- Email: [email protected]
Reply to the letter to the Editor on “Low-dose propranolol for infantile haemangioma”
1124
Correspondence and communications
In conclusion, we believe in the approach of tattooing nipples after they are reconstructed and have been achieving satisfactory results from the point of view of both patients and surgeons. The objective of tattooing the nipple after reconstruction is to allow scarring of the nipple to settle and give the tattooist a final template to work and design on. With this approach, better symmetry and a greater patiente surgeon satisfaction rate can be achieved.
such cases bone remodelling often continues for several months or years following tumour resection. This represents a further alternative explanation of the changes in physiognomy seen in this patient. It would be of interest to review serial radiological images in order to determine if true hypertelorism exists and if so if it is a primary dysmorphism or indeed secondary to the presence of the olfactory groove meningioma, as would be our suspicion.
Reference
Conflict of interest
1. White CP, Gdalevitch P, Strazar R, et al. Surgical tips: areolar tattoo prior to nipple reconstruction. J Plast Reconstr Aesthet Surg 2011 Dec;64(12):1724e6. Epub 2011 Jul 21.
None declared.
Charles Yuen Yung Loh Philip Lim David Lam Royal Hallamshire Hospital, Plastic Surgery Department, Glossop Road, Sheffield WC1E 6BT, United Kingdom E-mail address: [email protected]
None declared.
ª 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2012.03.011
Letter of response: Recognising phenytoin therapy as a cause of thickening of the eyelids and paranasal region Dear Sir/Madam We read with interest your account of the potential cutaneous side effects of phenytoin therapy in a patient who underwent debulking therapy of an olfactory groove meningioma one year previously.1 As in the reported case many patients who undergo intracranial surgery are concomitantly prescribed prophylactic anti-epileptic therapy and it is useful to highlight the potential cutaneous manifestations of this drug. Interestingly, in the images presented, the patient has a broad philtral column and telecanthus. Such facial dysmorphism is found in patients with frontoethmoidal meningoencephalocele, which may present in isolation or in association with a Tessier Class 0 midline cleft.2,4 These features appear to be static, with further thickening of nasal bridge, glabellar region and medial canthi attributed to overlying soft tissue changes, secondary to pharmacotherapy. You mention calvarial thickening in your report and it would be of interest to review radiological images to identify if there was an associated nasal bridge hyperostosis present in this patient, although, this may be less likely to spontaneously resolve on withdrawing phenytoin therapy. Bony hypertrophy has also been described as a mechanotropic response to accommodate enlarging tumours.3 In DOI of original article: 10.1016/j.bjps.2011.06.021.
Funding
References 1. Sira M, Gilbert P, Sneddon N, Akinwunmi J, Malhorta R. Recognising phenytoin therapy as a cause of thickening of the eyelids and paranasal region. J Plast Reconstruct Aesthet Surg 2011;64(12):720e1. 2. Tessier P. Anatomical calssification of facial, craniofacial andlatero-facial clefts. J Maxillofac Surg 1976;4:69e71. 3. Matschke J, Addo J, Bernreuther C, Zustin J. Osseous changes in meningioma en plaque. Anticancer Res 2011 Feb;31(2):591e6. 4. Pinzer T, Gollogly J, Krishnan K. Telecanthus and hypertelorism in frontoethmoidal meningoencephaloceles and the surgical correction of these conditions: part II. A novel surgical approach in the treatment of telecanthus. J Craniofac Surg 2008;19:149e55.
S.E. Thomson A. Tahir C. Dunkin Department of Plastic and Reconstructive Surgery, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK E-mail address: [email protected] Crown Copyright ª 2012 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2012.01.004
Reply to the letter to the Editor on “Low-dose propranolol for infantile haemangioma” Dear Editor, We thank you for the opportunity to respond to Dr Zheng’s letter regarding our article, Low-Dose Propranolol for Infantile Haemangioma.1 The serendipitous discovery of accelerated involution of infantile haemangioma induced by propranolol2 and acebutalol3 has resulted in a paradigm shift in the management for this condition. This mirrors the DOI of original article: 10.1016/j.bjps.2010.09.021.
Correspondence and communications previous serendipitous observation of the effect of high dose steroids on infantile haemangioma4 which naturally invited logical questions on the (1) mechanism of action; (2) the optimal dose regimen and duration of treatment; and (3) the side effects of treatment in infants and young children with problematic infantile haemangioma. Over the last 40 years, some of these questions have been answered and the dose regimen settled on 2e3 mg/kg/day5 but the mechanism of action of steroid therapy remains incompletely elucidated with induced apoptosis through the up-regulation of mitochondrial cytochrome b gene being proposed.6,7 The intriguing biologic response of infantile haemangioma to b-blockers; propranolol, a non-selective b-blocker2; and acebutalol, a predominantly selective b1 adrenergic receptor blocker,8 has similarly attracted speculations on the possible mechanisms of action5 although these have not been substantiated. It is likely that the action of b-blockers reflects a group response rather than specific b-adrenergic receptor sub-type blockade. Our recent data demonstrating the neural crest phenotypic primitive mesodermal origin of infantile haemangioma,9,10 regulated by the renin-angiotensin system,11 provides some insights into the mechanism of action of bblockers in this condition. Further elucidation of these novel mechanisms may lead to scientifically based and a rational approach in the use of b-blockers, including propranolol, in their novel indication in infantile haemangioma. In the absence of proper scientific basis, the empirical nature of the treatment using b-blockers, including propranolol, must be viewed with circumspection. Dr Zheng quotes the paper by Storch et al.,12 stating that propranolol is now widely used worldwide for the treatment of infantile haemagioma. This is misleading. Storch et al.12 simply commented that propranolol is now becoming the first choice of therapy for complicated infantile haemangioma. More significantly these authors were careful in highlighting the need for further studies to assess the optimal dosing and duration of propranolol treatment. Whilst it may be true that b-blockers have a long and good safety record in the treatment of young children with hypertension and other cardiovascular diseases,13 this cannot be extrapolated to infants (some of whom are born prematurely) and young children with infantile haemangioma, who are otherwise normo-tensive. Caution has been justifiably expressed around the world to resist any cavalier approach14,15 with respect to using non-specific bblockade on this quite different cohort of patients. Dr Zheng’s statement that very few and minor side effects were observed and reported, is incorrect. Reports published recently15,16 describing cases of infants developing symptomatic and/or near fatal hypoglycaemia whilst on propranolol for infantile haemangioma, underscore the need for caution in using this drug. Such adverse effect occurred despite gradual dose escalation, divided dosing, and in one instance, modest dosage of 1.25 mg/kg/day. This empirical nature of propranolol treatment in infantile haemangioma is reflected, in the literature, with a range of doses being used, from 1 mg/kg/ day to 3 mg/kg/day, all given in three divided doses.1,2,17e20 In due respect to Dr Zheng’s claim of the safety of what appears to be an empirical protocol applied to a Chinese population, we are not in the position to comment on the methodology and results in the cited publications, which are not easily accessible by us.
1125 We questioned the necessity to use the higher dose range of 2e3 mg/kg/day of propranolol reported in the literature, initially by the French group2 and subsequently by others17,18 for the treatment of infantile haemangioma and hence adopted the dose escalation regimen reported in our study.1 Contrary to Dr Zheng’s understanding of our study, the primary reason for the dose regimen we used in that study1 was to work out the minimal dosage that could trigger a biologic response whilst closely monitoring for potential side effects. As reported, we found that a subcardiovascular dose of 1.5 mg/kg/day was sufficient for the majority of patients. It may be that Dr Zheng and his colleagues did end up on the same landing place, but what we had attempted was a systematic and safe approach to gather data. Furthermore, it is not correct that the end point was always 2 mg/kg/day in our cohort of Caucasian, Pacific Island and non-Chinese patients. The title of our original manuscript was amended to reflect the largely subcardiovascular dosage needed, at the advice of one of the reviewers, which we agreed to be reasonable. Having now expanded our series we can confirm that only a small proportion of patients required a dosage of 2 mg/kg/day, all of whom were girls. Dr Zheng’s regimen would not be effective in these patients. We have also found that a few younger children did not respond adequately to doses less than 2 mg/kg/day. These observations are likely to reflect the heterogeneity and biological variances within and between the treatment populations. While we appreciate that the pharmacokinetics of the controlled release formulation of propranolol may enable once daily dosing as this has been shown to achieve similar bioavailability levels when compared to divided dosing21 application of such formulations would require formal assessment in haemangioma patients. The potential side effects of propranolol treatment in this population, including hypoglycaemia, bradycardia and hypotension,1,17e20 warrant caution in gradual dose escalation and careful monitoring as routinely performed in our Centre and others.1,17e20 Dr Zheng advocates propranolol to be given as “a daily “pulse”, not twice or three times per day and cited the benefit of a “pulse” dose is the higher blood concentration and greater accelerating effect on the tumour within a certain time period”. We feel that this opinion needs to be supported by data. In the absence of an evidence-based protocol, a treatment regimen with divided doses has been recommended.14 We believe the divided dosing and non-precipitous escalation such as reported by us may add a margin of safety while providing an opportunity to use a minimal dosage to achieve the desired effect of propranolol. Accepting that Dr Zheng and his colleagues have come up with an optimal regimen for the Chinese population, the data may not be applicable to other populations. Given the evidence of the involvement of the renin-angiotensin system in the aetio-biology of infantile haemangioma and that the levels of renin are higher in white (compared with black), female and premature infants,11 there may also be differences in renin levels in other racial groups including Chinese, compared with the Caucasian population. It is clear that large multicentre trials such as one being undertaken,22 is likely to define the objective indications, rational treatment protocol and documented safety profiles of propranolol in this cohort of patients. It is also possible that large-scale
1126 clinical trials may identify certain patient or lesion characteristics that predict a more favourable response and hence the need for a lower dosage of propranolol. Finally the discovery of the involvement of the reninangiotensin system in the biology of infantile haemangioma11 has led to an on-going clinical trial using an angiotensin converting enzyme inhibitor in our Centre. Preliminary results of our study are promising but this is the subject of a separate report.23 It is hoped that identification of more specific but equally effective modulators of the renin-angiotensin axis without the unwanted adverse effects of b-blockers may lead to even better treatment of infantile haemangioma. We believe the key in achieving this lies in the understanding of the cellular and molecular basis that underscore the programmed behaviour of infantile haemangioma, and let’s hope that it will not take another 40 years!
Correspondence and communications
17. 18.
19.
20.
21.
22.
References 1. Tan ST, Itinteang T, Leadbitter P. Low-dose propranolol for infantile haemangioma. Plast Reconstr Surg 2010;64:292e9. 2. Leaute-Labreze C, Dumasde la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649e51. 3. Bigorre M, Van Kien AK, Huguette V. Beta-blocking agent for the treatment of infantile hemangioma. Plast Reconstr Surg 2009;123:195ee6. 4. Zarem HA, Edgerton MT. Induced resolution of cavernous hemangiomas following prednisolone therapy. Plast Reconstr Surg 1967;39:76e83. 5. Boon LM, MacDonald DM, Mulliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg 1999;104:1616e23. 6. Hasan Q, Tan ST, Gush J, Peters S, Davis PF. Steroid therapy of a hemangioma: histochemical and molecular changes. Pediatrics 2000;105:117e21. 7. Hasan Q, Tan ST, Gush J, Davis PF. Altered mitochondrial cytochrome b gene expression during the regression of hemangioma. Plast Reconstr Surg 2001;108:1471e6. 8. Naline E, Sarria B, Ertzbischoff O, Ozanne P, Advenier C. Comparative b-adrenorecptor blocking effects of propranolol, bisoprolol, atenolol, acebutalol and diacetolol on the human isolated bronchus. Br J Clin Parmac 1990;30:135e9. 9. Itinteang T, Tan ST, Brasch H, Day DJ. Primitive mesodermal cells with a neural crest stem cell phenotype predominate proliferating infantile haemangioma. J Clin Pathol 2010;63:771e6. 10. Itinteang T, Tan ST, Brasch H, Day DJ. Haemogenic endothelium in infantile haemangioma. J Clin Pathol 2010;63:982e6. 11. Itinteang T, Brasch HD, Tan ST, Day DJ. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution. Plast Reconstr Aesthet Surg 2010;64:759e65. 12. Storch CH, Hoeger PH. Propranolol for infantile haemangiomas:insights into the molecular mechanisms of action. Brit J Dermatol 2010;63:269e74. 13. Artman M, Grayson M, Boerth RC. Propranolol in children: safety-toxicity. Pediatrics 1982;70:30e1. 14. Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med 2008;359:2846e7. 15. Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA. Hypoglycaemia in children taking propranolol for the treatment of infantile haemangioma. Arch Dermatol 2010; 146:775e8. 16. Bonifazi E, Acquafredda A, Milano A, Montagna O, Laforgia N. Severe hypoglycaemia during successful treatment of diffuse
23.
hemangiomatosis with propranolol. Pediatr Dermatol 2010;27: 195e6. Sans V, de la Roque ED, Berge J, et al. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics 2009;124:e423e31. Denoyelle F, Leboulanger N, Enjolras O, Harris R, Roger G, Garabedian E. Role of propranolol in the therapeutic strategy of infantile laryngotracheal hemangioma. Int J Pediatr Otorhinolaryngol 2009;73:1168e72. Manunza F, Syed S, Laguda B, et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants. Brit J Dermatol 2010;162:452e68. Arneja JS, Pappas PN, Shwayder TA, et al. Management of complicated facial hemangiomas with [beta]-blockers (propranolol) therapy. Plast Reconstr Surg 2010;126:889e95. Sica D, Frishman WH, Manowitz N. Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or propranolol (innopran XL), a new chronotherapeutic formulation. Heart Dis 2003;5:176e81. Leaute-Labreze C, de la Roque ED, Taieb A. More on propranolol for hemangiomas of infancy. N Engl J Med 2008;359:2846e7. Tan ST, Itinteang T, Day JD, O’Donnell C, Mathy JA, Leadbitter P. Treatment of infantile hemangioma with captopril. Brit J Dermatolol; 2012 (Accepted).
Swee T. Tan Tinte Itinteang Philip Leadbitter Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, High Street, Private Bag 31-907, Lower Hutt, New Zealand E-mail address: [email protected] ª 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2012.01.001
Should we treat all haemangiomas with beta-blockers? Dear Sir, We read with interest the recent article in your journal by Chang et al.1 regarding the management of lip haemangiomas. We would like to congratulate the authors on their excellent results and well thought out strategy for debulking of these difficult cases. This study describes appropriate treatment over the time period that these cases have been taken from. However, with the recent serendipitous discovery of the effects of propranolol on haemangiomas,2 we feel that beta-blockers should be considered as first line treatment in many of these patients. Whilst the effects are variable, propranolol may significantly reduce or even arrest the growth of many haemangiomas. As its use in these children becomes more widespread it has become apparent that the treatment is comparatively safe with significantly less side effects than systemic steroids. Whilst initiation of therapy as an inpatient to monitor for potential hypoglycaemia and cardio-respiratory side effects remains common there is a move towards outpatient treatment from
Correspondence and communications
In conclusion, we believe in the approach of tattooing nipples after they are reconstructed and have been achieving satisfactory results from the point of view of both patients and surgeons. The objective of tattooing the nipple after reconstruction is to allow scarring of the nipple to settle and give the tattooist a final template to work and design on. With this approach, better symmetry and a greater patiente surgeon satisfaction rate can be achieved.
such cases bone remodelling often continues for several months or years following tumour resection. This represents a further alternative explanation of the changes in physiognomy seen in this patient. It would be of interest to review serial radiological images in order to determine if true hypertelorism exists and if so if it is a primary dysmorphism or indeed secondary to the presence of the olfactory groove meningioma, as would be our suspicion.
Reference
Conflict of interest
1. White CP, Gdalevitch P, Strazar R, et al. Surgical tips: areolar tattoo prior to nipple reconstruction. J Plast Reconstr Aesthet Surg 2011 Dec;64(12):1724e6. Epub 2011 Jul 21.
None declared.
Charles Yuen Yung Loh Philip Lim David Lam Royal Hallamshire Hospital, Plastic Surgery Department, Glossop Road, Sheffield WC1E 6BT, United Kingdom E-mail address: [email protected]
None declared.
ª 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2012.03.011
Letter of response: Recognising phenytoin therapy as a cause of thickening of the eyelids and paranasal region Dear Sir/Madam We read with interest your account of the potential cutaneous side effects of phenytoin therapy in a patient who underwent debulking therapy of an olfactory groove meningioma one year previously.1 As in the reported case many patients who undergo intracranial surgery are concomitantly prescribed prophylactic anti-epileptic therapy and it is useful to highlight the potential cutaneous manifestations of this drug. Interestingly, in the images presented, the patient has a broad philtral column and telecanthus. Such facial dysmorphism is found in patients with frontoethmoidal meningoencephalocele, which may present in isolation or in association with a Tessier Class 0 midline cleft.2,4 These features appear to be static, with further thickening of nasal bridge, glabellar region and medial canthi attributed to overlying soft tissue changes, secondary to pharmacotherapy. You mention calvarial thickening in your report and it would be of interest to review radiological images to identify if there was an associated nasal bridge hyperostosis present in this patient, although, this may be less likely to spontaneously resolve on withdrawing phenytoin therapy. Bony hypertrophy has also been described as a mechanotropic response to accommodate enlarging tumours.3 In DOI of original article: 10.1016/j.bjps.2011.06.021.
Funding
References 1. Sira M, Gilbert P, Sneddon N, Akinwunmi J, Malhorta R. Recognising phenytoin therapy as a cause of thickening of the eyelids and paranasal region. J Plast Reconstruct Aesthet Surg 2011;64(12):720e1. 2. Tessier P. Anatomical calssification of facial, craniofacial andlatero-facial clefts. J Maxillofac Surg 1976;4:69e71. 3. Matschke J, Addo J, Bernreuther C, Zustin J. Osseous changes in meningioma en plaque. Anticancer Res 2011 Feb;31(2):591e6. 4. Pinzer T, Gollogly J, Krishnan K. Telecanthus and hypertelorism in frontoethmoidal meningoencephaloceles and the surgical correction of these conditions: part II. A novel surgical approach in the treatment of telecanthus. J Craniofac Surg 2008;19:149e55.
S.E. Thomson A. Tahir C. Dunkin Department of Plastic and Reconstructive Surgery, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK E-mail address: [email protected] Crown Copyright ª 2012 Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2012.01.004
Reply to the letter to the Editor on “Low-dose propranolol for infantile haemangioma” Dear Editor, We thank you for the opportunity to respond to Dr Zheng’s letter regarding our article, Low-Dose Propranolol for Infantile Haemangioma.1 The serendipitous discovery of accelerated involution of infantile haemangioma induced by propranolol2 and acebutalol3 has resulted in a paradigm shift in the management for this condition. This mirrors the DOI of original article: 10.1016/j.bjps.2010.09.021.
Correspondence and communications previous serendipitous observation of the effect of high dose steroids on infantile haemangioma4 which naturally invited logical questions on the (1) mechanism of action; (2) the optimal dose regimen and duration of treatment; and (3) the side effects of treatment in infants and young children with problematic infantile haemangioma. Over the last 40 years, some of these questions have been answered and the dose regimen settled on 2e3 mg/kg/day5 but the mechanism of action of steroid therapy remains incompletely elucidated with induced apoptosis through the up-regulation of mitochondrial cytochrome b gene being proposed.6,7 The intriguing biologic response of infantile haemangioma to b-blockers; propranolol, a non-selective b-blocker2; and acebutalol, a predominantly selective b1 adrenergic receptor blocker,8 has similarly attracted speculations on the possible mechanisms of action5 although these have not been substantiated. It is likely that the action of b-blockers reflects a group response rather than specific b-adrenergic receptor sub-type blockade. Our recent data demonstrating the neural crest phenotypic primitive mesodermal origin of infantile haemangioma,9,10 regulated by the renin-angiotensin system,11 provides some insights into the mechanism of action of bblockers in this condition. Further elucidation of these novel mechanisms may lead to scientifically based and a rational approach in the use of b-blockers, including propranolol, in their novel indication in infantile haemangioma. In the absence of proper scientific basis, the empirical nature of the treatment using b-blockers, including propranolol, must be viewed with circumspection. Dr Zheng quotes the paper by Storch et al.,12 stating that propranolol is now widely used worldwide for the treatment of infantile haemagioma. This is misleading. Storch et al.12 simply commented that propranolol is now becoming the first choice of therapy for complicated infantile haemangioma. More significantly these authors were careful in highlighting the need for further studies to assess the optimal dosing and duration of propranolol treatment. Whilst it may be true that b-blockers have a long and good safety record in the treatment of young children with hypertension and other cardiovascular diseases,13 this cannot be extrapolated to infants (some of whom are born prematurely) and young children with infantile haemangioma, who are otherwise normo-tensive. Caution has been justifiably expressed around the world to resist any cavalier approach14,15 with respect to using non-specific bblockade on this quite different cohort of patients. Dr Zheng’s statement that very few and minor side effects were observed and reported, is incorrect. Reports published recently15,16 describing cases of infants developing symptomatic and/or near fatal hypoglycaemia whilst on propranolol for infantile haemangioma, underscore the need for caution in using this drug. Such adverse effect occurred despite gradual dose escalation, divided dosing, and in one instance, modest dosage of 1.25 mg/kg/day. This empirical nature of propranolol treatment in infantile haemangioma is reflected, in the literature, with a range of doses being used, from 1 mg/kg/ day to 3 mg/kg/day, all given in three divided doses.1,2,17e20 In due respect to Dr Zheng’s claim of the safety of what appears to be an empirical protocol applied to a Chinese population, we are not in the position to comment on the methodology and results in the cited publications, which are not easily accessible by us.
1125 We questioned the necessity to use the higher dose range of 2e3 mg/kg/day of propranolol reported in the literature, initially by the French group2 and subsequently by others17,18 for the treatment of infantile haemangioma and hence adopted the dose escalation regimen reported in our study.1 Contrary to Dr Zheng’s understanding of our study, the primary reason for the dose regimen we used in that study1 was to work out the minimal dosage that could trigger a biologic response whilst closely monitoring for potential side effects. As reported, we found that a subcardiovascular dose of 1.5 mg/kg/day was sufficient for the majority of patients. It may be that Dr Zheng and his colleagues did end up on the same landing place, but what we had attempted was a systematic and safe approach to gather data. Furthermore, it is not correct that the end point was always 2 mg/kg/day in our cohort of Caucasian, Pacific Island and non-Chinese patients. The title of our original manuscript was amended to reflect the largely subcardiovascular dosage needed, at the advice of one of the reviewers, which we agreed to be reasonable. Having now expanded our series we can confirm that only a small proportion of patients required a dosage of 2 mg/kg/day, all of whom were girls. Dr Zheng’s regimen would not be effective in these patients. We have also found that a few younger children did not respond adequately to doses less than 2 mg/kg/day. These observations are likely to reflect the heterogeneity and biological variances within and between the treatment populations. While we appreciate that the pharmacokinetics of the controlled release formulation of propranolol may enable once daily dosing as this has been shown to achieve similar bioavailability levels when compared to divided dosing21 application of such formulations would require formal assessment in haemangioma patients. The potential side effects of propranolol treatment in this population, including hypoglycaemia, bradycardia and hypotension,1,17e20 warrant caution in gradual dose escalation and careful monitoring as routinely performed in our Centre and others.1,17e20 Dr Zheng advocates propranolol to be given as “a daily “pulse”, not twice or three times per day and cited the benefit of a “pulse” dose is the higher blood concentration and greater accelerating effect on the tumour within a certain time period”. We feel that this opinion needs to be supported by data. In the absence of an evidence-based protocol, a treatment regimen with divided doses has been recommended.14 We believe the divided dosing and non-precipitous escalation such as reported by us may add a margin of safety while providing an opportunity to use a minimal dosage to achieve the desired effect of propranolol. Accepting that Dr Zheng and his colleagues have come up with an optimal regimen for the Chinese population, the data may not be applicable to other populations. Given the evidence of the involvement of the renin-angiotensin system in the aetio-biology of infantile haemangioma and that the levels of renin are higher in white (compared with black), female and premature infants,11 there may also be differences in renin levels in other racial groups including Chinese, compared with the Caucasian population. It is clear that large multicentre trials such as one being undertaken,22 is likely to define the objective indications, rational treatment protocol and documented safety profiles of propranolol in this cohort of patients. It is also possible that large-scale
1126 clinical trials may identify certain patient or lesion characteristics that predict a more favourable response and hence the need for a lower dosage of propranolol. Finally the discovery of the involvement of the reninangiotensin system in the biology of infantile haemangioma11 has led to an on-going clinical trial using an angiotensin converting enzyme inhibitor in our Centre. Preliminary results of our study are promising but this is the subject of a separate report.23 It is hoped that identification of more specific but equally effective modulators of the renin-angiotensin axis without the unwanted adverse effects of b-blockers may lead to even better treatment of infantile haemangioma. We believe the key in achieving this lies in the understanding of the cellular and molecular basis that underscore the programmed behaviour of infantile haemangioma, and let’s hope that it will not take another 40 years!
Correspondence and communications
17. 18.
19.
20.
21.
22.
References 1. Tan ST, Itinteang T, Leadbitter P. Low-dose propranolol for infantile haemangioma. Plast Reconstr Surg 2010;64:292e9. 2. Leaute-Labreze C, Dumasde la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649e51. 3. Bigorre M, Van Kien AK, Huguette V. Beta-blocking agent for the treatment of infantile hemangioma. Plast Reconstr Surg 2009;123:195ee6. 4. Zarem HA, Edgerton MT. Induced resolution of cavernous hemangiomas following prednisolone therapy. Plast Reconstr Surg 1967;39:76e83. 5. Boon LM, MacDonald DM, Mulliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg 1999;104:1616e23. 6. Hasan Q, Tan ST, Gush J, Peters S, Davis PF. Steroid therapy of a hemangioma: histochemical and molecular changes. Pediatrics 2000;105:117e21. 7. Hasan Q, Tan ST, Gush J, Davis PF. Altered mitochondrial cytochrome b gene expression during the regression of hemangioma. Plast Reconstr Surg 2001;108:1471e6. 8. Naline E, Sarria B, Ertzbischoff O, Ozanne P, Advenier C. Comparative b-adrenorecptor blocking effects of propranolol, bisoprolol, atenolol, acebutalol and diacetolol on the human isolated bronchus. Br J Clin Parmac 1990;30:135e9. 9. Itinteang T, Tan ST, Brasch H, Day DJ. Primitive mesodermal cells with a neural crest stem cell phenotype predominate proliferating infantile haemangioma. J Clin Pathol 2010;63:771e6. 10. Itinteang T, Tan ST, Brasch H, Day DJ. Haemogenic endothelium in infantile haemangioma. J Clin Pathol 2010;63:982e6. 11. Itinteang T, Brasch HD, Tan ST, Day DJ. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution. Plast Reconstr Aesthet Surg 2010;64:759e65. 12. Storch CH, Hoeger PH. Propranolol for infantile haemangiomas:insights into the molecular mechanisms of action. Brit J Dermatol 2010;63:269e74. 13. Artman M, Grayson M, Boerth RC. Propranolol in children: safety-toxicity. Pediatrics 1982;70:30e1. 14. Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med 2008;359:2846e7. 15. Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA. Hypoglycaemia in children taking propranolol for the treatment of infantile haemangioma. Arch Dermatol 2010; 146:775e8. 16. Bonifazi E, Acquafredda A, Milano A, Montagna O, Laforgia N. Severe hypoglycaemia during successful treatment of diffuse
23.
hemangiomatosis with propranolol. Pediatr Dermatol 2010;27: 195e6. Sans V, de la Roque ED, Berge J, et al. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics 2009;124:e423e31. Denoyelle F, Leboulanger N, Enjolras O, Harris R, Roger G, Garabedian E. Role of propranolol in the therapeutic strategy of infantile laryngotracheal hemangioma. Int J Pediatr Otorhinolaryngol 2009;73:1168e72. Manunza F, Syed S, Laguda B, et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants. Brit J Dermatol 2010;162:452e68. Arneja JS, Pappas PN, Shwayder TA, et al. Management of complicated facial hemangiomas with [beta]-blockers (propranolol) therapy. Plast Reconstr Surg 2010;126:889e95. Sica D, Frishman WH, Manowitz N. Pharmacokinetics of propranolol after single and multiple dosing with sustained release propranolol or propranolol (innopran XL), a new chronotherapeutic formulation. Heart Dis 2003;5:176e81. Leaute-Labreze C, de la Roque ED, Taieb A. More on propranolol for hemangiomas of infancy. N Engl J Med 2008;359:2846e7. Tan ST, Itinteang T, Day JD, O’Donnell C, Mathy JA, Leadbitter P. Treatment of infantile hemangioma with captopril. Brit J Dermatolol; 2012 (Accepted).
Swee T. Tan Tinte Itinteang Philip Leadbitter Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, High Street, Private Bag 31-907, Lower Hutt, New Zealand E-mail address: [email protected] ª 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bjps.2012.01.001
Should we treat all haemangiomas with beta-blockers? Dear Sir, We read with interest the recent article in your journal by Chang et al.1 regarding the management of lip haemangiomas. We would like to congratulate the authors on their excellent results and well thought out strategy for debulking of these difficult cases. This study describes appropriate treatment over the time period that these cases have been taken from. However, with the recent serendipitous discovery of the effects of propranolol on haemangiomas,2 we feel that beta-blockers should be considered as first line treatment in many of these patients. Whilst the effects are variable, propranolol may significantly reduce or even arrest the growth of many haemangiomas. As its use in these children becomes more widespread it has become apparent that the treatment is comparatively safe with significantly less side effects than systemic steroids. Whilst initiation of therapy as an inpatient to monitor for potential hypoglycaemia and cardio-respiratory side effects remains common there is a move towards outpatient treatment from