid and effective treatment for IHs at 4 weeks (P < 0.001), at 8 weeks (P < 0.001 compared with the value at 4 weeks), at 12 weeks (P < 0.05 compared with the value at 8 weeks), and thereafter up to 32 weeks (P < 0.01 compared with the value at 16 weeks). The response of IHs to propranolol was similar regardless of gender, age at the onset of treatment, type of involvement (local and extended), facial segments affected, special locations (eyelid, nasal tip, and parotid regions), ulceration, and depth of IHs. In the series of patients in this study, oral propranolol at a dosage of 2 mg/kg/day was a well-tolerated and effective treatment for IHs.
Introduction
Infantile hemangiomas (IHs) are benign tumours of endothelial cells that show a rapid proliferating phase, usually followed by variable degrees of spontaneous regression. However, problematic hemangiomas occur when they ulcerate, have massive growth, cause disfigurement, or impact normal function or cosmetic development.1 0901-5027/000001+05 $36.00/0
Common locations for problematic hemangiomas include the face, ear, orbit, and airway. These hemangiomas subsequently require early and aggressive treatment for ideal functional and cosmetic outcomes. Moreover, ulcerated IHs usually require treatment. Corticosteroids have been considered the first-line therapy for severe or complicated IHs.1–3 Other treatments, including interferon alpha, vincristine,
Key words: propranolol; beta-blockers; hemangioma; disfigurement; vascular tumour; surgery. Accepted for publication 18 March 2013
laser therapy, topical imiquimod, and surgical excision have been reported to be effective alternatives.4 However, all these options have potential side effects or unknown long-term safety.5 Currently, no medications exist that are specifically labelled to treat IHs. Recent reports of the successful treatment of IHs in a small number of patients using the beta-blocker agent propranolol have led to considerable
# 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015
YIJOM-2649; No of Pages 5
2
Sadykov et al.
excitement and have prompted the largescale use of propranolol for infants.5–9 The medical treatment of IHs in the maxillofacial region is important to cure complications and prevent disfigurement. Materials and methods
Patients with problematic hemangiomas in the maxillofacial region were reviewed from January 2011 to August 2012. Problematic hemangiomas were defined as hemangiomas with imminent undesirable functional or cosmetic outcomes if left untreated. Alternative interventions (steroid injections, laser treatment, and surgery) would have been performed in these patients despite the availability of oral propranolol. Consent to treat with propranolol and documentation of the disease response were received from all parents whose infants and children participated in the present study.
Severity scoring system
To measure the effect of the treatment, a photograph-based visual scale was used. Front and lateral pictures of each patient were taken before treatment and at every follow-up visit. The size and colour were the main features considered for the severity score of all IHs. Measurements were obtained through photographs and ultrasound investigation pictures taken during the scheduled and other non-programmed visits. The results of the treatment of the IHs were scored from 10 to 0, with a score of 10 indicating the original size and colour of the IHs before treatment and a score of 0 indicating completely normal skin. Improvement with a value of 1–3 was considered a poor response; 4–6 indicated an estimated 50% reduction of the IHs and was considered a good response; an improvement of 7 and more was considered an excellent response.
Evaluations before and during treatment
Statistical analysis
Before treatment, all patients underwent a cardiologic examination, including clinical examination, ultrasound investigation, electrocardiogram (ECG), and blood pressure measurements. Monthly follow-up visits were scheduled for severity scoring of the IHs, physical examination (including blood pressure and heart rate measurements), and recording of adverse effects, until the end of treatment. A cerebral magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) and a cardiac ultrasound were performed in patients with segmental facial IHs before initiating therapy to rule out PHACES syndrome (Posterior fossa anomalies, Hemangiomas, Arterial lesions, Cardiac abnormalities/aortic coarctation, Eye abnormalities, Sternal abnormalities).
The change in the severity score values of the IHs was evaluated using the t-test, comparing the different weeks. Statistical significance was set at a P-value of less than 0.05.
Dosage and duration
All patients were treated with oral propranolol; the initial dosage was 1 mg/kg/day divided three times for 1 day, and then the dosage was increased to the full dosage at 2 mg/kg/day. This dosage was maintained during the entire period of the study. A treatment period of at least 12 weeks was scheduled, however this duration could be further extended if the patient required additional time to achieve resolution of the problem that had led to the initiation of propranolol therapy. When such problems were resolved, or for IHs treated with propranolol in infancy that were expected to have completed their growth, the treatment was withdrawn.
Results
Seventy-one patients (15 male and 56 female; gender ratio 4:1) were enrolled in the study. Fifty patients started therapy before 6 months of age and 21 patients began treatment after 6 months of age (mean age 5.8 years). Facial IHs were divided as follows: frontal, nasal, temporal, maxillary, and mandibular. The IHs were regional in 21 patients and local in 50 patients. Propranolol had been the only treatment administered to 63 patients, whereas four patients had previously been treated with corticosteroids and four patients had previously been treated with surgical excision (Table 1). Propranolol was a rapid and effective treatment for IHs in this series of patients. At 4 weeks of treatment, the average score was 6.8 (P < 0.001 compared with the initial value); at 8 weeks of treatment, the average score was 5.6 (P < 0.001 compared with the value at 4 weeks); at 12 weeks, the average score was 4.8 (P < 0.05 compared with the value at 8 weeks); at 16 weeks, the average score was 4.4 (P < 0.01 compared with the value at 8 weeks); at 20 weeks, the average score was 3.9 (P < 0.01 compared with the value at 12 weeks); at 24 weeks, the average score was 3.9 (P < 0.01
Table 1. Characteristics of the study population. Characteristic
Number of patients (%)
Gender Female 56 (78.9) Male 15 (21.1) Mean age 5.8 months Range 1–45 months Age at the beginning of treatment <6 months 60 (84.5) >6 months 11 (15.5) Superficial 26 (36.6) Mixed 45 (63.4) Regional (extended) 21 (29.6) Local (localized) 50 (70.4) Facial segments Frontal 14 (19.7) Nasal 16 (22.5) Maxillary 12 (16.9) Mandibular 20 (28.2) Special locations Eyelid 11 (15.5) Parotid 5 (7.0) Nasal tip 6 (8.5) Previous treatments Surgery 4 (5.6) Corticosteroids 4 (5.6) Ulcerated hemangiomas 8 (11.3)
compared with the value at 12 weeks); at 28 weeks, the average score was 3.5 (P < 0.01 compared with the value at 16 weeks); and at 32 weeks, the average score was 3.2 (P < 0.01 compared with the value at 16 weeks). At 20 weeks of treatment, a mean score of 4 was achieved, thus indicating an average reduction of 60% of the IHs. After this initial response, less impressive size reductions were obtained after 20 weeks of treatment. Eight of 71 (11%) IHs had undergone a reduction of at least 50% in the severity score at 4 weeks, 24 of 71 (34%) had undergone a reduction of at least 50% in the severity score at 8 weeks, and 42 of 71 (59%) had undergone a reduction of at least 50% in the severity score at 16 weeks. We observed that the reduction in the IHs was more marked during the first 10 weeks of treatment, and the effect of propranolol on IHs seemed to stabilize after week 20. The mean duration of treatment was 20 weeks, and only 15 patients continued treatment for more than 32 weeks, achieving further lesion reduction. The low number of patients on extended therapy does not permit evaluation at this time (Figs 1–4). Adverse events
A few side effects were observed. All patients had regular blood pressure
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015
YIJOM-2649; No of Pages 5
Propranolol for infantile hemangiomas
3
values of blood pressure and heart rate carefully measured in these patients were minimally reduced from the baseline values and caused no symptoms. Discussion
Fig. 1. Poor response after propranolol therapy. A 6-month-old patient with oral ulcer bleeding who had a change in score of 3 after 72 weeks of treatment. The ulcer healed, with no bleeding, and the hemangioma was partly resolved.
monitoring; no patient showed symptomatic hypotension. The mean values of the lowest measurements showed a reduction in the blood pressure of 7 mmHg and 10 mmHg below mean baseline
measurements for systolic and diastolic blood pressure, respectively. Additionally, the mean of the lowest values of the heart rate in all patients was 18 bpm below the mean baseline. Hence, even the lowest
Fig. 2. Good response after propranolol therapy. A 4-month-old patient with no active opening of the left eye; ultrasound of the buccal region revealed lower lid IHs. After 28 weeks of treatment the IHs received a score of 4; ultrasound revealed that 50% of the IHs had resolved, with little change to the skin.
Le´aute´-Labre`ze et al.3 first reported the effectiveness of propranolol for the treatment of IHs. They presented the cases of 11 children with severe IHs, which improved after the first day of treatment. Since that report, many physicians have used propranolol for IHs. The results in our series of patients confirm that 2 mg/ kg/day propranolol is a useful treatment for severe or complicated IHs, achieving a rapid and significant reduction in their size. This reduction was mainly achieved during the first 20 weeks of treatment, and further treatment induced a less dramatic therapeutic effect. In our experience, propranolol was equally effective for the treatment of IHs in both genders, in both local and extended IHs, in IHs beyond the proliferative phase, and in every location on the skin treated in our series. However, we acknowledge that the number of patients in the present study was very small; data from additional patients and morphological evaluations are needed before definitive conclusions can be drawn. We did not include any patient with PHACES syndrome in our series, because we were concerned about the potential effects of propranolol on congenital heart disease, aortic coarctation, or cerebral blood flow in patients with cerebral vascular disease. In particular, there is a theoretical risk that propranolol might increase the likelihood of intracranial ischemia in patients with intracranial arteriopathy by lowering the blood pressure. Superficial ulceration was present in eight of our patients, and this low figure does not allow firm conclusions to be drawn concerning the efficacy of propranolol for ulcerated IHs. Nevertheless, all ulcers healed within 2 weeks of therapy, and it is our impression that propranolol is helpful for ulcerated IHs. However, it was not possible to compare these results with a control group. The potential side effects of beta-blockers are well known and include bradycardia, hypotension, and hypoglycaemia.9–12 Propranolol is contraindicated in patients with asthma, and it is not recommended during episodes of bronchiolitis.13,14 Very few adverse effects were observed in our series, and the ones that occurred were mild and did not imply dose reduction or treatment withdrawal.
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015
YIJOM-2649; No of Pages 5
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Sadykov et al.
Fig. 3. Good response after propranolol therapy. A 10-month-old patient with IHs in the buccal and parotid ear regions. Invasion into the external ear canal was evident. The IHs received a score of 6 after 8 weeks of treatment. Ultrasound control revealed that 50% of the IHs had resolved, with little change to the skin.
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015
YIJOM-2649; No of Pages 5
Propranolol for infantile hemangiomas
6.
7.
8.
9.
10.
11.
12.
Fig. 4. Poor response after propranolol therapy. A 10-month-old patient with ulcerative scarring of the left side of the nose, upper and lower eyelid, infraorbital region, and buccal (maxillary) region. After 24 weeks of treatment, the IHs had a change in score of 3.
In conclusion, in the series of patients in the present study, 2 mg/kg/day oral propranolol was a well-tolerated and effective treatment for IHs. Funding
There was no funding for this study. Competing interests
There are no conflicts of interest. Ethical approval
This study was approved by the ethics board of the University Tashkent Medical Academy, Uzbekistan.
References 1. Sundine MJ, Wirth GA. Hemangiomas: an overview. Clin Pediatr 2007;46:206–21. 2. Martinez MI, Sanchez-Carpintero I, North PE, Mihm Jr MC. Infantile hemangioma: clinical resolution with 5% imiquimod cream. Arch Dermatol 2002;138:881–4. 3. Le´aute´-Labre`ze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taı¨eb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649–51. 4. Vassallo P, Forte R, Di Mezza A, Magli A. Treatment of Infantile capillary hemangioma of the eyelid with systemic propranolol. Am J Ophthalmol 2013;155(1):165–70. 5. Sans V, de la Roque ED, Berge J, Grenier N, Boralevi F, Mazereeuw-Hautier J, et al. Propranolol for severe infantile hemangiomas:
13. 14.
5
follow-up report. Pediatrics 2009;124: e423–31. Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med 2008;359:2846–7. Phillips RJ, Penington AJ, Bekhor PS, Crock CM. Use of propranolol for treatment of infantile haemangiomas in an outpatient setting. J Paediatr Child Health 2012;48: 902–6. Martin K, Bleib F, Chamlin SL, Drolet BA, Robert J. Propranolol treatment of infantile hemangiomas: anticipatory guidance for parents and caretakers. Pediatr Dermatol 2013;30: 155–9. Lawley LP, Siegfried E, Todd JL. Propranolol treatment for hemangioma of infancy: risks and recommendations. Pediatr Dermatol 2009;26:610–4. Haggstrom AN, Lammer EJ, Schneider RA. Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Pediatrics 2006;117:698–703. Manunza F, Syed S, Laguda B. Propranolol for complicated infantile haemangiomas: a case series of 30 infants. Br J Dermatol 2010;162:466–8. Theletsane T, Redfern A, Raynham O. Lifethreatening infantile haemangioma: a dramatic response to propranolol. J Eur Acad Dermatol Venereol 2009;23:1465–6. Farel RM. Drug therapy for asthma. N Engl J Med 2009;360:2579. Dennis KE, Froman D, Morrison AS. Betablocker therapy: identification and management of side effects. Heart Lung 1991;20: 459–63.
Address: Rasul Rustamovich Sadykov Tashkent Medical Academy St. M. Rieziy 100007 Tashkent Uzbekistan Tel: +998 909540977 E-mails: [email protected], [email protected]
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015
Int. J. Oral Maxillofac. Surg. 2013; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2013.03.015, available online at http://www.sciencedirect.com
Clinical Paper Clinical Pathology
Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region
R. R. Sadykova,b, F. Podmellec, R. A. Sadykovb, K. R. Kasimovad, H. R. Metellmannc a
Department of General Surgery with Plastic Operations, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany; bTashkent Medical Academy, Tashkent, Uzbekistan; c Department of Maxillofacial and Plastic Surgery, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany; dOntario Cancer Institute, Biophysics & Bioimaging, Toronto, Ontario, Canada
R. R. Sadykov, F. Podmelle, R. A. Sadykov, K. R. Kasimova, H. R. Metellmann: Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region. Int. J. Oral Maxillofac. Surg. 2013; xxx: xxx–xxx. # 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. Propranolol has been used successfully in a limited number of children with infantile hemangiomas (IHs). This study describes the efficacy and adverse effects of propranolol in IH. Seventy-one infants with IHs were treated with oral propranolol, administered at a dose of 2 mg/kg/day, for at least 12 weeks. A photograph-based severity scoring assessment was performed by five observers to evaluate efficacy, utilizing a score of 10 as the original IHs before treatment and 0 as completely normal skin. The mean of the five independent measurements was used in the analysis. Propranolol was a rapid and effective treatment for IHs at 4 weeks (P < 0.001), at 8 weeks (P < 0.001 compared with the value at 4 weeks), at 12 weeks (P < 0.05 compared with the value at 8 weeks), and thereafter up to 32 weeks (P < 0.01 compared with the value at 16 weeks). The response of IHs to propranolol was similar regardless of gender, age at the onset of treatment, type of involvement (local and extended), facial segments affected, special locations (eyelid, nasal tip, and parotid regions), ulceration, and depth of IHs. In the series of patients in this study, oral propranolol at a dosage of 2 mg/kg/day was a well-tolerated and effective treatment for IHs.
Introduction
Infantile hemangiomas (IHs) are benign tumours of endothelial cells that show a rapid proliferating phase, usually followed by variable degrees of spontaneous regression. However, problematic hemangiomas occur when they ulcerate, have massive growth, cause disfigurement, or impact normal function or cosmetic development.1 0901-5027/000001+05 $36.00/0
Common locations for problematic hemangiomas include the face, ear, orbit, and airway. These hemangiomas subsequently require early and aggressive treatment for ideal functional and cosmetic outcomes. Moreover, ulcerated IHs usually require treatment. Corticosteroids have been considered the first-line therapy for severe or complicated IHs.1–3 Other treatments, including interferon alpha, vincristine,
Key words: propranolol; beta-blockers; hemangioma; disfigurement; vascular tumour; surgery. Accepted for publication 18 March 2013
laser therapy, topical imiquimod, and surgical excision have been reported to be effective alternatives.4 However, all these options have potential side effects or unknown long-term safety.5 Currently, no medications exist that are specifically labelled to treat IHs. Recent reports of the successful treatment of IHs in a small number of patients using the beta-blocker agent propranolol have led to considerable
# 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015
YIJOM-2649; No of Pages 5
2
Sadykov et al.
excitement and have prompted the largescale use of propranolol for infants.5–9 The medical treatment of IHs in the maxillofacial region is important to cure complications and prevent disfigurement. Materials and methods
Patients with problematic hemangiomas in the maxillofacial region were reviewed from January 2011 to August 2012. Problematic hemangiomas were defined as hemangiomas with imminent undesirable functional or cosmetic outcomes if left untreated. Alternative interventions (steroid injections, laser treatment, and surgery) would have been performed in these patients despite the availability of oral propranolol. Consent to treat with propranolol and documentation of the disease response were received from all parents whose infants and children participated in the present study.
Severity scoring system
To measure the effect of the treatment, a photograph-based visual scale was used. Front and lateral pictures of each patient were taken before treatment and at every follow-up visit. The size and colour were the main features considered for the severity score of all IHs. Measurements were obtained through photographs and ultrasound investigation pictures taken during the scheduled and other non-programmed visits. The results of the treatment of the IHs were scored from 10 to 0, with a score of 10 indicating the original size and colour of the IHs before treatment and a score of 0 indicating completely normal skin. Improvement with a value of 1–3 was considered a poor response; 4–6 indicated an estimated 50% reduction of the IHs and was considered a good response; an improvement of 7 and more was considered an excellent response.
Evaluations before and during treatment
Statistical analysis
Before treatment, all patients underwent a cardiologic examination, including clinical examination, ultrasound investigation, electrocardiogram (ECG), and blood pressure measurements. Monthly follow-up visits were scheduled for severity scoring of the IHs, physical examination (including blood pressure and heart rate measurements), and recording of adverse effects, until the end of treatment. A cerebral magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) and a cardiac ultrasound were performed in patients with segmental facial IHs before initiating therapy to rule out PHACES syndrome (Posterior fossa anomalies, Hemangiomas, Arterial lesions, Cardiac abnormalities/aortic coarctation, Eye abnormalities, Sternal abnormalities).
The change in the severity score values of the IHs was evaluated using the t-test, comparing the different weeks. Statistical significance was set at a P-value of less than 0.05.
Dosage and duration
All patients were treated with oral propranolol; the initial dosage was 1 mg/kg/day divided three times for 1 day, and then the dosage was increased to the full dosage at 2 mg/kg/day. This dosage was maintained during the entire period of the study. A treatment period of at least 12 weeks was scheduled, however this duration could be further extended if the patient required additional time to achieve resolution of the problem that had led to the initiation of propranolol therapy. When such problems were resolved, or for IHs treated with propranolol in infancy that were expected to have completed their growth, the treatment was withdrawn.
Results
Seventy-one patients (15 male and 56 female; gender ratio 4:1) were enrolled in the study. Fifty patients started therapy before 6 months of age and 21 patients began treatment after 6 months of age (mean age 5.8 years). Facial IHs were divided as follows: frontal, nasal, temporal, maxillary, and mandibular. The IHs were regional in 21 patients and local in 50 patients. Propranolol had been the only treatment administered to 63 patients, whereas four patients had previously been treated with corticosteroids and four patients had previously been treated with surgical excision (Table 1). Propranolol was a rapid and effective treatment for IHs in this series of patients. At 4 weeks of treatment, the average score was 6.8 (P < 0.001 compared with the initial value); at 8 weeks of treatment, the average score was 5.6 (P < 0.001 compared with the value at 4 weeks); at 12 weeks, the average score was 4.8 (P < 0.05 compared with the value at 8 weeks); at 16 weeks, the average score was 4.4 (P < 0.01 compared with the value at 8 weeks); at 20 weeks, the average score was 3.9 (P < 0.01 compared with the value at 12 weeks); at 24 weeks, the average score was 3.9 (P < 0.01
Table 1. Characteristics of the study population. Characteristic
Number of patients (%)
Gender Female 56 (78.9) Male 15 (21.1) Mean age 5.8 months Range 1–45 months Age at the beginning of treatment <6 months 60 (84.5) >6 months 11 (15.5) Superficial 26 (36.6) Mixed 45 (63.4) Regional (extended) 21 (29.6) Local (localized) 50 (70.4) Facial segments Frontal 14 (19.7) Nasal 16 (22.5) Maxillary 12 (16.9) Mandibular 20 (28.2) Special locations Eyelid 11 (15.5) Parotid 5 (7.0) Nasal tip 6 (8.5) Previous treatments Surgery 4 (5.6) Corticosteroids 4 (5.6) Ulcerated hemangiomas 8 (11.3)
compared with the value at 12 weeks); at 28 weeks, the average score was 3.5 (P < 0.01 compared with the value at 16 weeks); and at 32 weeks, the average score was 3.2 (P < 0.01 compared with the value at 16 weeks). At 20 weeks of treatment, a mean score of 4 was achieved, thus indicating an average reduction of 60% of the IHs. After this initial response, less impressive size reductions were obtained after 20 weeks of treatment. Eight of 71 (11%) IHs had undergone a reduction of at least 50% in the severity score at 4 weeks, 24 of 71 (34%) had undergone a reduction of at least 50% in the severity score at 8 weeks, and 42 of 71 (59%) had undergone a reduction of at least 50% in the severity score at 16 weeks. We observed that the reduction in the IHs was more marked during the first 10 weeks of treatment, and the effect of propranolol on IHs seemed to stabilize after week 20. The mean duration of treatment was 20 weeks, and only 15 patients continued treatment for more than 32 weeks, achieving further lesion reduction. The low number of patients on extended therapy does not permit evaluation at this time (Figs 1–4). Adverse events
A few side effects were observed. All patients had regular blood pressure
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015
YIJOM-2649; No of Pages 5
Propranolol for infantile hemangiomas
3
values of blood pressure and heart rate carefully measured in these patients were minimally reduced from the baseline values and caused no symptoms. Discussion
Fig. 1. Poor response after propranolol therapy. A 6-month-old patient with oral ulcer bleeding who had a change in score of 3 after 72 weeks of treatment. The ulcer healed, with no bleeding, and the hemangioma was partly resolved.
monitoring; no patient showed symptomatic hypotension. The mean values of the lowest measurements showed a reduction in the blood pressure of 7 mmHg and 10 mmHg below mean baseline
measurements for systolic and diastolic blood pressure, respectively. Additionally, the mean of the lowest values of the heart rate in all patients was 18 bpm below the mean baseline. Hence, even the lowest
Fig. 2. Good response after propranolol therapy. A 4-month-old patient with no active opening of the left eye; ultrasound of the buccal region revealed lower lid IHs. After 28 weeks of treatment the IHs received a score of 4; ultrasound revealed that 50% of the IHs had resolved, with little change to the skin.
Le´aute´-Labre`ze et al.3 first reported the effectiveness of propranolol for the treatment of IHs. They presented the cases of 11 children with severe IHs, which improved after the first day of treatment. Since that report, many physicians have used propranolol for IHs. The results in our series of patients confirm that 2 mg/ kg/day propranolol is a useful treatment for severe or complicated IHs, achieving a rapid and significant reduction in their size. This reduction was mainly achieved during the first 20 weeks of treatment, and further treatment induced a less dramatic therapeutic effect. In our experience, propranolol was equally effective for the treatment of IHs in both genders, in both local and extended IHs, in IHs beyond the proliferative phase, and in every location on the skin treated in our series. However, we acknowledge that the number of patients in the present study was very small; data from additional patients and morphological evaluations are needed before definitive conclusions can be drawn. We did not include any patient with PHACES syndrome in our series, because we were concerned about the potential effects of propranolol on congenital heart disease, aortic coarctation, or cerebral blood flow in patients with cerebral vascular disease. In particular, there is a theoretical risk that propranolol might increase the likelihood of intracranial ischemia in patients with intracranial arteriopathy by lowering the blood pressure. Superficial ulceration was present in eight of our patients, and this low figure does not allow firm conclusions to be drawn concerning the efficacy of propranolol for ulcerated IHs. Nevertheless, all ulcers healed within 2 weeks of therapy, and it is our impression that propranolol is helpful for ulcerated IHs. However, it was not possible to compare these results with a control group. The potential side effects of beta-blockers are well known and include bradycardia, hypotension, and hypoglycaemia.9–12 Propranolol is contraindicated in patients with asthma, and it is not recommended during episodes of bronchiolitis.13,14 Very few adverse effects were observed in our series, and the ones that occurred were mild and did not imply dose reduction or treatment withdrawal.
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015
YIJOM-2649; No of Pages 5
4
Sadykov et al.
Fig. 3. Good response after propranolol therapy. A 10-month-old patient with IHs in the buccal and parotid ear regions. Invasion into the external ear canal was evident. The IHs received a score of 6 after 8 weeks of treatment. Ultrasound control revealed that 50% of the IHs had resolved, with little change to the skin.
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015
YIJOM-2649; No of Pages 5
Propranolol for infantile hemangiomas
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Fig. 4. Poor response after propranolol therapy. A 10-month-old patient with ulcerative scarring of the left side of the nose, upper and lower eyelid, infraorbital region, and buccal (maxillary) region. After 24 weeks of treatment, the IHs had a change in score of 3.
In conclusion, in the series of patients in the present study, 2 mg/kg/day oral propranolol was a well-tolerated and effective treatment for IHs. Funding
There was no funding for this study. Competing interests
There are no conflicts of interest. Ethical approval
This study was approved by the ethics board of the University Tashkent Medical Academy, Uzbekistan.
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Address: Rasul Rustamovich Sadykov Tashkent Medical Academy St. M. Rieziy 100007 Tashkent Uzbekistan Tel: +998 909540977 E-mails: [email protected], [email protected]
Please cite this article in press as: Sadykov RR, et al. Use of propranolol for the treatment infantile hemangiomas in the maxillofacial region, Int J Oral Maxillofac Surg (2013), http://dx.doi.org/10.1016/j.ijom.2013.03.015