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Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic

Infantile Hemangiomas: A Randomized Clinical Trial

Article  in  JAMA Otolaryngology - Head and Neck Surgery · April 2021

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 Research

JAMA Otolaryngology–Head & Neck Surgery | Original Investigation

Efficacy and Safety of Propranolol vs Atenolol in Infants

With Problematic Infantile Hemangiomas
A Randomized Clinical Trial
Yi Ji, MD, PhD; Siyuan Chen, MD, PhD; Kaiying Yang, MD; Xuepeng Zhang, MD; Jiangyuan Zhou, MD;
Lizhi Li, MD; Bo Xiang, MD, PhD; Tong Qiu, MD; Shiyi Dai, MD; Xian Jiang, MD, PhD; Guoyan Lu, MD;
Liqing Qiu, MD; Feiteng Kong, MD; Yongbo Zhang, MD

Visual Abstract
IMPORTANCE Propranolol has become the first-line therapy for problematic infantile Supplemental content
hemangiomas (IHs) that require systemic therapy. However, different adverse events have
been reported during propranolol treatment. The positive efficacy and safety of atenolol raise
the question of whether it could be used as a promising therapy for IH.

OBJECTIVE To compare the efficacy and safety of propranolol vs atenolol in infants (between
age 5 and 20 weeks) with problematic IHs who required systemic therapy.

DESIGN, SETTING, AND PARTICIPANTS This was a prospective, multicenter, randomized,

controlled, open-label clinical trial conducted in collaboration among 6 separate investigation
sites in China from February 1, 2015, to December 31, 2018. A total of 377 patients met the
criteria for inclusion and were randomized to the propranolol (190 [50.4%]) and atenolol (187
[49.6%]) groups. Data were analyzed in June 2020.

INTERVENTIONS Participants were randomized to receive either propranolol or atenolol for at

least 6 months. They completed efficacy assessments at 2 years after the initial treatment.

MAIN OUTCOMES AND MEASURES The primary outcome was any response or nonresponse at
6 months. The key secondary outcome was changes in the hemangioma activity score.

RESULTS Of 377 participants, 287 (76.1%) were female, and the mean (SD) age was 10.2 (4.0)
weeks in the propranolol group and 9.8 (4.1) weeks in the atenolol group. After 6 months of
treatment, in the propranolol and atenolol groups, the overall response rates were 93.7% and
92.5%, respectively (difference, 1.2%; 95% CI, −4.1% to 6.6%). At 1 and 4 weeks after
treatment, and thereafter, the hemangioma activity score in the atenolol group aligned with
the propranolol group (odds ratio, 1.034; 95% CI, 0.886-1.206). No differences between the
propranolol group and atenolol group were observed in successful initial responses, quality of
life scores, complete ulceration healing times, or the rebound rate. Both groups presented a
similar percentage of complete/nearly complete responses at 2 years (82.1% vs 79.7%;
difference, 2.4%; 95% CI, −5.9% to 10.7%). Adverse events were more common in the
propranolol group (70.0% vs 44.4%; difference, 25.6%; 95% CI, 15.7%-34.8%), but the
frequency of severe adverse events did not differ meaningfully between the groups.

CONCLUSIONS AND RELEVANCE In this randomized clinical trial, when compared with
propranolol, atenolol had similar efficacy and fewer adverse events in the treatment of
infants with problematic IHs. The results suggest that oral atenolol can be used as an
alternative treatment option for patients with IH who require systemic therapy.

TRIAL REGISTRATION ClinicalTrial.gov Identifier: NCT02342275

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Authors: Yi Ji, MD,
PhD, Division of Oncology,
Department of Pediatric Surgery
(jijiyuanyuan@163.com), and Siyuan
Chen, MD, PhD, Pediatric Intensive
Care Unit, Department of Critical Care
Medicine (siy_chen@163.com), West
China Hospital of Sichuan University,
JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2021.0454 37# Guo-Xue-Xiang, Chengdu,
Published online April 15, 2021. 610041, China.

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 Research Original Investigation Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas
I
nfantile hemangiomas (IHs) are the most common
tumors of childhood. A typical characteristic of IH is its
rapid proliferation and development into a disorganized
vascular mass within the first several months of life. Subse-
quently, a slow spontaneous involution begins and contin-
ues for several years. In most cases, IHs are self limited.
However, in approximately 10% of patients, the lesions can
be disfiguring, destructive, functionally significant, or even
life threatening.1,2
Propranolol, a lipophilic nonselective β-adrenergic recep-
tor (β-AR)–blocking agent, is currently approved by the US Food
and Drug Administration for problematic IHs that require sys-
temic treatment.3-6 Although propranolol overall has a well-
established safety profile, there have been severe adverse
events reported in some patients who were treated with this
medication for IH.7,8 Bronchial irritation and hypoglycemia
are potential effects of β2-AR blockade that are caused by
propranolol.9 In addition, the highly lipophilic nature of pro-
pranolol can facilitate its crossing of the blood brain barrier to
enter the brain. Therefore, patients may have a high risk of cen-
tral nervous system (CNS)–related adverse events (eg, sleep dis-
turbance and agitation), which can theoretically influence brain
development in young infants.10 These issues may outweigh
the drug’s benefits because of the long-term administration of
propranolol required for this patient group.
Atenolol, a large, hydrophilic, selective β1-AR blocker that
can be administered in a once-daily dose, is an attractive al-
ternative to propranolol for treating IH. In this context, sev-
eral studies generated optimism regarding the efficacy and
safety of atenolol regimens.11-14 However, there are limita-
tions to each of these studies in terms of the study design (eg,
inadequate case-control), sample size, and/or age of the pa-
tients enrolled.11-14 Therefore, a large, randomized compari-
son is still needed to compare the efficacy and safety of aten-
olol with propranolol in treating IH. The purpose of this study
was to compare the efficacy and safety of orally administered
propranolol vs atenolol in treating potentially disfiguring or
functionally threatening IHs.
Methods
Study Design
This was a multicenter, randomized, controlled, open-label
clinical noninferiority trial comparing propranolol and aten-
olol for the management of problematic IHs. The study was de-
signed to establish whether atenolol was noninferior to pro-
pranolol. The trial was collaboratively conducted among 6
tertiary referral centers in China. These 6 large referral cen-
ters provide care for a population of approximately 120 mil-
lion people per year who live in the southwest region and east
region of China. Data were collected from each participating
site and sent to the principal investigation site at West China
Hospital of Sichuan University for analysis. The study proto-
col was approved by the ethics committee on medical re-
search of each participating site. All procedures followed the
study protocol and were conducted according to the Declara-
tion of Helsinki. Patients’ parents or guardians gave written
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Key Points
Question In light of the positive efficacy and safety of atenolol,
can it be used as a promising therapy for infantile hemangiomas?
Findings In this randomized clinical trial of 377 patients with
infantile hemangiomas, the response rate and hemangioma
activity score after 6 months of treatment were similar in the
propranolol and atenolol groups. Adverse events were more
common in the propranolol group than the atenolol group.
Meaning Atenolol can be considered a first-line treatment for
infantile hemangiomas.
informed consent before enrollment. The study has been reg-
istered at http://www.clinicaltrial.gov (NCT02342275).
Study Patients
Patients were eligible for inclusion if they were between age 5
and 20 weeks and had proliferating and problematic IH of the
superficial or mixed type that required systemic therapy. In ad-
dition, the following diameters of the IH had to be present for
inclusion: (1) 1.5 cm or greater on the face, (2) 3.0 cm or greater
on locations outside of the face, and (3) 1.5 cm or greater on any
location if ulcerated. Key exclusion criteria were as follows: pa-
tients contraindicated for the administration of β-blockers (eg,
those with an allergy or hypersensitivity to propranolol); pa-
tients previously treated with any IH therapies, including cor-
ticosteroids, propranolol, topical timolol, or other treatments;
and patients with an inability to participate in or follow-up dur-
ing the study treatment and assessment plan. Hemangioma le-
sions were classified by morphologic subtypes, comprising lo-
calized, segmental, and indeterminate. Hemangioma lesions
were also classified by soft-tissue depth, comprising superfi-
cial, deep, and mixed. Detailed definitions and inclusion and
exclusion criteria are provided in the trial protocol (Supple-
ment 1). When patients had more than 1 IH, detailed informa-
tion was obtained for the most clinically important heman-
gioma (typically the largest or most ulcerated lesion).
Randomization and Masking
The families and the investigators who treated and followed
the patients were not masked to the treatment. The central in-
vestigators who measured the primary and key secondary out-
comes were masked to the patient’s treatment allocation. Eli-
gible patients were randomly assigned at a 1:1 ratio to the
propranolol group or atenolol group. The Department of
Pediatric Surgery at West China Hospital of Sichuan Univer-
sity generated a randomization list and implemented random-
ization using an interactive web-based system (http://www.
sealedenvelope.com; Clerkenwell Workshops).
Study Intervention
All patients received at least 6 months of treatment and were
followed for 2 years. In the propranolol group, propranolol was
initiated at a dosage of 1.0 mg/kg/d (10-mg tablets) divided 3
times daily for 1 week, which was then increased to 2.0 mg/
kg/d divided 3 times daily from week 2. In the atenolol group,
jamaotolaryngology.com
 Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas
atenolol was initiated at a dosage of 0.5 mg/kg/d (5-mg tab-
lets) in a single dose for 1 week and then increased to 1.0 mg/
kg/d in a single dose from week 2. The atenolol dose used was
based on previous studies.13,15 Before treatment, the families
were provided a handout on safety monitoring during the treat-
ment phase. The dosage of propranolol or atenolol was ad-
justed for weight (weekly for 2 weeks, then every other week
for 2 weeks, then monthly thereafter). In both treatment
groups, the treatment was tapered and discontinued on com-
plete or nearly complete resolution of IH or if no further im-
provement of IH (for 12 weeks of observation) was observed
after month 6. In both arms, oral antibiotics, topical oint-
ment antibiotics, and/or wound dressings were permitted to
treat ulcerated IH and were recorded. A requirement for any
additional IH-specific interventions was considered treat-
ment failure. Termination of the study was mandatory in the
following situations: any grade 4 or greater adverse event; re-
current or persistent cases of hypoglycemia, bronchitis with
dyspnea, bronchial hyperreactivity, or bronchospasms; and
persistent hypotension or bradycardia.
Study Outcomes
In both treatment groups, scheduled visits occurred at baseline
(week 0); 1, 4, 12, 24, 36, 48, 60, 72, and 84 weeks; and 2 years.
Digital photographs of IHs were taken at baseline; 1, 4, 12, and
24 weeks; and 2 years and were assessed independently by each
of the 3 research assistants (3 interpretations for each patient).
The color (measured by color chart) and size of the IH (cm2) were
analyzed. The research assistants were masked to the study group
assignment and trained specifically to assess hemangioma evo-
lution. They resolved the discrepancies by consensus. The pri-
mary outcome measure was any response or nonresponse at 6
months in the intention-to-treat population of all patients who
underwent randomization (Table 1).
The key efficacy secondary outcome was the heman-
gioma activity score (HAS), which was measured at baseline
and at 1, 4, 12, and 24 weeks. Consecutive digital photo-
graphs were assessed by trained research assistants. The HAS,
a validated measure, is calculated based on 3 scoring forms,
including the degree of deep swelling, color of the heman-
gioma, and ulceration assessment. Overall, for an individual
hemangioma lesion, the HAS scale ranges from 0 to 8. One
point change in HAS scores would be considered clinically
meaningful.16,17 Baseline scores were subtracted from post-
treatment scores to obtain the change in HAS or the decrease
in hemangioma proliferative activity after treatment.
Other secondary outcome measures included a success-
ful initial response; complete ulceration healing time; scores
on the quality of life (QOL) instrument for IH (IH-QOL) and the
Pediatric Quality of Life Inventory 4.0 family impact module
(PedsQL 4.0 FIM; PedsMetrics),18,19 which were measured at
baseline and 48 weeks; the rebound rate; and the response at
week 96. The successful initial response was defined as a de-
crease in the HAS score during the first week of treatment. The
HAS score can reflect the rapid effect of β-blocker (either pro-
pranolol or atenolol) therapy shortly after initiation.16,17 The
complete healing time of the ulceration was defined as the time
from the first dosage of propranolol or atenolol until com-
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Original Investigation Research
Table 1. Primary Outcome Measure
Responsea Description
Any response
Complete A complete response was defined as no redundant tissue or
response telangiectasia was identified
Nearly A nearly complete response was defined as a minimal degree
complete of telangiectasis, erythema, and skin thickening
response
Partial A partial response was defined as a size reduction or change
response in color that did not meet the nearly complete resolution
criteria
Nonresponse
Stable Stable was defined as no changes in size or color between
baseline and month 6
Deterioration Deterioration was defined as further growth of the target
hemangioma
a
The primary outcome was any response or nonresponse at 6 months.
plete healing of the hemangioma ulceration. The IH-QOL and
PedsQL 4.0 FIM were self-administered by the patients’ par-
ents. In 2 questionnaires, standardized response choices com-
prised 5 categories that were scored from 0 to 4. The items were
then linearly transformed to a 0 to 100 scale (0 = 100, 1 = 75,
2 = 50, 3 = 25, and 4 = 0), with higher scores indicating better
QOL. Regrowth of more than 20% in hemangioma appear-
ance (including changes in color and/or volume) after discon-
tinuing use of the medication was considered significant re-
bound. The inclusion criteria for rebound analysis were as
follows: (1) patients who completed 6 months of treatment and
(2) patients who discontinued therapy or were tapering treat-
ment after achieving an any response. A complete/nearly com-
plete response at week 96 was considered median-term
efficacy (Supplement 1).
Safety Assessment
We assessed the patients’ body weight, height, heart rate, blood
pressure, and blood glucose level and the occurrence of any
complications, such as hypotension, bradycardia, and hypo-
glycemia. Adverse events were monitored during in-house
monitoring at the scheduled visits by physical examination and
routine laboratory studies (eg, glucose level, full blood cell
count, and liver function). The site investigators also asked the
parents if there were any new concerns since the last evalua-
tion. All adverse events were collected and graded according
to the Common Terminology Criteria for Adverse Events, ver-
sion 4.0. The causality of the adverse event was determined
by the investigators and classified as definitively not related,
probably not related, possibly related, probably related, or de-
finitively related. Compliance of medication use was as-
sessed by counting the number of remaining study tablets at
follow-up visits and asking parents “Has your infant been tak-
ing the medication as prescribed?” Any dose reductions, in-
terruptions, or cessations enacted at the discretion of the in-
vestigators were recorded. Adverse events during the initial 6
months of treatment were compared between the 2 groups.
Statistical Analysis
The sample size required to compare propranolol and atenolol
at month 6 was calculated before enrollment. Assuming the ul-
ceration rate in both groups to be 10%, a sample size of 180
(Reprinted) JAMA Otolaryngology–Head & Neck Surgery Published online April 15, 2021 E3
 Research Original Investigation Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas

Figure. Consolidated Standards of Reporting Trials Flow Diagram Table 2. Demographic and Clinical Characteristics in the
Intention-to-Treat Population at Baselinea
436 Patients assessed for eligibility Group, No. (%)
Propranolol Atenolol
Characteristics (n = 190) (n = 187)
59 Excluded
31 Did not meet inclusion Patients
criteria
Female sex 146 (76.8) 141 (75.4)
17 Declined to participate
5 Enrolled in other studies Mean (SD) age, wk 10.2 (4.0) 9.8 (4.1)
6 Other reason
Weight, mean (SD), kg 5.9 (1.2) 6.0 (1.2)
Height, mean (SD), cm 59.1 (4.4) 59.2 (4.1)
377 Randomized Born prematurely 166 (87.4) 163 (87.2)
Infantile hemangiomas
Head and face 102 (53.7) 97 (51.9)
190 Randomized to 187 Randomized to
propranolol group atenolol group Neck, trunk, and extremity 88 (46.3) 90 (48.1)
Lesion size, median (IQR), cm2b 8.1 (5.5-15.3) 8.8 (5.0-18.0)
24-wk Follow-up 24-wk Follow-up Morphologic subtype
1 Lost to follow-up 1 Lost to follow-up Localized 98 (51.6) 99 (52.9)
10 Discontinued treatment 9 Discontinued treatment
3 Intolerance to therapy 1 Intolerance to therapy Indeterminate 50 (26.3) 47 (25.1)
2 Inadequate response 4 Inadequate response
Segmental 42 (22.1) 41 (21.9)
2 Parents’ choice 3 Parents’ choice
3 Nonadherent 1 Nonadherent Description
190 Included in intention-to- 187 Included in intention-to-
Superficial 27 (14.2) 21 (11.2)
treat analysis treat analysis
184 Included in per-protocol 182 Included in per-protocol Mixed 163 (85.8) 166 (88.8)
analysis analysis
Ulceration 25 (13.2) 23 (12.3)
PHACE syndrome 6 (3.2) 8 (4.3)
96-wk Follow-up 96-wk Follow-up
0 Lost to follow-up 2 Lost to follow-up Abbreviation: PHACE syndrome, posterior fossa malformations, hemangiomas,
169 Treatment completed 160 Treatment completed arterial malformations, coarctation of the aorta and other cardiac defects, and
7 Discontinued treatment 9 Discontinued treatment eye anomalies.
5 Inadequate response 7 Inadequate response a
The intention-to-treat population was defined as all the patients who had
2 Parents’ choice 1 Parents’ choice
1 Nonadherent
undergone randomization. If after assignment a patient did not receive a drug
0 Nonadherent
administration, or if an evaluation was never made after a drug administration,
the patient was excluded from the intention-to-treat population. In both
190 Included in safety analysis 187 Included in safety analysis groups, patients received at least 6 months of treatment.
b
The lesion sizes (surface areas) were recorded using hemispheric
measurements. A soft tape measure was draped over the hemangioma, and
the longest diameter and a measurement perpendicular to it were noted to
obtain a measurement.
patients was required for each group to show the noninferior-
ity of atenolol treatment with a 2-sided α level of .05 and ap-
proximately 90% power. Assuming that the atenolol on the pro-
pranolol response rate does not fall by greater than 15%, the Results
noninferiority margin was selected to be −15%. We set a 24-
month recruitment period (Supplement 1). Data are expressed Participants
as numbers (percentages), means (SDs), and medians (inter- The participants were enrolled from February 2015 to January
quartile ranges) as appropriate. Analyses of treatment effects 2017. A total of 436 patients were screened for eligibility, and 377
were performed according to the intention-to-treat principle. met the criteria for inclusion and were ultimately enrolled in the
Binary outcomes, such as the response rate, were assessed with study (Figure). This sample size allowed us to compare proprano-
the Fisher exact test or χ2 tests, and an odds ratio (OR) and lol and atenolol treatments in the hemangioma ulceration sub-
2-sided 95% CI were calculated. Sensitivity analyses were per- groups. No differences in anatomic subsites and initial severity
formed to assess the effect of missing values on the primary out- were found between patients who were included and patients
comes in 2 ways: imputing all missing values as a response and who were not included (data not shown). The included patients
a nonresponse. Generalized linear mixed models were used to were randomized to the propranolol group (190 [50.4%]) and the
compare the difference between the 2 groups in HAS score atenolol group (187 [49.6%]). Demographic and clinical charac-
changes from baseline to 6 months. Other variable contrasts and teristics were generally well balanced between the 2 groups
safety comparisons were constructed with the Student t test or (Table 2). The mean (SD) age at the start of treatment was 10.0
the nonparametric Mann-Whitney U test for continuous vari- (3.7). The head-face area accounted for 52.8% of all IHs. Among
ables when appropriate and Fisher exact test or χ2 test for cat- IHs in the cohort, 52.3% were of the localized morphologic sub-
egorical variables. Statistical analyses were conducted using type, and 87.3% were mixed hemangiomas. A total of 21 patients
SPSS, version 23.0 for Windows (IBM). P values less than .05 (5.6%; 11 in the propranolol group and 10 in the atenolol group)
were considered statistically significant. discontinued treatment prematurely before month 6 because of

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 Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas Original Investigation Research

Table 3. Primary and Secondary Efficacy Outcomes According to Treatment Group in the Intention-to-Treat Populationa

Group, No. (%)

Outcomes Propranolol (n = 190) Atenolol (n = 187) OR (95% CI)
Primary outcomeb
Any response (6 mo) 178 (93.7) 173 (92.5) 1.200 (0.540-2.669)c
Secondary outcomes
HAS score
Baseline 4.61 (0.82) 4.54 (0.76)
Week 1 3.41 (0.72) 3.37(0.75)
Week 4 2.42 (0.60) 2.33 (0.65) 1.034 (0.886-1.206)d
Week 12 1.54 (0.79) 1.54 (0.72)
Week 24 0.82 (0.64) 0.82 (0.68)
Successful initial responsee 171 (90.0) 163 (87.2) 1.325 (0.699-2.511)b
f
Complete ulceration healing time, wk 4.94 (2.16) 4.82 (1.75) NA
Rebound rateg 19 (11.2) 12 (7.5) 1.562 (0.732-3.332)b
h
Complete/nearly complete response (week 96) 156 (82.1) 149 (79.7) 1.170 (0.700-1.957)b
Abbreviations: HAS, hemangioma activity score; NA, not applicable; OR, odds first dosage of propranolol or atenolol until complete healing of the
ratio. hemangioma ulceration.
a g
Unless otherwise indicated, values are presented as mean (SD). Data only included patients who attempted to discontinue β-blockers
b
The primary outcome measure was any response or nonresponse at 6 months. according to the treatment plan between weeks 24 and 96. Whether a patient
c
had hemangioma rebound was based on the site investigators’ assessments
The values were calculated using a χ2 test.
after the week 24 treatment.
d
The values were calculated using generalized linear mixed models. h
A complete/nearly complete response at week 96 was considered
e
A successful initial response was defined as a HAS score decrease at 1 week median-term efficacy.
after treatment.
f
The complete healing time of the ulceration was defined as the time from the

loss of follow-up or other reasons (eTable 1 and eFigure 1 in
Supplement 2).
Primary Outcome
In relation to the primary outcome, atenolol treatment resulted
in a similar incidence of any response at month 6 (93.7% in the
propranolol group vs 92.5% in the atenolol group; difference,
1.2%; 95% CI, −4.1% to 6.6%) (Table 3; eFigures 2-6 in Supple-
ment 2). In addition, consistent results were obtained by sensi-
tivity analyses (eTable 2 in Supplement 2). Among patients who
had completed the treatments, those who received atenolol had
a longer mean treatment time than was found in those who re-
ceived propranolol treatment (57.2 weeks vs 61.5 weeks; differ-
ence, −4.3 weeks; 95% CI, −8.3 to −0.3 weeks).
ter treatment were 4.94 (2.16) weeks and 4.82 (1.75) weeks in
the propranolol group and atenolol group, respectively
(eTable 4 and eFigure 9 in Supplement 2).
Quality of Life
Overall, parents and patients showed improvements in QOL
measurements in both groups (eTables 5 and 6 in Supple-
ment 2). There were no meaningful differences that favored
propranolol in the changes from baseline to 48 weeks in total
scores on the IH-QOL (79.7 vs 81.2 at baseline and 91.9 vs 91.5
at week 48) and PedsQL 4.0 FIM (78.5 vs 77.5 at baseline and
87.2 vs 86.6 at week 48). In addition, the changes in other sub-
scales of health-related QOL did not differ between the 2 groups
(eTables 5 and 6 in Supplement 2).

Secondary Outcomes Response at Week 96

HAS and Successful Initial Response
The HAS was scored by the investigators (eTable 3 and eFig-
ures 7 and 8 in Supplement 2). Throughout the 6 months of
treatment, the mean (SD) overall HAS scores were similar be-
tween the2 groups (4.61 [0.82] vs 4.54 [0.76] at baseline and
0.82 [0.64] vs 0.82 [0.68] at week 24) (OR, 1.034; 95% CI,
0.886-1.206). After 1 week of treatment, both study groups pre-
sented a similar rate of successful initial response (90.0% vs
87.2%; difference, 2.8%; 95% CI, −3.7% to 9.4%) (Table 3).
Complete Healing Time of Ulceration
In total, 48 patients (12.7%) had hemangioma ulceration at the
time they began to take propranolol (n = 25) or atenolol (n = 23).
The mean (SD) times to complete healing of the ulceration af-
In total, 184 patients treated with propranolol (48.8%) and 182
patients treated with atenolol had follow-up data at week 96.
In the propranolol group, 156 (82.1%) of these patients had a
complete/nearly complete response, whereas 149 (79.7%) had
a complete/nearly complete response in the atenolol group (dif-
ference, 2.4%; 95% CI, −5.5% to 10.4%).
Rebound Rate
Before week 96, a total of 169 patients (88.9%) in the proprano-
lol group and 160 patients (85.6%) in the atenolol group had
completed treatment (eTable 7 in Supplement 2). Rebound
growth that required an additional course of β-blocker therapy
was observed in 31 patients (8.2%; eTable 8 in Supplement 2).
The overall rebound rate was 9.4% (excluding 13 patients who

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 Research Original Investigation Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas

Table 4. Adverse Events During Treatment (Week 24) in the Safety Populationa

Group, No. (%)

Propranolol (n = 190) Atenolol (n = 187)
Adverse eventsb All adverse events Severe adverse eventsc All adverse events Severe adverse eventsc
Diarrhea 25 (13.2) 0 28 (15.0) 1 (0.5)
Sleep disturbanced 27 (14.2) 2 (1.1) 9 (4.8) 0
Agitation 16 (8.4) 0 5 (2.7) 0
Cool extremities 14 (7.4) 0 6 (3.2) 0
Bradycardiae 13 (6.8) 0 9 (4.8) 0
Vomiting 7 (3.7) 0 5 (2.7) 0
Hypotensiond 9 (4.7) 0 4 (2.1) 0
Bronchiolitis 6 (3.2) 2 (1.1) 3 (1.6) 1 (0.5)
Decreased appetite 7 (3.7) 0 5 (2.7) 0
Constipation 4 (2.1) 0 6 (3.2) 0
Viral upper respiratory tract infection 3 (1.6) 0 3 (1.6) 1 (0.5)
Bronchial hyperreactivity 2 (1.1) 1 (0.5) 0 0
Total 133 (70.0) 5 (2.6) 83 (44.4) 3 (1.6)
a
The safety population included all the patients who received at least 1 dose of identified during the 24 weeks of treatment: grade 3 or greater of any adverse
trial treatment. events, persistent hypotension, persistent bradycardia, and intolerable central
b
Adverse events were assessed with the Common Terminology Criteria for nervous system–related adverse effects.
d
Adverse Events, version 4.0. Causality with β-blockers was determined by the Severe sleep disturbance was defined as sleep disturbance that did not
relationships of time to propranolol or atenolol intake, effect of dechallenge or disappear or was not relieved after treatment administration was altered (eg,
rechallenge of drug, absence of other disease or drug explaining the adverse earlier evening dose or a decrease in daily dose).
event, and whether the adverse event was a known adverse effect of e
All of the cardiac and vascular events were transient and not associated with
β-blockers. observable clinical symptoms.
c
A serious adverse event was defined as any of the following toxicities

were receiving the full dose of drugs and did not have a his-
tory of rebound at week 96). The rebound rate was lower in
the atenolol group than in the propranolol group (11.2% vs
7.5%). However, the difference was not meaningful (differ-
ence, 3.7%; 95% CI, −2.7% to 10.2%).
Safety Outcomes
During the 8 hours after the initial propranolol or atenolol treat-
ment and after the first dose adjustment, decreases in the mean
heart rate, systolic blood pressure, and diastolic blood pres-
sure were observed (eTables 9-12 in Supplement 2). However,
these hemodynamic changes were not clinically significant and
were within expected ranges. No significant differences in the
mean blood glucose levels were observed between the 2 groups
(eTable 13 in Supplement 2). No appreciable difference was
noted between the propranolol group and the atenolol group
in growth variables at week 96 (data not shown).
No deaths were documented throughout the treatment or
follow-up periods. Adverse events that occurred during the ini-
tial 6 months are summarized in Table 4. Both treatments were
generally well tolerated. Most of the adverse effects were mild
to moderate (grade 1 or 2) and usually resolved spontane-
ously without requiring any further intervention. The most
common adverse events were diarrhea (in 13.2% of the pa-
tients in the propranolol group and 15.0% of those in the aten-
olol group; difference, 1.8%; 95% CI, −5.3% to 8.9%) and sleep
disturbance (14.2% vs 4.8%; difference, 9.4%; 95% CI, 3.5% to
15.5%). Several other adverse events were observed in more
than 3% of the patients in each group and included cool ex-
tremities and bradycardia. All adverse events were previ-
ously described or reported (Table 4). The frequency of ad-
verse events was higher in the propranolol group than in the
atenolol group (70.0% vs 44.4%; difference, 25.6%; 95% CI,
15.7% to 34.8%) (eTable 13 in Supplement 2). There was no
meaningful difference between the 2 groups in the incidence
of severe adverse events (2.6% vs 1.6%; difference, 1.0%; 95%
CI, −2.3% to 4.6%) (eTables 14 and 15 in Supplement 2). No se-
vere adverse events were identified by the investigators as at
least possibly treatment-related after month 6.
Discussion
Several studies have generated optimism regarding the effec-
tiveness of atenolol in problematic IHs.11-14 However, previ-
ous studies that compared propranolol and atenolol in smaller
cohorts and retrospective studies have yielded conflicting
results.12,13,15 To our knowledge, only 1 previous randomized
clinical trial for atenolol and propranolol has been reported.
However, that study was not designed as a confirmative study
because the sample size of the study was not predetermined
for enough statistical power.13 Therefore, large randomized
clinical trials that compare these 2 β-blocker regimens are re-
quired to provide higher-level evidence of their efficacy and
safety. To our knowledge, this is the largest study comparing
the efficacy and safety of propranolol and atenolol as treat-
ment choices for problematic IHs that has been performed
to date.
In agreement with previous observations, both treat-
ment protocols effectively halted hemangioma growth.5,13 We

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 Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas
found that propranolol and atenolol were not completely ef-
fective in our study, and our findings were also comparable with
those of other prospective studies.13,20,21 The primary effi-
cacy analysis of this trial demonstrated that at 6 months of
treatment with either propranolol or atenolol, a similar any re-
sponse was observed in both groups (93.7% in the proprano-
lol group vs 92.5% in the atenolol group). However, primary
outcomes are difficult to compare across studies because of
the various definitions of outcomes and follow-up durations.
A somewhat higher 6-month complete/nearly complete re-
sponse rate (60%) was observed in a previous trial by Léauté-
Labrèze et al,22 possibly because the authors used a proprano-
lol dosage of 3 mg/kg/d and excluded patients with severe IH.
A single measure at a particular point may be insufficient
to assess the overall efficacy of the drugs. To account for the
constant effect of oral β-blockers during the first 6 months of
treatment, we chose to dynamically measure the treatment re-
sponse by using the HAS score. This different perspective could
complement the findings of previous trials that focused on a
single point. One notable observation was the high percent-
age of successful initial response that was observed in both
groups at 1 week after treatment. The rapid onset of the effect
of propranolol has also been documented by others.5,23 Simi-
larly, our data demonstrated that atenolol could also promptly
stabilize IHs in their growth phase.
Our evaluation of a longer duration of treatment showed
that significant improvements in clinical responses were also
observed after the initial 6 months of treatment. Our study re-
vealed that a complete/nearly complete response was achieved
in approximately 80% of patients at 2 years of follow-up in both
groups. Although 80% of IH growth occurs during the first 3
months, IHs with a significant subcutaneous component may
continue to proliferate for up to 6 to 12 months, and segmen-
tal IHs have been reported to continue to proliferate for even
longer.24 Therefore, the optimal treatment must at least cover
the entire proliferative phase and should be continued indi-
vidually until maximal improvement has been achieved.25 In
this study, the noninferiority of the efficacy of atenolol at week
96 may have been somewhat underestimated because of the
longer drug administration in the atenolol arm. Nonetheless,
with a slightly longer terminal half-life of 6 to 8 hours (vs pro-
pranolol, 3-6 hours), atenolol has the advantage of once-
daily treatment. The reliable ability of atenolol to achieve he-
mangioma involution as a once-daily therapy is a major
practical benefit to many parents, and may improve adher-
ence. However, current data do not permit evidence-based rec-
ommendations on propranolol dosing frequency (twice daily
vs 3 times daily). In addition, we found a meaningful differ-
ence in treatment time between the 2 medications, although
it was only 4.3 weeks. It is plausible that atenolol works more
slowly than propranolol and requires more time to achieve a
complete or nearly complete response.
Treatment choices in IH are driven not only by efficacy but
also by safety and tolerability considerations. The unantici-
pated death with nadolol treatment for IH further reflects the
importance of caution.26 In this study, no deaths occurred
throughout the treatments, and severe adverse events were
rarely documented with either treatment. Compared with pro-
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Original Investigation Research
pranolol, atenolol was less likely to produce CNS-related (sleep
disturbance and agitation) and bronchial-related adverse
events. Although less frequent, sleep disturbance and agita-
tion were experienced by some patients who were treated with
atenolol. However, these symptoms were mild and subsided
without any intervention. We also found that there was no
meaningful difference in severe adverse events between the
propranolol group and the atenolol group (2.6% vs 1.6%). A few
studies have already indicated that atenolol is well tolerated
in children who have experienced sleep disturbance and re-
current respiratory distress with propranolol. Recently, pro-
pranolol was found in higher amounts in brain tissue than aten-
olol. However, propranolol and atenolol were able to modulate
the release of signaling molecules (eg, nitric oxide) in
the hypothalamus. 27 Our ongoing neurodevelopmental
follow-up of patients with IHs beyond the 96-week period of
supervision in this study should provide additional informa-
tion on the long-term safety of β-blocker treatment in IHs.
Strengths and Limitations
As there is no consensus regarding outcome criteria for treat-
ing IH, effort should be made to use objective, reliable instru-
ments to compare the efficacy of propranolol and atenolol. The
first strength of this study is that its design was based on stan-
dardized definitions and outcome criteria for IH. We used stan-
dardized image analyses and regular follow-up, and median-
term follow-up data (2 years) were available for our cohort.
However, we acknowledge that the lack of use of a validated
instrument for our primary outcome represents a substantial
limitation. We did use a validated assessment tool, the HAS
score, as a secondary outcome in an attempt to minimize
variability.16,17 An additional strength of this study is that only
treatment-naive patients were included, with the aim of avoid-
ing possible bias in baseline characteristics with respect to pre-
vious therapies. Third, we included patients with function-
threatening, severely segmental, and ulcerated IHs. We targeted
the problems that closely resemble the clinical circum-
stances. Therefore, the findings presented by this study pro-
vide valuable data for further clinical practice and research.
Several limitations of our study deserve comment. First,
all of our participants were recruited from tertiary referral cen-
ters. This study design may limit the generalizability of our re-
sults to other centers and introduce a referral bias because of
increased disease severity. Second, only patients with super-
ficial and mixed IHs were included, and the results are there-
fore not generalizable to all practice or research settings. Third,
our study was not a double-blind trial. Local investigators and
patients’ parents were aware of the group in which the pa-
tients were placed. These factors may have limited the re-
sults, especially for QOL assessments. However, our trained
data managers and statistical team were unaware of the study
group assignments and masked to the clinical information. In
addition, our outcome assessments involved standardized im-
age analyses and independent readings. We believe that the
limitations that are associated with an open-label study were
minimized by the objective nature of our study outcomes.
Fourth, the fact that we did not use a validated measure as the
primary outcome is another limitation of this study. Finally,
(Reprinted) JAMA Otolaryngology–Head & Neck Surgery Published online April 15, 2021 E7
 Research Original Investigation Efficacy and Safety of Propranolol vs Atenolol in Infants With Problematic Infantile Hemangiomas

compared with a dose of 1 mg/kg/d, treatment with proprano-
lol at a dose of 3 mg/kg/d has been demonstrated to result in a
significantly higher success rate.22 Therefore, propranolol used
at a higher dose might have been superior to atenolol.
Conclusions
The results from this prospective, multicenter, randomized
clinical trial suggest that, compared with propranolol treat-
ment, atenolol treatment provided equivalent efficacy out-
comes as an initial treatment for problematic IHs in early and
late follow-up. In addition, these findings reveal that, com-
pared with propranolol, atenolol produced a comparable re-
bound growth rate and better tolerance. These results indi-
cate that atenolol is an effective and safe therapy for
problematic IHs. Atenolol can be used as a first-line treat-
ment for problematic IHs that require systemic treatment or
as an alternative treatment for patients who cannot tolerate
or have a contraindication to propranolol.

ARTICLE INFORMATION
Accepted for Publication: February 23, 2021.
Published Online: April 15, 2021.
doi:10.1001/jamaoto.2021.0454
Author Affiliations: Division of Oncology,
Department of Pediatric Surgery, West China
Hospital of Sichuan University, Chengdu, China (Ji,
Yang, Zhou, Xiang, T. Qiu, Dai); Pediatric Intensive
Care Unit, Department of Critical Care Medicine,
West China Hospital of Sichuan University,
Chengdu, China (Chen, X. Zhang); Department of
Pediatric Surgery, Fujian Provincial Hospital,
Fuzhou, China (Li); Department of Dermatology,
West China Hospital of Sichuan University,
Chengdu, China (Jiang); Department of Pediatrics,
West China Second University Hospital, Sichuan
University Chengdu, China (Lu); Department of
Pediatric Surgery, Chengdu Shangjin Nanfu
Hospital, Chengdu, China (L. Qiu); Department of
Pediatric Surgery, Sichuan Women and Children’s
Hospital, Chengdu, China (Kong); Department of
Pediatric Surgery, Chengdu Women and Children’s
Central Hospital, Chengdu, China (Y. Zhang).
Author Contributions: Drs Ji and Chen had full
access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Ji, Chen, Zhou, Jiang, Y. Zhang.
Acquisition, analysis, or interpretation of data: Ji,
Yang, X. Zhang, Li, Xiang, T. Qiu, Dai, Lu, L. Qiu,
Kong.
Drafting of the manuscript: Ji, Chen, Yang, X. Zhang,
Zhou, T. Qiu, Dai, Jiang, Lu.
Critical revision of the manuscript for important
intellectual content: Ji, Chen, Li, Xiang, L. Qiu, Kong,
Y. Zhang.
Statistical analysis: Ji, Yang, X. Zhang, Zhou, T. Qiu,
Dai, Jiang, Y. Zhang.
Obtained funding: Ji, Chen.
Administrative, technical, or material support: Ji, Li,
Xiang, Lu, L. Qiu, Kong.
Supervision: Ji.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by
grants 81400862 and 81401606 from the National
Natural Science Foundation of China, grant
2019YFS0322 from the Key Project in the Science &
Technology Program of Sichuan Province, grant
2015SU04A15 from the Science Foundation for The
Excellent Youth Scholars of Sichuan University, and
grants 2019HXFH056 and 2020XHFH048 from
the 1·3·5 project for disciplines of excellence for the
Clinical Research Incubation Project of West China
Hospital of Sichuan University.
Role of the Funder/Sponsor: The funding
organizations had no role in the design and conduct
of the study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: We acknowledge the
support of all other involved investigators and
participating practitioners, nurses, and residents for
their valued contributions. We thank all of the
patients and their parents and/or guardians who
participated in this study. Additionally, we thank the
parents of the patients who appear in images and
are described in Supplement 2 for permission to
publish this information. None of these individuals
were compensated for their contributions.
Data Sharing Statement: See Supplement 3.
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