Propranolol, a very promising treatment for ulceration in infantile hemangiomas: A study of 20 cases with matched historical controls

Denise Josephina Johanna Hermans, MD,a Ingrid Mathilde van Beynum, MD,b Leonardus Jan Schultze Kool, PhD,c Peter Cornelius Maria van de Kerkhof, PhD,a Marcus Henricus Wilhelmus Andreas Wijnen, PhD,d and Catharina Joanna Maria van der Vleuten, PhDa Nijmegen, The Netherlands
Background: Ulceration is a common but poorly understood complication of infantile hemangiomas (IH) that is difcult to control. Objective: To investigate the possible role of monotherapy with propranolol for ulcerating IH. Methods: Propranolol was given to 20 patients with IH, who suffered from ulceration at the start of treatment (mean age at onset of treatment, 3.5 months; standard error of the mean: 0.4). After cardiac screening, propranolol was administered in a progressive schedule to 2 to 2.5 mg/kg per day, divided in 3 doses. Blood pressure, heart rate, and fasting glucose levels were monitored during the rst 3 days in hospital and, in the absence of complications, treatment was continued at home until the age of approximately 1 year. The 20 propranolol-treated patients were matched to patients from a historical control group, seen before the propranolol era. These matches were randomly made by using clinical pictures based on type, location and size of the IH, extent of ulceration, and age at the start of ulceration. Results: The time to complete healing from the onset of ulceration was signicantly shorter for the propranolol-treated patients, compared with the control group (8.7 vs 22.4 weeks; t test: P \ .015). In the propranolol group, a tendency to shorter ulceration duration was seen in patients starting propranolol at an earlier stage of disease. Limitations: The study was limited by the partially retrospective design and the small number of patients. Conclusion: Propranolol reduces the duration of ulceration in IH and seems to be more effective when started in an early phase. We propose propranolol as the treatment of rst choice for ulcerating IH. ( J Am Acad Dermatol 2011;64:833-8.) Key words: beta-blocker; infantile hemangioma; infants; propranolol; ulceration.

INTRODUCTION
nfantile hemangiomas (IH) occur in approximately 10% to 12% of children younger than 1 year of age. The most common complication is ulceration, possibly affecting 5% to 13% of children with IH.1,2 Ulceration is nearly always painful, and

Abbreviations used: IH: infantile hemangioma PDL: pulsed dye laser SEM: standard error of the mean

From the Departments of Dermatology,a Pediatric Cardiology,b Intervention Radiology,c Pediatric Surgery,d Radboud University Medical Centre. Funding sources: None. Conflicts of interest: None declared. Accepted for publication January 21, 2011.

Correspondence to: Denise Josephina Johanna Hermans, MD, Ren Descartesdreef 1, 6500 HB, Nijmegen, The Netherlands. e E-mail: D.Hermans@derma.umcn.nl. Published online February 28, 2011. 0190-9622/$36.00 2011 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2011.01.025

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this leads to problems with eating and sleeping. Propranolol was administered in the hospital with a There may also be bleeding and infection requiring starting dose of 0.7 to 1.0 mg/kg per day, divided in 3 treatment with oral antibiotics. Finally, ulceration daily doses, increasing over a 3-day period to 2.0 to heals with scarring, leading to functional problems 2.5 mg/kg per day. Blood pressure, heart rate, and and cosmetic disfigurement.3-6 There is no uniform fasting glucose levels were monitored during the rst approach to treatment in the literature. In addition 3 days. In the absence of complications, treatment to all kinds of wound dressings, topical or oral was continued at home until about the age of 1 year. antibiotics and pain manageThe patients were evaluated ment, treatment with oral every 6 weeks after starting CAPSULE SUMMARY corticosteroids, vincristine, treatment with propranolol, interferon, flashlamp pulsed and more often if necessary. Ulceration is a common complication of dye laser therapy, and surgiIn the nal phase of treatinfantile hemangiomas and can be cal options have been dement, clinic visits were exdifficult to manage. scribed, often with tended to every 3 months. In this study of 20 patients, treatment disappointing results.1,5,7 During the study period, no Propranolol was recently with propranolol significantly shortened other systemic treatment mointroduced as a promising the ulceration time when compared with dalities, apart from oral antitreatment for complicated a group of matched historical controls. biotics or analgesia, were IH.8 There have been several administered. It is possible that early administration of case-reports of propranolol Historical data of IH papropranolol in the proliferation phase therapy for ulcerating IH, tients from our center during may prevent ulceration by limiting but no comparative studies the period 1997 to 2007 were expansile growth of the hemangioma. have been published.8-10 In analyzed retrospectively and our study, the role of this used to establish controls.11 nonselective beta-blocker was explored by treating Ulceration was present in 107 of these 465 IH cases. 20 patients with an ulcerating IH in the proliferation Using clinical pictures and medical records, two phase and comparing this patient group with similar investigators, who were blinded as to the clinical historical controls. outcomes, made a random selection of 20 patients with a comparable ulcerating IH. The comparisons were based on age at onset of ulceration, type, PATIENTS AND METHODS location and size of the IH, and extent of ulceration. Patients Follow-up evaluations in this patient group were An observational analysis was performed of IH similar to those of the propranolol-treated group. patients treated with propranolol at the Radboud University Medical Centre Nijmegen (UMCN), the Analysis Netherlands, from October 2008 to March 2010. The In the event of missing data in the control group, medical records and photo-documentation of 56 an interview with the parents by telephone was infants were reviewed and all patients with ulceraperformed. The maximum age of the patient at the tion were selected. Twenty patients suffered from time of the interview was 5 years. Data from the ulceration at the start of the treatment (mean age at patient les were transported into a database and onset of treatment: 3.5 months, standard error of the analyzed to dene the characteristics of the study mean [SEM] 0.4). Ulceration was not always the main group. The numeric data were reported as mean plus indication for propranolol treatment. or minus SEM. Ulceration was dened as a break in the continuFor statistical analysis the t test for unpaired values ity of the surface epithelium with or without infecwas used. The other non-numeric data were anation. The total ulceration time was dened as the lyzed with the chi-square test. A two-tailed hypothtime from the rst sign of ulceration until complete esis was employed to interpret data. A P value less healing, without complete healing in the intervening than or equal to .05 was regarded as statistically period. Long-lasting ulceration was ulceration with significant. a longer duration than the mean ulceration time. Early starters were patients started on propranolol RESULTS before the mean age at onset of treatment. Propranolol group At inclusion, a clinical evaluation including physPatient characteristics. The 20 patients (Table I) ical examination, renal function tests, an electrocarwith an ulcerating IH had a total of 78 IH, with an diogram, and echocardiography was performed to average number of 3.9 IH per patient (SEM 1.7). exclude contraindications to propranolol treatment.
d d d

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Table I. Clinical characteristics of 40 patients with ulcerated hemangioma

Propranolol group Gender Clinical subtype Other Duration of Morphological Oral systemic ulceration Control subtype AB tx (wk) group Gender Clinical subtype Morphological Oral subtype AB Other systemic tx Duration of ulceration (wk)

Location

Location

1a 2a 3a 4a 5a 6a 7a 8a 9a 10a 11a 12a 13a 14a 15a 16a 17a 18a 19a 20a

F F F M F M M F F F F F F M F F F F F F

Face/cheek/mouth Sup/Nod Diaper area (labium majus) Diaper area (buttocks) Scalp Lip Shoulder Face Face (nose/cheek) Ear Face Leg/buttocks Face (lip/mouth) Buttocks Scalp Scalp Lip Arm Scalp Lip Face/neck Sup/Nod Sup/Nod Sup/Nod Sup/Nod Sup/Nod Mixed Mixed Sup/Nod Sup/Mac Sup/Mac Sup/Mac Sup/Mac Sup/Nod Sup/Nod Sup/Nod Sup/Nod Sup/Nod Sup/Nod Sup/Nod

Loc Loc Loc Loc Loc Loc Segm Segm Loc Segm Segm Loc Loc Loc Loc Loc Loc Loc Segm Segm

e e

3* 13y 2 13 11 4 5 7 19 5 6 15 8 10 12 4 4 19 1 13

1b 2b 3b 4b 5b 6b 7b 8b 9b 10b 11b 12b 13b 14b 15b 16b 17b 18b 19b 20b

F F F F F F M F M F M F M F F F F F F M

1 1 e e e e e 1 e e e e 1 e e 1 e 1

e e e e e e e e e e e e e e e e e e

Face (cheek/mouth) Diaper area (buttocks) Diaper area (buttocks) Scalp Lip Shoulder Face Face (cheek/ear) Neck Face Buttocks Face (ear/neck) Buttocks Neck Scalp Lip Arm Scalp Beard area/lip Face (neck)

Sup/Nod Sup/Nod Sup/ Nod Sup/Nod Sup/Nod Sup/Nod Mixed Sup/Nod Sup/Nod Sup/Mac Sup/Mac Sup/Mac Sup/Nod Sup/Nod Sup/Nod Sup/Nod Sup/Nod Sup/Nod Sup/Nod Sup/Nod

Loc Loc Loc Loc Loc Loc Segm Segm Loc Segm Segm Loc Loc Loc Loc Loc Loc Loc Segm Segm

e Prednisone 1 1 1 e 1 1 1 e e e e e e e

6* 30y 96 16 24 4 20 36 4 20 4 56 24 10 2 44 6 10 12 24

e e 1 e 1 e 1 Prednisone, PDL e Prednisone 1 e e e e Prednisone e e 1 1 1 Prednisone e e

Hermans et al 835

1, Prescribed; e, not prescribed; AB, antibiotics; Loc, localized; PDL, pulsed dye laser; Sup/Mac, superficial/macular; Sup/Nod, superficial nodular; tx, therapy. *Patients shown in Fig 1. y Patients shown in Fig 2.

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Of this group, 16 (80%) were girls. The mean gestational age was 36.8 weeks (SEM 0.7). The mean birth weight was 3017 grams (SEM 195). Nine patients (45%) were born prematurely (before 37 weeks gestation), one with extreme prematurity (gestational age 30.7 weeks). The anatomic location of the ulcerating IH was as follows: 14 (70%) in the head and neck region, 1 on the shoulder, 1 on the arm, and 4 (20%) in the diaper region. The following clinical IH subtypes were recorded: 14 (70%) supercial nodular, 4 (20%) supercial macular and 2 (10%) mixed; no IH had an exclusively deep growth pattern. Morphological subtypes included 14 (70%) with a localized and 6 (30%) with a segmental distribution. The mean age at which the IH was rst noted by the parents was 6.4 days (SEM 2.4). Propranolol. Ulceration was the main indication for treatment with propranolol in 18 cases (90%). In these patients, painful ulceration resulted in problems with drinking, sleeping, defecation or restriction of movement. In the two other infants, tachypnea and inspiratory stridor due to airway obstruction were the primary indications for treatment. The mean age of starting propranolol was 3.5 months (SEM 0.3). At the time of data analysis, 19 patients had discontinued propranolol and the remaining infant was in the nal phase of treatment. The average treatment duration for the 19 patients was 9.1 months (SEM 0.6). Within the rst 3 days of starting treatment in the hospital, a decrease in redness and tenseness of the IH was observed in all cases. This effect was sustained over the remaining treatment period. Four (21.1%) of the 19 patients who completed treatment showed some regrowth and slightly increased redness after stopping propranolol, but there was no recurrence of ulceration. In one patient propranolol was restarted because of the mass effect of the IH. Nine patients (45%) experienced no adverse effects at all. The parents of 11 patients reported temporary drowsiness/tiredness (n = 6), restless sleeping (n = 2), cold extremities (n = 6), poor feeding (n = 2) and gastrointestinal complaints (diarrhea, vomiting) (n = 1). Six patients (30%) were treated with an oral pain medication (acetaminophen) and 7 patients (35%) were treated with oral antibiotics. Eleven patients (55%) were additionally treated with topical ointments and wound dressings either before or during propranolol treatment. No other systemic treatment modalities for the IH (such as systemic corticosteroids) were necessary.

Ulceration All patients had an ulcerating IH at the time of starting propranolol. The mean age of the patients at the start of ulceration was 2.3 months (SEM 0.3). Complete healing was obtained after an average total ulceration time of 8.7 weeks (SEM 8.5). In the propranolol-treated group, a tendency to a shorter ulceration time was seen in patients starting propranolol at an early age. Seven of the 10 late starters (70%) (started propranolol at [3.5 months of age) had a long lasting ulceration ([8.7 weeks) compared with only 2 (20%) of the 10 early starters (2 = 5.051, df = 1, P = .025). Most parents reported a decrease in pain within a few days after initiation of propranolol. Historical control group The historical control group consisted of 20 comparable cases from a historical group treated before the propranolol era (see Table I). These control patients had similar complications from an ulcerating IH, including problems with eating, sleeping, defecation, and restriction in movement due to pain. Five patients (25%) in the control group were treated with oral corticosteroids, 1 (5%) with pulsed dye laser therapy, 12 (60%) with one or more oral antibiotics, and all 20 with a variety of local wound dressings and ointments. The mean age of the patients at the start of ulceration was 2.7 months (SEM 0.3), not dissimilar to the propranolol-treated group (P = .49). The mean ulceration time for the control group was 22.4 weeks (SEM 5.2). The outliers in both the propranolol and control groups were patients with ulceration in skin folds and locations with extensive exposure to friction, maceration, and external factors (eg, feces, urine, food), which delayed the healing process. Comparison IH groups: Ulceration time The t test for unpaired values showed a significant difference in mean ulceration duration between the 20 patients treated with propranolol and the 20 cases in the control group, including both patients treated with supportive care only and with systemic therapy (8.7 vs 22.4 weeks; t = 2.6, df = 38, P = .012, 95% confidence interval, 3.2-24.2). An additional analysis was performed to compare the 20 patients in the propranolol group with the 5 patients in the historical group treated with oral corticosteroids. This comparison showed a signicant difference in mean ulceration time (8.7 vs 28.4, t = 3.88, df = 23, P = .001, 95% confidence interval 9.2-30.2). Finally, a comparison was made between the 20 patients treated with propranolol and the 15 patients

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Fig 1. A, Ulcerating IH on left cheek, before treatment with propranolol: total ulceration time 3 weeks (patient 1a in Table I). B, Ulcerating IH on right cheek, before treatment with oral corticosteroids, not treated with propranolol:.Total ulceration time 6 weeks (patient 1b in Table I).

in the control group treated with supportive care only (oral antibiotics and wound dressings). This also showed a signicant difference (8.7 vs 20.4, t = 2.17, df = 33, P = .037, 95% confidence interval 0.7-22.7). An illustration of the duration of ulceration in patients treated with propranolol compared with historical controls is given in Figs 1 and 2.

DISCUSSION
A review of the literature reveals no evidencebased or uniformly accepted treatment plan for ulcerating IH. This is in part because of the unclear pathogenesis of the ulceration but also to the variable course of ulceration and involution of IH.6 The generally accepted triad for treatment of ulcerating IH is (1) wound care, (2) topical or oral antibiotics, and (3) adequate pain management. In addition, various therapeutic agents aimed at promoting involution of the IH have been used (eg, corticosteroids, vincristine, interferon, flashlamp pulsed dye laser and surgical intervention), often with unsatisfactory results.1,5,7,12,13 There is a need for a new treatment modality to control this challenging complication more effectively. The extraordinary response of infantile IH to propranolol, rst reported in the New England Journal of Medicine by Leaut-Labrze et al, introe e duced a new therapeutic option.8 Our multidisciplinary hemangioma treatment group subsequently initiated propranolol treatment for complicated IH, including ulcerated lesions. There was almost

immediate cessation of proliferation in every patient, leading to considerable shortening of the natural course of IH. This termination of proliferation had a direct effect on the duration of ulceration. Recently, a few case series of patients with ulcerating IH successfully treated with propranolol have been described.8-10 As a great number of patients with complicated IH are treated at our tertiary referral center, it was possible to select a similar control patient from our historical database for each of the propranololtreated cases. After the two groups were compared, it was found that the mean ulceration time was signicantly shorter for the patients treated with propranolol compared with the historical matched control group (8.7 vs 22.4 weeks). When the propranolol-treated patients were compared with patients in the control group treated with systemic corticosteroids or with supportive management only, a signicantly shorter ulceration time for the propranolol group was still found. The relatively long ulceration time for both the propranolol group (8.7 weeks) and the control group (22.4 weeks) may be explained by the fact that, as a tertiary referral center, we treat more complicated IH with larger ulcerations. Ulceration is a dynamic process and new adjacent ulceration may develop before healing of the rst area of ulceration. These consecutive lesions mean that some ulcerations take a long time to heal completely. The effect of propranolol on ulceration in IH also seemed to be related to the time of onset of

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Fig 2. A, Ulcerating IH on left labium majus, before treatment with propranolol: total ulceration time 13 weeks (patient 2a in Table I). B, Ulcerating IH on left buttock, not treated with propranolol or oral corticosteroids: total ulceration time 30 weeks (patient 2b in Table I).

treatment. Initiation earlier in the proliferation phase nearly always resulted in a tendency to faster healing. Only 2 (20%) of the early starters had a prolonged ulceration compared with 70% of the late starters. From earlier studies it is known that larger, more supercial IH in areas susceptible to trauma and contamination are more likely to ulcerate.11,14 Possibly, the best way to treat these potentially complicated IH is to start propranolol early in the proliferation phase to prevent ulceration. The observation that propranolol is very effective in the treatment of ulcerating IH compared with historical controls should be discussed in light of the limitations of this study. The data were obtained retrospectively for the control group, but were recorded by physicians unaware of the specic hypothesis of the study. The risk of confounding is a threat to the validity of observational studies. The strongest evidence that propranolol is an effective treatment for ulcerating IH would be provided by a randomized placebo-controlled trial. However, the undoubted clinical efcacy of propranolol in treating IH now makes this type of study almost unethical. In our opinion, clinically useful conclusions can be drawn despite the limitations of this study design. We propose that propranolol should be the treatment of rst choice for seriously ulcerating IH.
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