Topical Betaxolol Hydrochloride for the Treatment of Supercial Infantile Hemangiomas: A Single Institutional Retrospective Study

Background Objectives: Beta-blockers have gradually become an attractive option for the treatment of infantile hemangiomas (IHs). Topical application of beta-blockers is more preferred over oral administration since their potential systemic adverse effects. Besides timolol, as the mainstream medication for supercial IHs, however other types of beta-blockers are rarely reported. To develop a brand-new effective approach, in this present study, betaxolol as a topical treatment for IHs was specically observed and recorded.


Introduction
As the most commonly benign vascular neoplasms among infancy (affect 4%-10% of infants), infantile hemangiomas (IHs) present early in life occurring with a female to male ratio of 3:2 approximately. 1 In general terms, IHs appear as the precursory lesion, i.e. a rosy spot, telangiectatic macules or limited areas with bruises, 2 and they are characterized by rapid growth in the rst months of postnatal stage which followed by a protracted period of relative stabilization and then regressed slowly. [3][4] Due to IHs' clinical manifestation combined with ultrasonography, the diagnosis can be made typically. Moreover, based on the extent and degree of involvement of surrounding tissues, IHs can be classi ed into three categories: super cial, mixed and deep type. [5][6] Despite most IHs have the nature to self-limit as well as the vast majority of super cial ones are capable to fade away spontaneously without any medical intervention, there still exist several complications like ulceration, infection, malformation, dis guration, visual impairment, unconscious hemorrhage, and even airway obstruction. [7][8] Of IHs, around 60% can be found in the head and neck area, preferentially occurred on the face, eyelids, ears, lips, cornea or genitalia, whereas about 25% and 15% respectively located in the trunk and extremities. Given the possibility of negative emergence, for instance functional impairment, morphological deformation or general complications, it is necessary to intervene as soon as possible. [9][10][11][12] Treatments aimed at super cial IHs have gone through intralesional injection, local laser radiation, oral medication, and nally topical delivery of remedy. 13 Since Léauté-Labrèze et al 14 rst reported that propranolol had a signi cant effect on hemangiomas of infancy, many kinds of β-blockers are being more and more recommended than any other therapeutic schedules for clinical application. 10,15 However, not only were identi ed sorts of serious side-effects after oral administration of β-blockers (e.g., cardiovascular risks like hypotension, bradycardia or atrioventricular block; metabolic risks like hypoglycemia, hyperkalemia in ulcerative IHs; respiratory risks like bronchial spasm or asthma; neurological disorders like relevant epilepsia or transient ischemic stroke; and abnormalities occurred in eyes, heart and blood vessels of head and neck), [16][17][18] but also it is di cult for drug concentration to act precisely on lesional locality via systemic circulation. Hence, the local administration of βblockers represented by propranolol has been successively launched in clinical practice, until now timolol as the rst-line drug has gradually become the main topical therapy for super cial IHs. 6,[19][20] Nevertheless, either some adverse effects that still exist or irresponsive / allergic to timolol, an alternative option should be prepared.
Betaxolol, which is a relatively selective β-1 adrenergic receptor blocker, initially emerged for ophthalmological disorders, and has almost identical function with timolol in lowering intraocular pressure. 21 Furthermore, for structure and e cacy, betaxolol is practically as same as atenolol which is a good substitute to selective β-adrenergic-receptor blocker for IHs with fewer adverse events. [22][23][24] More importantly, it has been con rmed that betaxolol has approximately ten times higher skin permeability than timolol because betaxolol is more lipophilic, whilst that makes topical application of betaxolol possible to achieve higher concentration at the same dosage over the super cial IHs. [25][26] Considering no clinical data on the use of betaxolol for treating IHs, this present study is the rst description focused on the characteristics of topical administration of betaxolol hydrochloride in super cial IHs and may provide preliminary information for a new idea.

Patients And Methods
This was a retrospective, observational clinical study involving 74 infants. All infants were recruited from the Outpatient of Oncological Department of Oral Eligible subjects were infants aged younger than 12 months. The inclusion criteria were as followed: a. infants suffered from super cial hemangiomas who had not accepted any previous treatment; b. the diagnosis was con rmed by the criteria of International Society for the Study of Vascular Anomalies (ISSVA). 27 The following as exclusion criteria were: a. infants had other types of vascular anomalies besides super cial hemangiomas; b. the general condition was unhealthy which amalgamated with fever, hypotension, atrioventricular block, bradycardia, pneumonia, bronchial asthma or diarrhea; c. infants had contraindications of betaxolol hydrochloride; d. during the clinical treatment, infants took β-agonist, or received medication other than β-blockers.
All infants met the selective criteria of study were assigned into three groups according to their age: a. 0-3 months; b. 3-6 months; c. 6-9 months. The general characteristics of infants, particularly the description of their hemangiomas, are shown in Table 1. Prior to treatment, the admitted infants well-received relevant examinations completely, which consisted of ultrasonography, electrocardiogram, blood routine examination, blood glucose concentration, serum potassium concentration and test of hepatic and renal function, in order to evaluate vital signs as well as recognize contraindications. Infants of this analysis only accepted betaxolol hydrochloride as topical administration apart from any other therapies. Speci c therapeutic regimen was as followed: sterile gauze soaked fully of 0.25% betaxolol hydrochloride ophthalmic suspension (catalog nr. 111820, content 5ml: 12.5mg, S.A. ALCON-COUVREUR N.V.) was applied to cover hemangioma lesion three times per day (every six to eight hours); the dosage kept 30-40 μl/cm 2 on surface and each time lasted 5-15 minutes (depending on the thickness of hemangioma and the reaction to treatment); preventing drugs in ltrating into eye or reproductive tract.
Parents were required to closely monitor the changes of complexion, heart and respiration rate after each local medication. Especially, the heart rates of preand post treatment, rest-activity and sleep-wake should be recorded. Once they had lower heartbeats than the normal minimum (neonate 120 /min, infant 100 /min), the drug must be stopped immediately. In case of ulceration appeared, it was necessary to avoid topical drugs on the wound. The whole process sustained for six months. Through each subsequent visit monthly, the same doctor took a standardized digital photograph and emphasized on checking heart rate (HR) and blood pressure (BP). Last but not least, in line with the extent of IHs regression, withdrawal of topical betaxolol was assessed. What should be recommended was that, gradual reduction or proper decrease the frequency of use until nal discontinuing, so as to avoid drug withdrawal symptom. Every patient needed to be followed up for half a year after the treatment.
Based on clinical photographs, the e cacy of topical betaxolol hydrochloride was estimated by visual analog scale (VAS) at the onset, during and in the end of treatment separately. VAS for color (VAS-C) and for size, tension and thickness (VAS-STT), with scores ranging from -100 to 100, were assessed outcome measures. Among them, -100, 0, and 100 respectively signi ed doubling in size, no change, and complete healing for VAS-SEV, whilst doubling in intensity of color, no change, and complete absence of discoloration contrasted by the surrounding skin. Therapeutic response was graded into four levels:

Results
Even though we launched treatment for a total of 83 infants with topical betaxolol hydrochloride initially, 9 were excluded from the nal analysis because 5 were lack of photograph records, 2 had to alter regimen to oral propranolol, and 2 were lost to follow-up. Eventually, there left 74 subjects characterized by dominancy in females with a ratio of 2.4:1 versus males (52 females, 22 males). The mean age of these infants was 4.5 months ranging from 2.5 to 37 weeks. For the classi cation of super cial hemangioma, plaque was the predominant type (44.59%). The primary location of lesions distributed in head and neck region (27), trunk (22) and extremities (25). Baseline data and implement scheme were shown in Table 1 and Figure 1 in detail.
Clinical responses to topical betaxolol hydrochloride after six-month therapy are summarized in Tables 2. There was Figure 3. According to their different areas, there may be involved different potential high-risks.
Firstly, IHs in maxillofacial and cervical region have a high risk of scarring, and IHs' association with PHACE syndrome* should be vigilant especially for the big ones. Besides, IHs within orbital region pose a hazard to vision affection; severe ones occurred in ear, nose and lip may cause permanent distortion or dis gurement of anatomic landmarks. Secondly, numerous lesions of torso (beyond ve, or even more cutaneous hemangiomas) are potential to associate with hepatic hemangiomas. Herein, genital, perineal or perianal IHs may increase the risk of ulceration; it is also necessary to pay attention to prevention for IHs along with decubitus in posterior trunk; IHs invaded in lumbosacral or perineal area should be noticed for LUMBAR syndrome*. Thirdly, IHs located in extremities may be easily jeopardized into permanent hyperplasia or atrophy of skin tissue. Typical examples are illustrated in Figure 4. Among them, Patient 1 is a 3-month-old girl with super cial IH located in left nipple; patient 2 is a 7 month-and-24 day-old girl with super cial IH located in left anterior thoracic region; patient 3 is a 2 month-and-2 week-old girl with super cial IH located in interior region of left lower leg; patient 4 is a 2-month-old boy with super cial IH located in left middle toe.

Discussion
It has been reached a consensus that more aggressive interventions should manage higher risks for complications, especially prioritized to possibly functional impairments and potentially life-threatening symptoms. After a constant-growing development treating against IHs, including surgery, photodynamic therapy, interventional sclerotherapy, and oral corticosteroids, propranolol as a revolution was welcomed in the year of 2008. 14 Propranolol that is only available as systemic medication in most countries, however, may cause adverse effects via blood circulation. Even though some of them like hypotension, bradycardia, hypoglycemia, diarrhoea and sleep disturbance can be self-limited, 31 anxieties concerned on neurocognitive capacity have been recently proposed. 32 Since then, raising numbers of pediatric or dermatological specialists have conducted lots of clinical researches about diverse beta blockades treating IHs, and suggested local administration to point at super cial hemangiomas as well. 33 Along with the very rst report of a successful outcome after adopting timolol solution as a topical treatment for a four-month-old girl with a super cial capillary hemangioma located in her left eyelid, 34 a series of relevant studies were con rmed subsequently. 20,[29][30]35 Nevertheless, with the deep-going development of clinical studies concentrated on topical timolol for super cial hemangioma, several side-effects and adverse events were also pointed out. 29,[36][37][38][39][40] Betaxolol, a relatively selective β-1 adrenergic receptor blocker, originally as a satisfactory remedy for glaucoma, has been widely used for more than approximately thirty years. Aside from several principal self-restrictive adverse effects containing local pruritus, bronchial spasm, hypotension and hypoglycemia found in rare cases, betaxolol always proves its safety, stability and e ciency. In this study, the overall rate of clinical effectiveness was 89.19% (66/74), whereas only 2 cases changed into oral propranolol because of poor response, and no one arose adverse effects. These results were better than those stated by Pope and Chakkittakandiyil (2010), 39 Chakkittakandiyil et al (2012), 41 Gong et al (2015), 30 Püttgen et al (2016), 20 and Wu et al (2018). 42 Expected consequences might result either from the low density of intracorporal distribution via topical application, or from the less drug concentration itself (0.25% betaxolol hydrochloride versus 0.5% timolol maleate). Both sides could notably reduce the absorption inside bloodstream, while topical betaxolol made the infants' prognosis satisfactory. As an aside, we also proved the conclusions of Chantasart D et al 25 and Zhang Q et al 26 that, a small amount of betaxolol hydrochloride (0.25%) can work the same or even better than timolol maleate (0.5%), arising from its superior cutaneous permeation because of stronger liposolubility Table 5. Accordingly, less topical betaxolol hydrochloride has opportunity to pass blood-brain barrier which can bring about fatigue, anxiety and sleep disturbance.
On-going researches involved in mechanisms have found that, β-blockades make the actions of matrix metalloproteinase (MMP), endothelial nitric oxide synthase (ENOS), vascular endothelial growth factor (VEGF), and basic broblast growth factor (BFGF) suppressed by inhibiting β-adrenergic receptor, so as to further lead to proangiogenic signal blockage, and nally result in arrest of hemangioma growth. [43][44][45] Remarkably, β-blockers may not participate in one single mechanism, but in a multiple combinations of regulations of anti-hemangioma passways Figure 5. Nonetheless, how the β1-blocker impacts on the promotion of anti-hemangioma e cacy is still poorly understood.
Our present study also discovered that, the children aged younger than three months have the most effective outcomes (32/33, 96.97%) compared with those in three-to-six (20/21, 95.24%) and six-to-nine months (14/20, 70.00%). What is more is that, children within six months have a similar effectiveness but they are much more than the older-than-six children. That is probably in line with the process of development of IHs, which can be divided into proliferation, regression and regressive completion stage typically. In addition, the proliferation stage is comprised of two representative periods of rapid growth within one year after birth: one is four to six weeks postnatally; another is four to ve months. Our results possibly imply that betaxolol played a key role in preventing sorts of cytokines from hemangiogenesis promotion, and consequently medical interventions have better expectations within IHs' proliferation stage. The recordation of HR and BP after infants' acceptance of topical betaxolol therapy supported that no obvious abnormal HR and BP uctuation appeared in three age groups. It is worth mentioning that, only a minor unexpected result of HR (95.90±6.05 Bpm) was observed in the 6-9 months group at the end of therapy, and no relevant cardiac symptoms behaved though. We believe, on one hand, the age of this group is close to one-year old at that time, so the HR of them is nearly 90 Bpm (prescribed minimum of normal HR of children aged 1-3 years old) as physiological changes. On the other hand, under normal circumstances, from birth the BP of children is slowly rising while their HR is falling slowly. The most important is, these physiological changes were not destroyed during the whole procedure of treatment according to our recordation.

Conclusion
This proof of this pilot study reported betaxolol hydrochloride, 0.25%, suspension, a relatively selective β-1 adrenergic receptor blocker in topical formulation, was safe and effective for treatment of 74 cases with super cial IHs for the rst time. Despite no inhibition of hemangioma progression after accepting topical betaxolol of two subjects, almost all infants showed well-tolerated responses and no one complained any adverse events. This preliminary work supposes that topical betaxolol hydrochloride, 0.25%, suspension is a promising substitute for timolol maleate. Further double-blind, randomized controlled trials and prospective cohort studies are required to substantiate the safety and e cacy of betaxolol hydrochloride, 0.25%, suspension for curing super cial IHs.

Declarations
Ethics approval and consent to participate: The studies involving human participants were reviewed and approved by the Ethics Committee, Stomatology School of Xinjiang Medical University, The First A liated Hospital of Xinjiang Medical University (approval no. K202007-03). All methods involved in this study were carried out in accordance with relevant guidelines and regulations which were formulated by the identical group. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Consent for publication: All the patients' legal guardian/next of kin gave their consent for information about their children to be published in BMC Pediatrics. All authors approved the nal manuscript as submitted and agree to be accountable for all aspects of the work.
Availability of data and materials: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Competing interests: The authors declare that they have no competing interests.
Funding: All phases of this study were supported by Western Stomatological Clinical Research Foundation of Chinese Stomatological Association (grant number: CSA-W2019-01).
Authors' contributions: Dr. Hong Li drafted the initial manuscript, and carried out the initial analyses; Dr. Chen-Xi Li conceptualized and designed the study, designed the data collection instruments, optimized statistical methods, and critically revised the manuscript for important intellectual content; Dr. Yu-Chuan Zhou collected data, took in charge of follow-up assignment, and reviewed the manuscript; Prof. Zhong-Cheng Gong conceptualized and designed the study, and reviewed and revised the manuscript; Prof. Bin Ling conceptualized and designed the study, coordinated and supervised data collection, and reviewed and revised the manuscript. Classi cation criteria are in accordance with ISSVA [27].
* Figure 3 describes the precise body parts of infants' IHs and possible high-risks involving them.  *Mean values were expressed in terms of mean ± standard deviation.
*P < 0.05 was considered as signi cant. Table 4 The recordation of blood pressure and heart rate in the topical betaxolol hydrochloride treatment 95.90 ± 6.05 0.757 *A total of four times of recordation represented respectively commencement of treatment (baseline); the rst follow-up visit (one month later); the second follow-up visit (four month later); the end of treatment (six months). BP, blood pressure, expressed (systolic, diastolic pressure); HR, heart rate; Bpm, beat per minute.
*P < 0.05 was considered as signi cant.