Szychta, Pawel M.D., Ph.D.; Stewart, Ken M.D.; Anderson, Will M.D.
Infantile hemangioma is a benign vascular tumor.1 It is clinically diagnosed as the most common lesion of newborns, with an occurrence rate of between 4 and 10 percent, predominantly in preterm Caucasian women.2,3
Propranolol, a nonselective beta-blocker with membrane stabilizing activity, causes accelerated involution of infantile hemangioma. Several publications have reported the improved aesthetic appearance after propranolol treatment for infantile hemangioma using only subjective methods, with limited evidence based on validated objective analysis of treatment results.4–18 However, the evidence-based medicine level of proof is essential to support clinicians with guidance for infantile hemangioma treatment with propranolol.1,19
We aimed to validate objectively the aesthetic results after propranolol treatment for infantile hemangioma, and to produce a protocol of therapy, including optimal timing for introduction, pretreatment preparation, dosage, frequency of visits, duration, and patient safety.
PATIENTS AND METHODS
A prospective cohort study was conducted from March of 2009 through October of 2012 in the Plastic and Reconstructive Surgery Department, Royal Hospital of Sick Children, in Edinburgh, United Kingdom. No ethical approval from the National Health Service Ethical Committee was required because no additional medical interventions were performed other than those widely accepted by the National Health Service.
The management protocol was designed for the clinical trial. Inclusion criteria comprised the rapidly growing hemangioma, lesion with functional or significant cosmetic deformity, and lesion likely to affect physiological functions or cause significant cosmetic deformity in the future. Exclusion criteria were history of previous treatment for infantile hemangioma (such as laser or steroid), cardiac pathology (cardiac malformation, heart failure, cardiac arrhythmias, pulmonary hypertension), pulmonary pathology (asthma, bronchopulmonary dysplasia, bronchiolitis), Raynaud syndrome, pheochromocytoma, PHACES (posterior fossa malformations, facial hemangioma, arterial anomalies, cardiac defects, eye abnormalities, and sternal cleft and supraumbilical raphe) syndrome.20
Patients, consulted at the multidisciplinary clinic and referred for initiation of propranolol treatment as inpatients, were not fasted, had to be well, and had to take normal diet and fluids. The pretreatment steps at admission included physical examination, medical photographs, electrocardiogram, finger-prick blood glucose, and baseline blood pressure. Magnetic resonance imaging was conducted in some cases to exclude PHACES syndrome. Propranolol was commenced at the oral dose of 0.66 mg/kg three times per day if the child was older than 2 years of age. If the child was under 2 years of age, the oral dosage was 0.33 mg/kg three times per day over the first 24 hours and was increased to 0.66 mg/kg three times per day after the third dose when no adverse events were observed. Blood pressure and heart rate were monitored 30 minutes after the first dose and every 15 minutes for 1 hour. If blood pressure or heart rate dropped by 20 percent or more, medical review was requested. If no change was found, blood pressure and heart rate monitoring were stopped. Capillary blood glucose was measured at 1 hour and 2 hours after propanolol administration and was stopped if no change was found. In turn, medical advice should be requested if capillary blood glucose is less than 3.0 mmol/liter. If the child was 2 years of age or older, he or she was discharged 6 hours after the first treatment. Children younger than 2 years of age were monitored for 48 hours. Subsequently, treatment was continued with oral propranolol in liquid solution of 50 mg/10 ml or 10 mg/1 ml for up to 6 months, with the clinical review conducted every month. Medical two-dimensional photographs were taken every 4 weeks during treatment and 4 weeks after discontinuation of treatment. Three-dimensional scans of the superficial parts of hemangioma, which bulged over the surrounding skin, were conducted before administration of propanolol and 3, 6, 9, and 12 months after treatment, using a 3dMD camera (3dMD Ltd., London, United Kingdom). Patients were reviewed regularly in the outpatient clinic.
Side effects of propranolol treatment were noted and were divided into major effects that could lead to cessation of propranolol (e.g., hypotension, hypoglycemia) and minor side effects (e.g., asymptomatic deviations in laboratory tests) that prompted a decrease of the propranolol dose.
Each pretreatment and posttreatment two-dimensional photograph was subjected to subjective evaluation by three consultants in plastic surgery. They assessed general aesthetic outcome (subjective overall result) describing the overall improvement in the posttreatment hemangioma appearance, together with one of the main components of aesthetic result—color fading of infantile hemangioma (subjective fading result). In comparison, we performed computerized, triple objective assessment of color fading of infantile hemangioma (objective fading result) on two-dimensional photographs, using the Skin Lesion Color Change computer program (Anthroposcan3D, Lodz, Poland).21 In all three of the aforementioned instances, treatment outcome was presented as percentage of success, where –100 percent corresponded to total failure, 0 percent showed no change, and +100 percent described total success. Initial and final volumes of infantile hemangioma were measured in three-dimensional scans using the Anthroposcan3D computer program (Anthroposcan3D, Lodz, Poland).22
Reliability of subjective and objective methods to assess the propranolol treatment outcomes of infantile hemangioma was quantified as accuracy and repeatability of results.21 Accuracy of results was assessed by comparing the different methods with the subjective fading result. The overall repeatability of results with use of the particular method was calculated, based on the triple measurement of the treatment result in each patient. Both accuracy and repeatability were presented as technical error measurement and showed degree of variation between measurements. The resulting reliability was shown on a scale of 0 (weakest) to 1 (strongest).
The overall data recorded from the medical notes included initial age at follow-up, duration of follow-up, number of outpatient visits, ulceration and location of infantile hemangioma, diagnostic tests, and complications. The following parameters related to propranolol treatment were recorded: initial age at the beginning of treatment, duration of treatment, initial weight at the beginning of treatment, final age at the end of treatment, initial dose, final dose, relative dose at checkups before the dose adjustment, relative dose at checkups after the dose adjustment, relative dose during the whole treatment, number of dose adjustments, intervals between dose adjustments, and age at the infantile hemangioma rebound.
Statistical tests were used to analyze the results. The normality of the groups was assessed using the Shapiro–Wilk test. Two continuous parameters were compared with a t test for dependent samples, a t test for independent samples, or a Pearson’s correlation test. More than two continuous parameters were assessed with a multivariate analysis of variance. Dichotomous variables were assessed with a chi-square test. The difference was claimed as statistically significant when p < 0.05.
For the present study, we included 60 children who were diagnosed as having severe infantile hemangioma and who were referred for propranolol treatment. At the first presentation, patients’ age was 4.06 ± 3.76 months (Table 1). Average follow-up period after treatment was 6.30 ± 4.60 months, including 3.75 ± 1.55 outpatient visits with intervals of 2.33 ± 1.60 months.
Treatment with propranolol was initiated at 4.87 ± 4.45 months of age and was continued for 10.5 ± 6.98 months (p < 0.0001) (Table 2). Children’s weight was 5.56 ± 2.23 kg at the commencement of propranolol and 9.20 ± 2.25 kg at the cessation of pharmacological therapy (p< 0.0001), with an average weight of 7.46 ± 1.83 kg during the period of active treatment. The initial propranolol dose was 3.71 ± 1.48 mg three times per day and the final dosage was 5.83±1.79 mg three times per day, with the average dose during treatment of 4.76 ± 1.33 mg three times per day. The weight-matched relative dose during treatment was 0.62 ± 0.07 mg/kg three times per day, with 0.58 ± 0.10 mg/kg three times per day at checkups before the dose adjustment and 0.64 ± 0.07 mg/kg three times per day at checkups after the dose adjustment. The dose was adjusted 3.03 ± 2.00 times during treatment, with the average intervals between the dose adjustments of 2.48 ± 1.10 months (Figs. 1 through 3).
After treatment, we analyzed the aesthetic outcomes of therapy. Results were characterized with much higher repeatability when they were assessed using objective methods, compared with subjective evaluation, together with moderate consistency of results between the two methods (Table 3). Our analysis revealed that the infantile hemangioma color fading result was the dominant component of the overall aesthetic improvement and could be used as one of the main factors assessing the final outcome. Therefore, the treatment outcome was analyzed in detail in the objective method and quantified only as objective fading result. In general, the objective fading result was 51.0 ± 23.6 percent, which was lower than the subjective overall result of 61.2 ± 26.3 percent (p = 0.0168) and the subjective fading result of 60.2 ± 25.7 percent (p = 0.0152).
When aesthetic outcome was taken into consideration in relation to the location of infantile hemangioma, lesions resulted in a similar objective fading result (p > 0.05), including middle face (lower periorbital region, cheek, upper lip, and nose) 53.1 ± 25.7 percent, upper face 46.9 ± 25.4 percent, lower face 52.2 ± 25.2 percent, upper trunk 51.0 ± 14.8 percent, lower trunk 46.0 ± 11.3 percent, upper extremity 65.0 ± 16.9 percent, and lower extremity 70.0 percent.
In relation to ulceration and/or bleeding of infantile hemangioma, patients treated with propranolol benefited from insignificantly higher treatment success in cases of ulcerated lesions (62.9 ± 14.4 percent) compared with nonulcerated lesions (48.5 ± 24.5 percent) (p = 0.0805).
The average final volume of infantile hemangioma after treatment of 1.14 ± 1.80 ml was significantly lower than the average initial volume of 2.60 ± 4.04 ml (p = 0.0343), measured in three-dimensional scans from 14 individuals treated with propranolol. Consequently, we observed a decrease in volume of 1.46 ± 2.31 ml during treatment with propranolol.
In relation to duration of treatment, aesthetic results were insignificantly higher among patients who were under clinical care for more than 24 months (63.0 ± 9.84 percent), compared with treatment success sorted in decreasing order for 12 to 18 months of follow-up (60.0 ± 22.2 percent), fewer than 6 months (50.2 ± 29.4 percent), 6 to 12 months (47.5 ± 23.7 percent), and 18 to 24 months (43.8 ± 15.8 percent) (p = 0.2083) (Table 1).
During the propranolol treatment, we observed only minor complications. One patient had transient asymptomatic hypotension that occurred during a propranolol loading dose that resolved before the subsequent dose. Three patients had diarrhea, two suffered from sleep disturbances, and one child developed a rash on the torso, which resolved after a couple of hours (Figs. 1 through 3).
Infantile hemangioma is caused by excess angiogenesis.20,23 It has a typical immunohistochemical profile, which differentiates vascular tumors from malformations.24 Endothelial cells of infantile hemangioma express markers of the placenta capillaries in all stages of development (GLUT1, merosin, Lewis Y antigen, and FCG II receptor), which may indicate its origin from placental tissue.25 Shortly after birth, infantile hemangioma is present usually as a vascular spot or area of pallor. In the proliferative phase, which begins at 1 to 2 months of age, a compressible, nonpulsating tumor grows until 1 to 6 months of age; however, large, deeply penetrating lesions can grow until 2 years of age.26,27 Subsequently, infantile hemangioma goes into a dormant phase, maintaining a predefined shape and size. At 12 to 18 months of age, it enters the involutive phase, which lasts until 3 to 7 years of age.24,28 It disappears partially or completely in 30 percent of cases by 3 years of age, 20 percent by 5 years of age, and 30 to 40 percent by 9 years of age, while remaining unchanged in 10 and 20 percent of patients.24 About half of disappearing lesions transform into normal looking skin, whereas the other ones transform into remnants such as telangiectasia, fibrofatty tissue, or a scar.25 The majority of infantile hemangioma cases resolve spontaneously without intervention.29 In 10 percent of cases, infantile hemangioma leads to distortion of shape and functional disorders, and subsequently requires treatment.30
Until recently, the first-line treatment of infantile hemangioma in the proliferative phase included corticosteroids administered systemically or intralesionally (Table 4). In turn, localized or residual infantile hemangiomas in the involutive phase were treated with surgical excision or laser therapy.31,32 Conventional treatment was only partially effective with variable potential of complications, and outcomes were assessed with subjective measures.
Several reports showed the effectiveness of propranolol in rapid inhibition of proliferation and promotion of regression of infantile hemangioma, in cases of even large segmental, periorbital, or airway lesions, with a low rate of complications.1,26,27,33 In the previous studies, proliferation was inhibited by propranolol after less than 48 hours of treatment in 74 percent of patients and was clinically manifested as palpable softening of lesions with color changed from the primary deep red to blue or purple. In the remaining 26 percent of cases, inhibition of proliferation was demonstrated within 2 weeks.34 Regression was clinically observed in less than 2 weeks in 55 percent of cases and by 4 weeks in 16 percent, and lesions remained unchanged in 13 percent of patients.34 Outcomes of propranolol treatment, assessed with subjective measures, are summarized in Table 5.
Noticeably, previous studies used subjective methods to assess the perceptible aesthetic treatment results. Reliability of subjective assessment is affected by several factors, such as low repeatability, different lightning conditions, and even the emotional status of the infant. Thus, subjectively obtained analysis can produce only partially reliable clinical implications. In our series, variability of the subjectively obtained parameter, subjective fading result, which was repeatedly assessed by senior consultants in plastic surgery, ranged from 25.3 percent to even 27 percent. In contrast, variability was as low as from 2.87 to 2.99 percent for the objectively measured parameter, objective fading result, which was calculated three times with a computer program (Table 3).
Conclusively, management with propranolol should follow guidelines based on strong clinical evidence, obtained with objective measures. In the first objective report, Bingham et al.18 detected the decrease in the infantile hemangioma area, volume, and vessel density after propranolol treatment using grayscale and color Doppler. In turn, our study analyzed the perceptible aesthetic outcome of propranolol treatment for infantile hemangioma using both objective and subjective methods and taking into consideration general aesthetic improvement, color fading, and shrinkage.4–7,35 We observed a high correlation between the subjective overall result and the subjective fading result (technical error measurement, 5.35 to 5.66 percent; r, 0.95 to 0.97; p < 0.0001), the latter precisely described in the mathematical algorithms and thus applicable for the objective assessments. Subjective fading result was relatively consistent with objective fading result, with variation of 15.5 to 18.2 percent (r, 0.64 to 0.65; p< 0.0001) (Table 3). As a consequence, objective fading result was taken as a representative parameter for the treatment’s aesthetic outcome.
In our series, patients treated with propranolol experienced a high level of aesthetic improvement (Table 1). Longer follow-up correlated insignificantly with better treatment outcome. Patients with infantile hemangioma, regardless of the lesion’s location, experienced the similar advantage from propranolol treatment. In addition, patients treated with propranolol had a significant decrease in the volume of the hemangioma (p = 0.0343). In general, our findings confirm the previously reported results, summarized in Table 5, which showed the significantly accelerated involution of infantile hemangioma after propranolol administration.17,20,34
The detailed analysis of propranolol activity was undertaken in order to produce the treatment algorithm. We started propranolol treatment early, at an average patient age of 4.87 months and an average body mass of 5.56 kg. Similarly, the previously reported mean age at the start of treatment was 3.9 months and ranged from 1.2 to 9.7 months.34 In our series, patients with a younger age (p = 0.0170) and related lower weight (p = 0.0200) at commencement of therapy contributed to better aesthetic outcome.
For most infantile hemangiomas, the proliferative phase ends by age 7 months.36 As a consequence, we discontinued treatment after the end of the proliferative phase in children aged 12.3 months on average, and thus the final age (p > 0.05) and body mass (9.20 kg, p > 0.05) at cessation of propranolol treatment did not correlate with aesthetic outcome. Consequently, duration of propranolol treatment, which was about 10.5 months, did not correlate with aesthetic outcome (p > 0.05). The duration of propranolol treatment should be prolonged in cases of large or compound hemangiomas for an additional 6 months after the final desired effect. Similarly, propranolol treatment was stopped in the previous study at 1 year of age, with a rebound rate of 7 percent.20 In contrast, the previously reported treatment cessation at the earlier age of 6.5 months (range, 4 to 11.7 months) resulted in rebound growth in 24 percent of cases.34
Rebound growth of infantile hemangioma after treatment cessation is clinically manifested as a recurring bulge, relapsing color, and/or ulceration. Relapse episodes, as previously reported, were seen 2.3 weeks after treatment cessation and all responded well to reintroduction of therapy at 3 mg/kg/day for 9.3 weeks.34 Rebound growth at propranolol cessation was observed in younger children (5.1 ± 0.9 months versus 7.2 ± 1.0 months). To avoid rebound growth, treatment should be continued until a plateau of the hemangioma growth is sustained. However, regardless of the treatment result in an individual patient, the therapy should be continued minimally until the patient reaches the age of 7 to 8 months and optimally until 12 months of age, because it should cover the whole proliferative phase in each case. In our study, most of the 11 rebound patients were treated early in the study, and surprisingly propranolol was stopped relatively late, at age of 12.58 ± 3.51 months. However, most of the cases were compound infantile hemangioma, and now we treat such children for 6 months longer than we treat those with superficial infantile hemangioma. Moreover, propranolol administration should be gradually tapered over a period of 2 weeks, which minimizes the risk of rebound growth and hyperadrenergic withdrawal response.37
Propranolol efficacy was suggested to be dose-dependent in reducing proliferation of infantile hemangioma.4–7 The previously proposed empirical dosage among publications varied from 1 to 3 mg/kg/day administered daily with different modes and durations of treatment.4–17 In our study, the relative propranolol dose during treatment was precisely adjusted to body mass at the level of 0.62 ± 0.07 mg/kg three times per day on regular visits (3.03 on average), with intervals of about 2.48 months. As we have shown, the relative weight-adjusted dose remained constant throughout the entire treatment period, but the total dose became higher in correlation with the increasing body mass. There was no correlation between number and frequency of visits and aesthetic outcome, which proved the compliance of the proposed protocol among consultants. Surprisingly, the smaller the relative propranolol dose at the subsequent check-ups before the dose adjustment, the better the aesthetic outcome (p = 0.0050). This finding can be age-related and can result from the more rapid weight gain in the younger infants. Thus, more frequent visits are advised in younger children in order to allow accurate adjustment of the dosage in the early stages of treatment. Based on our results, the daily dosage should be re-evaluated frequently and should not fall below 2 mg/kg/day.
Ulceration occurs at 4 months age on average; thus, we recommend that severe infantile hemangioma should be treated earlier.29 In patients with ulcerating infantile hemangioma, the previously reported epithelialization was achieved in seven out of eight cases within 3 weeks after commencement of therapy with a dose of 3 mg/kg/day.34 In another report, where a dose of 1 to 2 mg/kg/day was administered, ulcers healed after 8 to 18 weeks.4,10,38 We observed prompt healing of ulcers in all cases. Children treated with propranolol for both ulcerated and nonulcerated infantile hemangioma had similar aesthetic results and thus we recommend the same dosage in both groups of patients.
Periorbital infantile hemangioma was managed successfully using oral propranolol, with an improvement in function and aesthetic appearance, as reported previously.39 In our study, 12 of 23 patients with periorbital infantile hemangioma had slight astigmatism and all of them recovered completely after commencement of propranolol.
Propranolol is a safe drug, as proven by previously reported large series with long follow-up, and has been used in children for various medical conditions in doses up to 7 mg/kg/day without any life-threatening complications.1 In our study, no major side effects were noted. Thus, we confirm that low-dose propranolol administered in divided doses with gradual increase is safe; however, a cardiac preparation for propranolol therapy is necessary to exclude contraindications for therapy.8
Propranolol is an effective, well-tolerated, and safe first-line treatment for proliferative hemangioma. Therapy should be commenced early, continued with the target dosage of 2 mg/kg/day in three divided doses through the proliferative phase of infantile hemangioma, and stopped gradually.
The authors are grateful to Hilal Bahia and Ahmed Jawad, from the Plastic and Reconstructive Surgery Department, St. John’s Hospital, Livingston, United Kingdom, for their assessments with questionnaires of the aesthetic outcomes after propranolol treatment for infantile hemangioma.
Parents or guardians provided written consent for use of patients’ images.
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