CLINICAL STUDY
Oral Propranolol for Parotid Infantile Hemangiomas Gang Li, MS, Da-Peng Xu, MS, Hua-Liang Sun, MS, Chen Cheng, MS, Zi-Mei Liu, MS, Shan-Long Xi, MS, and Xu-Kai Wang, DDS, PhD
Abstract: The aim of our study was to assess the efficacy and safety of oral propranolol for the treatment of parotid infantile hemangiomas. Between October 2009 and January 2013, propranolol was given orally to 30 infants with proliferating hemangiomas at a dose of 1.0 to 1.5 mg/kg per day in our department. The patients included 12 male infants and 18 female infants, aged between 2 and 13 months, with a median of 5.9 months. The lesions were located in the parotid region and measured from 1.5 cm 2 cm 0.5 cm to 6 cm 8 cm 3 cm in volume. Oral propranolol was administered once daily for a mean duration of 22.7 weeks (range, 14–32 wk). Follow-up times were from 1 to 10 months (median, 6.4 mo). Changes in the color and size of the tumor were recorded using hemisphere measurements and digital photographs. The treatment results were scored according to a 4-point scale. Overall response was graded scale 4 (excellent) in 18 patients, scale 3 (good) in 11 patients, scale 2 (moderate) in 1 patient, and scale 1 (poor) in none. No major collateral effects and rebounds were observed in any of the patients. Oral propranolol was a well-tolerated and effective treatment with mild adverse effects for parotid infantile hemangiomas. Key Words: Infantile hemangiomas, oral propranolol, parotid region (J Craniofac Surg 2015;26: 438–440)
I
nfantile hemangiomas (IHs) are the most common tumors in infancy and childhood, affecting as many as 4% to 10% of children and even 23% of premature infants, with a slight female predominance. Infantile hemangiomas are characterized by vascular endothelial cell proliferation, and the natural course of IHs includes 3 distinct phases: the proliferative (0–1 y), involution (1–5 y), and involuted (5–10 y) phases.1 Because hemangiomas can regress spontaneously, growth during the early phase is frequently rapid and unpredictable. Parotid hemangioma is the most common salivary gland hemangioma in children. Complicated parotid proliferating hemangioma can cause life-threatening airway obstruction, ulceration, and risk for
delay in language acquisition due to ear involvement; patients should, therefore, receive early treatment.2 In 2008, Léauté-Labrèze et al3 reported the incidental finding that hemangiomas regress in children treated with propranolol, a nonselective β-blocker used to treat infants with cardiac and renal conditions. Since then, propranolol has been gradually accepted as the treatment of choice for hemangioma. We began the administration of propranolol for IHs at the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University in 2009, with 30 cases occurring in the parotid region and showing an obvious curative effect, as subsequently reported.
PATIENTS AND METHODS Patients Thirty patients with parotid gland proliferating hemangioma were treated with propranolol orally from October 2009 to January 2013 at the Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, China Medical University. There were 12 male infants and 18 female infants, who had a mean age of 5.9 months (range, 2–13 mo). The volume of these tumors varied from 1.5 cm 2 cm 0.5 cm to 6 cm 8 cm 3 cm, as measured using Doppler ultrasonography scans. The diagnosis of hemangioma was based on clinical appearance and Doppler ultrasonography scans. Patient files were collected, including clinical characteristics, efficacy of treatment, and adverse reactions. Our inclusion criteria for this study were as follows: (1) no infants were given any treatment before propranolol; (2) any other vascular malformations were excluded, using the classification and nomenclature of vascular anomalies proposed by Waner and Suen4; and (3) patients had normal chest x-ray, electrocardiogram, blood coagulation, liver function, renal function, and routine blood examination findings. The ethical review board of China Medical University approved the study, and all infants' parents provided written informed consent.
Treatment Protocol From the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning Province, People's Republic of China. Received April 1, 2014. Accepted for publication September 13, 2014. Address correspondence and reprint requests to Xu-Kai Wang, DDS, PhD, Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, No. 117, Nan Jing N St, Heping District, Shenyang 110002, Liaoning Province, People's Republic of China; E-mail: [email protected] The authors report no conflicts of interest. Copyright © 2015 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000001335
438
All patients were admitted to the hospital while the hemangiomas were in the rapid proliferating phase. Propranolol (10-mg tablet; Tianjin Lisheng Pharmaceutical Co Ltd) was prepared from tablet to a suitable solution at a dose of 1.0 to 1.5 mg/kg per day (patients younger than 3 mo took 1.0 mg/kg, and those older than 3 mo took 1.5 mg/kg), in 1 dose. For the first 3 to 5 days of management, blood pressure, heart rate, and blood glucose levels were monitored at the inpatient ward. The patients who had no adverse reactions were given propranolol orally by their parents or guardians after discharge. The parents were instructed to detect adverse effects and discontinue administration of the drug if any symptoms appeared. All patients were followed up every month after discharge. The drug dose was altered according to weight changes and the degree of adverse reactions when following up. Treatment
The Journal of Craniofacial Surgery • Volume 26, Number 2, March 2015
Copyright © 2015 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
The Journal of Craniofacial Surgery • Volume 26, Number 2, March 2015
Oral Propranolol for Parotid IHs
FIGURE 1. Before starting the treatment, a female infant had a huge hemangioma in the left parotid region.
was continued until the patients were 1 year old or until complete resolution occurred.5 The follow-up timeline ranged from 1 month to 10 months.
Evaluation of Efficacy Therapeutic outcomes were evaluated using Doppler ultrasonography scans. The results were measured using hemisphere measurement6 and photographs. The clinical effect of treatment was graded on the 4-point scale proposed by Achauer et al.7 On the basis of improvement in volume, color, and texture after treatment, the tumors were categorized as follows: scale 1 (poor), tumor volume decreased by less than 25%; scale 2 (moderate), tumor volume decreased between 26% and 50%; scale 3 (good), tumor volume decreased between 51% and 75%; and scale 4 (excellent), tumor volume decreased between 76% and 100%.
FIGURE 3. Before treatment, a male infant had a huge hemangioma in the right parotid region.
had taken propranolol for more than 12 hours, and none required special treatment. There were no severe adverse gastrointestinal reactions.
DISCUSSION
Most of the tumors decreased in size after the treatment. Efficacy was evaluated as follows: scale 4 (excellent) in 18 patients (60%), scale 3 (good) in 11 patients (36.7%), and scale 2 (moderate) in 1 patient (3.3%). The parents were quite satisfied with the results. Twenty-four hours after the first dose, the color of the tumor lightened and the texture became softer. In 10 cases, the patients took the drug for 16 weeks; in 13 cases, for 24 weeks; in 4 cases, for 28 weeks; and in 3 cases, treatment continued for 32 weeks, with an overall mean duration of 22.7 weeks. Typical cases of the patients are shown in Figures 1 to 4. In all 30 infants, the heart rate slowed, the blood pressure dropped, and the breathing rate slowed after the oral administration of propranolol. However, the changes in the previously mentioned signs were not commonly associated with observable clinical symptoms and each of these signs returned to normal after the patients
Infantile parotid proliferating hemangioma, which is the most common parotid tumor type, most commonly occurs within 1 year after birth and accounts for more than 50% of parotid gland tumors in infants.8 The main complications are hemorrhage, ulcer, infection, and external auditory canal compression. Hemangiomas located in the face will bring a serious psychological burden to patients. At present, the methods for treatment of IHs are conservative and tend to observe such as drug or laser therapy. Hemangiomas with less influence on patients and those that do not affect appearance and function mainly require “wait and see”; however, patients prone to rapid growth, infection, ulcers, or bleeding complications during the observation period should be treated immediately. Common drugs used to treat hemangioma include corticosteroids, anticancer drugs, interferon, and imiquimod,9–14 but these methods cause different degrees of adverse effects. Laser treatment is only suitable for early superficial hemangiomas. The pointed or patchy lesions of small red ranges found shortly after birth can be treated early using laser removal. There are various arguments with respect to the timing of surgical intervention for parotid region hemangiomas; the optimal operation time is uncertain. Surgical treatment should be carefully chosen because of its main complications, which include temporary paralysis, recurrence, hematoma, salivary fistula, auriculotemporal nerve syndrome, scar, and facial nerve injury. Since Léauté-Labrèze et al3 first reported in 2008 the incidental finding that hemangiomas regressed in children treated with propranolol, physicians worldwide have started to use the drug to treat problematic IHs with remarkable curability and
FIGURE 2. The tumor almost disappeared after oral propranolol treatment for 8 months.
FIGURE 4. The tumor completely disappeared after oral propranolol treatment for 6 months.
RESULTS
© 2015 Mutaz B. Habal, MD
Copyright © 2015 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
439
Li et al
The Journal of Craniofacial Surgery • Volume 26, Number 2, March 2015
fewer adverse effects.15 We have used propranolol to treat patients with parotid proliferating IHs, and at the onset of propranolol, we found that the shape recovery of lesions was significant, particularly in cases of large hemangiomas; no insidious adverse gastrointestinal reactions or changes in mental status were observed. The potential adverse effects of propranolol in the treatment of hemangiomas mainly include bradycardia, hypotension, and hypoglycemia.16 In the current study, however, all vital signs returned to normal after the propranolol had been taken for more than 12 hours, and no special treatment was required. Because of the current lack of uniform safe dosage standards of propranolol for the treatment of hemangiomas, we reasonably strived to conclude, on the basis of reports of domestic scholars and our considerable clinical experience, that propranolol of 1.0 mg/kg for patients younger than 3 months and that of 1.5 mg/kg for those older than 3 months are dosages that ensure the safety of patients. However, we still suggest that it should be necessary for an infant to have a detailed general examination before propranolol is prescribed. In addition, all infants should remain under observation at the inpatient hospital for 3 to 5 days after the first treatment, with blood pressure, heart rate, and adverse reactions closely monitored. Propranolol is mainly used in the clinical treatment of myocardial infarction, hypertension, angina, and other cardiovascular diseases, and the main mechanism of the drug is as a nonselective β-blocker, blocking the β1 and β2 cardiac receptors. Propranolol was effective in the treatment of the hemangiomas; however, the mechanism responsible for this effect is still not clear. The main proposed mechanisms involved in the effectiveness of propranolol for IH include vasoconstriction, inhibition of angiogenesis, inhibition of the renin-angiotensin system, and induction of apoptosis.17,18 Apoptosis of endothelial cells in the hemangioma is presumed to be the most likely mechanism involved in its natural involution, and propranolol has been proven to induce apoptosis of such hemangioma cells. As suggested, apoptosis may not be complete in all cases after treatment withdrawal, and some endothelial cells may thus remain proliferative after treatment is stopped. Some scholars have detected matrix metalloproteinases 2 and matrix metalloproteinases 9 in the urine of patients with hemangiomas before and after propranolol treatment. Using healthy children as a control, 1 report suggested that the contents of matrix metalloproteinases in patients with hemangiomas were lower than those in healthy babies; 2 weeks after propranolol treatment, these levels increased significantly, but there were no significant differences in matrix metalloproteinase 9 levels between the experimental group and control group.19 Yuan et al20 detected the contents of vascular endothelial growth factor and endothelial nitric oxide synthase in peripheral blood in 35 cases of hemangioma before and after oral propranolol. The authors discovered that, after 2 months of treatment, the levels of vascular endothelial growth factor and endothelial nitric oxide synthase in the peripheral blood were lower than those before the treatment. However, this is not sufficient to explain the mechanism by which propranolol is effective for treating hemangioma; further research is still needed. This small-sample retrospective study indicated that oral propranolol had the desired effect on infantile parotid gland hemangiomas. The drug should thus now be used as a first-line treatment of hemangiomas when intervention is required. A cohort study with a majority of patients will still be necessary to establish the appropriate dose and duration of treatment.
440
REFERENCES 1. Weiss I, Lipari BA, Meyer L, et al. Current treatment of parotid hemangiomas. Laryngoscope. 2011;121:1642–1650. 2. Enjolras O, Gelbert F. Superficial hemangiomas: associations and management. Pediatr Dermatol. 1997;14:173–179. 3. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–2651. 4. Waner M, Suen JY. Management of congenital vascular lesions of the head and neck. Oncology. 1995;9:989–994. 5. Muneer AM, Prema M. Effect of propranolol vs prednisolone vs propranolol with prednisolone in the management of infantile hemangioma: a randomized controlled study. J Pediatr Surg. 2013;48:2453–2459. 6. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics. 2006;118:882–887. 7. Achauer BM, Chang CJ, Vander Kam VM. Management of hemangioma of infancy:review of 245 patients. Plast Reconstr Surg. 1997;99:1301–1308. 8. Mantadakis E, Tsouvala E, Deftereos S, et al. Involution of a large parotid hemangioma with oral propranolol:an illustrative report and review of the literature. Case Rep Pediatr. 2012;2012:353812. 9. Bennett ML, Fleischer AB Jr, Chamlin SL, et al. Oral corticosteroid use is effective for cutaneous hemangiomas:an evidence-based evaluation. Arch Dermatol. 2001;137:1208–1213. 10. Gangopadhyay AN, Sharma SP, Gopal SC. Local steroid therapy in cutaneous hemangiomas. Indian Pediatr. 1996;33:31–33. 11. Muir T, Kirsten M, Fourie P, et al. Intralesional bleomycin injection (IBI) treatment for haemangiomas and congenital vascular malformations. Pediatr Surg Int. 2004;19:766–773. 12. Omidvari S, Nezakatgoo N, Ahmadloo N. Role of intralesional bleomycin in the treatment of complicated hemangiomas: prospective clinical study. Dermatol Surg. 2005;31:499–501. 13. Enjolras O, Brevie`re GM, Roger G, et al. Vincristine treatment for function and life-threatening infantile hemangioma. Arch Pediatr. 2004;11:99–107. 14. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med. 1992;326:1456–1463. 15. Qin ZP, Liu XJ, Li KL, et al. Treatment of infantile hemangiomas with low-dose propranolol: evaluation of short-term efficacy and safety. Zhonghua Yi Xue Za Zhi. 2009;89:3130–3134. 16. Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med. 2008;359:2846–2847. 17. Storch CH, Hoeger PH. Propranolol for infantile hemangiomas:insights into the molecular mechanisms of action. Br J Dermatol. 2010;163:269–274. 18. Itinteang T, Brasch HD, Tan ST, et al. Expression of components of the renin-angiotensin system in proliferating infantile hemangioma may account for the propranolol-induced accelerated involution. J Plast Reconstr Aesthet Surg. 2010;64:759–765. 19. Kleber CJ, Spiess A, Kleber JB, et al. Urinary matrix metalloproteinases-2/9 in healthy infants and hemangioma patients prior to and during propranlol therapy. Eur J Pediatr. 2012;171:941–946. 20. Yuan WL, Jin ZL, Wei JJ, et al. Propranolol given orally for proliferating infantile haemangiomas: analysis of efficacy and serological changes in vascular endothelial growth factor and endothelial nitric oxide synthase in 35 patients. Br J Oral Maxillofac Surg. 2013;51:656–661.
© 2015 Mutaz B. Habal, MD
Copyright © 2015 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
Oral Propranolol for Parotid Infantile Hemangiomas Gang Li, MS, Da-Peng Xu, MS, Hua-Liang Sun, MS, Chen Cheng, MS, Zi-Mei Liu, MS, Shan-Long Xi, MS, and Xu-Kai Wang, DDS, PhD
Abstract: The aim of our study was to assess the efficacy and safety of oral propranolol for the treatment of parotid infantile hemangiomas. Between October 2009 and January 2013, propranolol was given orally to 30 infants with proliferating hemangiomas at a dose of 1.0 to 1.5 mg/kg per day in our department. The patients included 12 male infants and 18 female infants, aged between 2 and 13 months, with a median of 5.9 months. The lesions were located in the parotid region and measured from 1.5 cm 2 cm 0.5 cm to 6 cm 8 cm 3 cm in volume. Oral propranolol was administered once daily for a mean duration of 22.7 weeks (range, 14–32 wk). Follow-up times were from 1 to 10 months (median, 6.4 mo). Changes in the color and size of the tumor were recorded using hemisphere measurements and digital photographs. The treatment results were scored according to a 4-point scale. Overall response was graded scale 4 (excellent) in 18 patients, scale 3 (good) in 11 patients, scale 2 (moderate) in 1 patient, and scale 1 (poor) in none. No major collateral effects and rebounds were observed in any of the patients. Oral propranolol was a well-tolerated and effective treatment with mild adverse effects for parotid infantile hemangiomas. Key Words: Infantile hemangiomas, oral propranolol, parotid region (J Craniofac Surg 2015;26: 438–440)
I
nfantile hemangiomas (IHs) are the most common tumors in infancy and childhood, affecting as many as 4% to 10% of children and even 23% of premature infants, with a slight female predominance. Infantile hemangiomas are characterized by vascular endothelial cell proliferation, and the natural course of IHs includes 3 distinct phases: the proliferative (0–1 y), involution (1–5 y), and involuted (5–10 y) phases.1 Because hemangiomas can regress spontaneously, growth during the early phase is frequently rapid and unpredictable. Parotid hemangioma is the most common salivary gland hemangioma in children. Complicated parotid proliferating hemangioma can cause life-threatening airway obstruction, ulceration, and risk for
delay in language acquisition due to ear involvement; patients should, therefore, receive early treatment.2 In 2008, Léauté-Labrèze et al3 reported the incidental finding that hemangiomas regress in children treated with propranolol, a nonselective β-blocker used to treat infants with cardiac and renal conditions. Since then, propranolol has been gradually accepted as the treatment of choice for hemangioma. We began the administration of propranolol for IHs at the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University in 2009, with 30 cases occurring in the parotid region and showing an obvious curative effect, as subsequently reported.
PATIENTS AND METHODS Patients Thirty patients with parotid gland proliferating hemangioma were treated with propranolol orally from October 2009 to January 2013 at the Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, China Medical University. There were 12 male infants and 18 female infants, who had a mean age of 5.9 months (range, 2–13 mo). The volume of these tumors varied from 1.5 cm 2 cm 0.5 cm to 6 cm 8 cm 3 cm, as measured using Doppler ultrasonography scans. The diagnosis of hemangioma was based on clinical appearance and Doppler ultrasonography scans. Patient files were collected, including clinical characteristics, efficacy of treatment, and adverse reactions. Our inclusion criteria for this study were as follows: (1) no infants were given any treatment before propranolol; (2) any other vascular malformations were excluded, using the classification and nomenclature of vascular anomalies proposed by Waner and Suen4; and (3) patients had normal chest x-ray, electrocardiogram, blood coagulation, liver function, renal function, and routine blood examination findings. The ethical review board of China Medical University approved the study, and all infants' parents provided written informed consent.
Treatment Protocol From the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning Province, People's Republic of China. Received April 1, 2014. Accepted for publication September 13, 2014. Address correspondence and reprint requests to Xu-Kai Wang, DDS, PhD, Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, No. 117, Nan Jing N St, Heping District, Shenyang 110002, Liaoning Province, People's Republic of China; E-mail: [email protected] The authors report no conflicts of interest. Copyright © 2015 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000001335
438
All patients were admitted to the hospital while the hemangiomas were in the rapid proliferating phase. Propranolol (10-mg tablet; Tianjin Lisheng Pharmaceutical Co Ltd) was prepared from tablet to a suitable solution at a dose of 1.0 to 1.5 mg/kg per day (patients younger than 3 mo took 1.0 mg/kg, and those older than 3 mo took 1.5 mg/kg), in 1 dose. For the first 3 to 5 days of management, blood pressure, heart rate, and blood glucose levels were monitored at the inpatient ward. The patients who had no adverse reactions were given propranolol orally by their parents or guardians after discharge. The parents were instructed to detect adverse effects and discontinue administration of the drug if any symptoms appeared. All patients were followed up every month after discharge. The drug dose was altered according to weight changes and the degree of adverse reactions when following up. Treatment
The Journal of Craniofacial Surgery • Volume 26, Number 2, March 2015
Copyright © 2015 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
The Journal of Craniofacial Surgery • Volume 26, Number 2, March 2015
Oral Propranolol for Parotid IHs
FIGURE 1. Before starting the treatment, a female infant had a huge hemangioma in the left parotid region.
was continued until the patients were 1 year old or until complete resolution occurred.5 The follow-up timeline ranged from 1 month to 10 months.
Evaluation of Efficacy Therapeutic outcomes were evaluated using Doppler ultrasonography scans. The results were measured using hemisphere measurement6 and photographs. The clinical effect of treatment was graded on the 4-point scale proposed by Achauer et al.7 On the basis of improvement in volume, color, and texture after treatment, the tumors were categorized as follows: scale 1 (poor), tumor volume decreased by less than 25%; scale 2 (moderate), tumor volume decreased between 26% and 50%; scale 3 (good), tumor volume decreased between 51% and 75%; and scale 4 (excellent), tumor volume decreased between 76% and 100%.
FIGURE 3. Before treatment, a male infant had a huge hemangioma in the right parotid region.
had taken propranolol for more than 12 hours, and none required special treatment. There were no severe adverse gastrointestinal reactions.
DISCUSSION
Most of the tumors decreased in size after the treatment. Efficacy was evaluated as follows: scale 4 (excellent) in 18 patients (60%), scale 3 (good) in 11 patients (36.7%), and scale 2 (moderate) in 1 patient (3.3%). The parents were quite satisfied with the results. Twenty-four hours after the first dose, the color of the tumor lightened and the texture became softer. In 10 cases, the patients took the drug for 16 weeks; in 13 cases, for 24 weeks; in 4 cases, for 28 weeks; and in 3 cases, treatment continued for 32 weeks, with an overall mean duration of 22.7 weeks. Typical cases of the patients are shown in Figures 1 to 4. In all 30 infants, the heart rate slowed, the blood pressure dropped, and the breathing rate slowed after the oral administration of propranolol. However, the changes in the previously mentioned signs were not commonly associated with observable clinical symptoms and each of these signs returned to normal after the patients
Infantile parotid proliferating hemangioma, which is the most common parotid tumor type, most commonly occurs within 1 year after birth and accounts for more than 50% of parotid gland tumors in infants.8 The main complications are hemorrhage, ulcer, infection, and external auditory canal compression. Hemangiomas located in the face will bring a serious psychological burden to patients. At present, the methods for treatment of IHs are conservative and tend to observe such as drug or laser therapy. Hemangiomas with less influence on patients and those that do not affect appearance and function mainly require “wait and see”; however, patients prone to rapid growth, infection, ulcers, or bleeding complications during the observation period should be treated immediately. Common drugs used to treat hemangioma include corticosteroids, anticancer drugs, interferon, and imiquimod,9–14 but these methods cause different degrees of adverse effects. Laser treatment is only suitable for early superficial hemangiomas. The pointed or patchy lesions of small red ranges found shortly after birth can be treated early using laser removal. There are various arguments with respect to the timing of surgical intervention for parotid region hemangiomas; the optimal operation time is uncertain. Surgical treatment should be carefully chosen because of its main complications, which include temporary paralysis, recurrence, hematoma, salivary fistula, auriculotemporal nerve syndrome, scar, and facial nerve injury. Since Léauté-Labrèze et al3 first reported in 2008 the incidental finding that hemangiomas regressed in children treated with propranolol, physicians worldwide have started to use the drug to treat problematic IHs with remarkable curability and
FIGURE 2. The tumor almost disappeared after oral propranolol treatment for 8 months.
FIGURE 4. The tumor completely disappeared after oral propranolol treatment for 6 months.
RESULTS
© 2015 Mutaz B. Habal, MD
Copyright © 2015 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
439
Li et al
The Journal of Craniofacial Surgery • Volume 26, Number 2, March 2015
fewer adverse effects.15 We have used propranolol to treat patients with parotid proliferating IHs, and at the onset of propranolol, we found that the shape recovery of lesions was significant, particularly in cases of large hemangiomas; no insidious adverse gastrointestinal reactions or changes in mental status were observed. The potential adverse effects of propranolol in the treatment of hemangiomas mainly include bradycardia, hypotension, and hypoglycemia.16 In the current study, however, all vital signs returned to normal after the propranolol had been taken for more than 12 hours, and no special treatment was required. Because of the current lack of uniform safe dosage standards of propranolol for the treatment of hemangiomas, we reasonably strived to conclude, on the basis of reports of domestic scholars and our considerable clinical experience, that propranolol of 1.0 mg/kg for patients younger than 3 months and that of 1.5 mg/kg for those older than 3 months are dosages that ensure the safety of patients. However, we still suggest that it should be necessary for an infant to have a detailed general examination before propranolol is prescribed. In addition, all infants should remain under observation at the inpatient hospital for 3 to 5 days after the first treatment, with blood pressure, heart rate, and adverse reactions closely monitored. Propranolol is mainly used in the clinical treatment of myocardial infarction, hypertension, angina, and other cardiovascular diseases, and the main mechanism of the drug is as a nonselective β-blocker, blocking the β1 and β2 cardiac receptors. Propranolol was effective in the treatment of the hemangiomas; however, the mechanism responsible for this effect is still not clear. The main proposed mechanisms involved in the effectiveness of propranolol for IH include vasoconstriction, inhibition of angiogenesis, inhibition of the renin-angiotensin system, and induction of apoptosis.17,18 Apoptosis of endothelial cells in the hemangioma is presumed to be the most likely mechanism involved in its natural involution, and propranolol has been proven to induce apoptosis of such hemangioma cells. As suggested, apoptosis may not be complete in all cases after treatment withdrawal, and some endothelial cells may thus remain proliferative after treatment is stopped. Some scholars have detected matrix metalloproteinases 2 and matrix metalloproteinases 9 in the urine of patients with hemangiomas before and after propranolol treatment. Using healthy children as a control, 1 report suggested that the contents of matrix metalloproteinases in patients with hemangiomas were lower than those in healthy babies; 2 weeks after propranolol treatment, these levels increased significantly, but there were no significant differences in matrix metalloproteinase 9 levels between the experimental group and control group.19 Yuan et al20 detected the contents of vascular endothelial growth factor and endothelial nitric oxide synthase in peripheral blood in 35 cases of hemangioma before and after oral propranolol. The authors discovered that, after 2 months of treatment, the levels of vascular endothelial growth factor and endothelial nitric oxide synthase in the peripheral blood were lower than those before the treatment. However, this is not sufficient to explain the mechanism by which propranolol is effective for treating hemangioma; further research is still needed. This small-sample retrospective study indicated that oral propranolol had the desired effect on infantile parotid gland hemangiomas. The drug should thus now be used as a first-line treatment of hemangiomas when intervention is required. A cohort study with a majority of patients will still be necessary to establish the appropriate dose and duration of treatment.
440
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© 2015 Mutaz B. Habal, MD
Copyright © 2015 Mutaz B. Habal, MD. Unauthorized reproduction of this article is prohibited.
