\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[ngerman,polish,english]{babel}



\usepackage{float}








\begin{document}

\title{Hemangiol\selectlanguage{ngerman}® in infantile haemangioma: A paediatric post-marketing
surveillance drug study\selectlanguage{english}}



\author[1]{Floriane Socchi}%
\author[1]{Michele Bigorre}%
\author[1]{Marion Normandin}%
\author[1]{Guillaume Captier}%
\author[1]{Didier Bessis}%
\author[1]{Michel Mondain}%
\author[1]{Catherine  Blanchet}%
\author[1]{Mohamed Akkari}%
\author[1]{Pascal Amedro}%
\author[1]{GAVOTTO Arthur}%
\affil[1]{University Hospital Centre Montpellier}%


\vspace{-1em}



  
  \date{May 19, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Aim: Infantile haemangioma (IH) is the most common benign tumour in
children. Since 2014, propranolol has become the first-choice therapy
and currently Hemangiol\selectlanguage{ngerman}® is the only approved drug for complicated
haemangioma. This post-marketing study reported the use of Hemangiol®
for IH in paediatric practice. Method and Results: From January 2014 to
November 2018, 94 children (median age 4 {[}0;21{]} months; 75\% female)
treated with Hemangiol® for proliferative IH were enrolled in the study.
The systematic paediatric cardiology consultation never contraindicated
beta-blockers. Two Hemangiol® initiation protocols were used: a
conventional ambulatory 3-week titration phase protocol (N=76, 80.9\%),
and a rapid initiation protocol with a 48-hour dose escalation in
conventional hospitalization for severe proliferative IH (N=18, 19.1\%).
In both protocols, the haemodynamic tolerance was good. The mean
maintenance dose of Hemangiol® was 2.7±0.8 mg/kg/day, with a median
treatment duration of 7 {[}1.5;19{]} months. Adverse events (AEs) have
been found in 25 (26,6\%) patients including 8 (8.5\%) patients with
serious AEs (uncontrolled bronchial hyperreactivity, N=5; serious
hypoglycaemia, N=3). Some patients had one or more AEs, a total of 24
non-serious AEs was reported in 19 patients (sleep disturbances, N=9;
respiratory disorders, N=5; digestive disorders, N=6). No cardiac
adverse event was reported. Conclusion: This post-marketing surveillance
drug study supports the good tolerance of Hemangiol® in children with
IH. A rapid initiation protocol is of interest when treatment is urgent.
The pre-therapeutic paediatric cardiology consultation should not be
systematic but only indicated on specific patients. ClinicalTrials.gov:
NCT 04105517.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy




\textbf{Introduction}

Originally described by Mulliken and Glowacki\textsuperscript{1},
infantile haemangioma (IH) is the most common benign tumour in
children\textsuperscript{2,3}. IH belongs to the group of vascular
tumours in the ISSVA (international society for the study of vascular
anomalies) classification\textsuperscript{4}. Usually, IH will appear at
birth or within the first few weeks after birth, and up to 3 months of
age for subcutaneous haemangioma\textsuperscript{5}. IH is characterized
by its natural course divided into three phases, a proliferative phase
characterized by a rapid growth of the tumour (up to 6 to 12 months of
life), a stabilization phase (from 12 to 36 months of life), and an
involution phase marked by the regression of the
lesion\textsuperscript{6}. This regression is complete in 90\% of cases
by the age of 4, but without treatment we can observe up to 70\%
residual lesions, such as fibrofatty tissue, telangiectasia, skin laxity
and scars\textsuperscript{7}. The proliferative phase may be marked by
severe complications, such as necrosis, ulceration, bleeding or
infection. Obstruction and functional impairment such as amblyopia,
upper respiratory obstruction, obstruction of the nostrils or auditory
channel, sphincter dysfunction, or feeding disorders can be caused by
periorificial locations of IH (e.g. perioral and periorbital skin).
Moreover, the aesthetic impact is not trivial, especially when IHs
located in the centrofacial area are a source of
disfigurement\textsuperscript{8,9}. Large segmental facial IHs may be
part of the PHACES syndrome (posterior fossa anomalies, haemangioma,
arterial lesions, cardiac abnormalities, eye anomalies, sternal
defects)\textsuperscript{10,11} and segmental IHs of the lower body may
be part of the LUMBAR syndrome (lower body haemangioma, urogenital,
myelopathy, bony, anorectal and arterial, renal
anomalies)\textsuperscript{12}. Finally, liver haemangioma and
haemangiomatosis are high-risk complicated IHs as they may lead to
cardiac failure\textsuperscript{13}.

Initially, medical treatment of severe IH was based on systemic
corticosteroid therapy\textsuperscript{14,15}. In 2008, Leaute-Labreze
et al. fortuitously discovered the anti-proliferative effect of
propranolol, when using this non-selective beta-blocker for a
hypertrophic obstructive cardiomyopathy, in a child with a nasal IH
treated by corticosteroids\textsuperscript{16}. The efficacy of oral
propranolol in IH was demonstrated by two randomized controlled
trials\textsuperscript{17,18}. In 2014 Pierre Fabre dermo-cosmetics
laboratory (Paris, France) obtained EMA (European Medicines Agency) and
FDA (Food and Drug Administration) marketing authorization for
Hemangiol\selectlanguage{ngerman}®, the first and only drug currently approved for the treatment
of proliferating IH. Hemangiol® is indicated to treat IH in children
aged 5 weeks to 5 months, in case of life or functional risk, painful
ulcerated lesions, or risk of permanent scarring or facial damage.

In this paediatric post-marketing surveillance drug study, we aimed to
report the use of Hemangiol® in our institution from 2014 to 2018.

\textbf{Methods}

Study design and population

This retrospective study was carried out from January 2014 to November
2018 in Montpellier University Hospital, France. In this tertiary care
institution, all children with an IH requiring a medical treatment with
a beta-blocker are systematically hospitalized for treatment initiation.
In this study, the hospital discharge database (PMSI, Programme de
Medicalisation des Systemes d'Information) was used for patients
screening. The PMSI is a mandatory national database linked to the
social security, in which all hospitalizations are automatically and
prospectively registered. This database uses a standardized diagnosis
coding from the 10\textsuperscript{th} revision of the International
Classification of Diseases (ICD-10). The code associated to the term
``haemangioma'' (D13) was used to screen patients and finally only
children \textless{}2 years old treated with Hemangiol® were included in
the final analysis.

Initiation and use of Hemangiol®

Immediately after the marketing authorisation published by the EMA in
April 2014 (EU/1/14/919/001), our group of experts in proliferative IH,
involving plastic surgeons, dermatologists, ear nose and throat (ENT)
physicians, and paediatric cardiologists, drafted a single and common
institutional protocol on initiation and use of Hemangiol® for IH,
adapted from the summary of product characteristics (SPC). This protocol
included five consecutive stages:

1) The initial consultation with an expert in the diagnosis, treatment
and management of IH (paediatric dermatologist, paediatric plastic
surgeon, paediatric ENT physician, or paediatric cardiologist)
determined whether Hemangiol® was indicated or not.

2) The paediatric cardiology consultation with clinical examination,
electrocardiogram and echocardiography, assessed the absence of
contraindications for beta-blocker use: premature infants for whom the
corrected age of 5 weeks has not been reached, breastfed infants in
mothers treated with medicinal products contraindicated with
propranolol, hypersensitivity to the active substance or to any of the
excipients listed in section 6.1 of the SPC, asthma or history of
bronchospasm, second- or third-degree atrioventricular blocks, disease
of the sinus node (including sinoatrial block), bradycardia (heart rates
\textless{}100 beats per minute (bpm) in infants 0-3 months old,
\textless{}90 bpm in infants 3-6 months old, and \textless{}80 bpm in
infants 6-12 months old), low blood pressure (\textless{}65/45 mmHg in
infants 0-3 months old, \textless{}70/50 mmHg in infants 3-6 months old,
and \textless{}80/55 mmHg in infants 6-12 months old), cardiogenic
shock, heart failure not controlled by treatment, severe peripheral
arterial circulatory disturbances, infants prone to hypoglycaemia, and
pheochromocytoma.

3) To initiate Hemangiol® treatment, we defined a ``conventional''
initiation protocol and a ``rapid'' initiation protocol.

The conventional initiation protocol included a 3-week titration phase,
as reported in the SPC: starting dose of 1 mg/kg/day (0.5 mg/kg b.i.d.)
of propranolol base for 1 week, then 2 mg/kg/day (1 mg/kg b.i.d.) for 1
week, and finally 3 mg/kg/day (1.5 mg/kg b.i.d.) as a maintenance
therapeutic dose. During the titration phase, the child was hospitalised
in our ambulatory paediatric day care facility at day 1 (initiation),
day 7 (week 1) and day 14 (week 2) with close clinical monitoring for 3
hours after treatment's administration (hourly monitoring of vital
constants, and assessment of side effects). Bradycardia was defined as
heart rates \textless{}100 bpm in infants 0-3 months old, \textless{}90
bpm in infants 3-6 months old, and \textless{}80 bpm in infants 6-12
months old. Hypotension was defined as tensions \textless{}65/45 mmHg in
infants 0-3 months old, \textless{}70/50 mmHg in infants 3-6 months old,
and \textless{}80/55 mmHg in infants 6-12 months old.

Parental education was provided by a specialist nurse, focusing on the
three following key messages: i) Hemangiol® is to be given during or
right after feeding to avoid the risk of hypoglycaemia, with one dose in
the morning and one dose in late afternoon, respecting a time interval
of at least 9 hours between two intakes. ii) If the child is not eating
or is vomiting it is recommended to skip the dose. iii) In case the
child spits up a dose or does not take the entire medicinal product, no
other dose should be given before the next scheduled dose. The
information booklet provided by the pharmaceutical company (Pierre
Fabre) was systematically given to parents, as well as our emergency
paediatric cardiology 24/7 phone number.

The rapid initiation protocol was used for severe proliferative IH
involving any vital risk, uncontrolled bleeding, ulceration, pain, or
infectious risk. Such severe forms were managed in conventional
hospitalisation in the paediatric cardiology unit, using a rapid dose
escalation scheme: Hemangiol® initiation dose of 0.5 mg/kg (stage 1),
then 1 mg/kg 12 hours later (stage 2), then 1.5mg/kg 12 hours later
(stage 3), in order to reach the maintenance therapeutic dose of 3
mg/kg/day in two daily intakes at day 2. Analgesics, antibiotics and
local skin care were provided when required, upon IH specialist's
recommendation. Continuous clinical monitoring was provided (hourly
monitoring of vital constants, cardiac telemetry and assessment of side
effects), as well as parental education (cf. previous section). In the
absence of adverse effects or need for IH care, patient was discharged
after day 2 (rapid initiation protocol in supplementary Figure).

4) The children underwent follow-up examination with the IH specialist 4
to 8 weeks after Hemangiol® initiation in non-severe IH, and 2 weeks
after Hemangiol® initiation in severe cases. The IH specialist
determined the frequency of the following consultations, as well as the
overall treatment duration.

5) The child underwent a paediatric cardiology consultation 3 months
after Hemangiol® initiation, or at any time if required by the IH
specialist, the patient's family practitioner, or after any family
emergency phone call.

Outcome measures

The data collection included the population and IH characteristics and
the indication of treatment during the initial consultation. Patient
follow-up included treatment initiation until the end of treatment.

We collected all data from patient monitoring (cardiac examination,
echocardiogram, ECG, cardiac monitoring) before, during (at each
titration stage for both conventional and rapid protocols), and after
Hemangiol® initiation.

Parents of children under Hemangiol® were asked to call the paediatric
cardiology 24-hour hotline for any clinical symptom. Therefore, we
recorded all adverse events (AEs), defined as any undesirable experience
possibly associated with the use of Hemangiol® from drug initiation and
throughout the follow-up. Serious adverse events (SAEs) were defined as
life-threatening events or adverse events leading to death,
hospitalization, disability or permanent damage, intervention to prevent
permanent impairment, or any important medical event as defined by the
drug agencies. SAEs were reported to pharmacovigilance and causality was
established using the standard method derived from Bégaud et
al\textsuperscript{19}. This algorithm is based on an intrinsic score
including chronological and semiological criteria ranging from 0 to 6
(from absence to strong relationship between drug and the occurrence of
adverse event; scores \selectlanguage{english}[?]2 indicating possible relation to treatment) and
an extrinsic score based on bibliography\textsuperscript{20}.

Formal aspects

The study was conducted in compliance with the Good Clinical Practices
and Declaration of Helsinki principles. The study was approved by
Montpellier University Hospital's institutional review board
(2019\_IRB-MTP\_09-07). The study was registered on ClinicalTrials.gov
(NCT 04105517).

Statistical analyses

The study population was described using means and standard deviations
(SD) for quantitative variables with normal distribution or medians and
minimal/maximal values {[}min; max{]} otherwise. Frequencies and their
associated percentage were used for qualitative variables. The normal
distribution of continuous variables was explored graphically.
Quantitative variables were compared using Student's t-test when the
distribution was Gaussian, or the Mann-Whitney test otherwise. For
qualitative variables, groups were compared using the chi-squared test
or Fisher's exact test. The statistical significance was set at 0.05 and
analyses were performed using Excel(r) software.

\textbf{Results}

Population

During the 5-year study period, 189 children \textless{}2 years old were
hospitalized in our institution with a main diagnosis of ``haemangioma''
identified from the hospital PMSI database. From this cohort, 95
patients were not included in the study: 43 (22.8\%) cases were included
in a concomitant randomised controlled trial comparing acebutolol versus
propranolol in IH (NCT01743885), 24 (12.7\%) cases were treated with
another drug than Hemangiol(r) (atenolol, N=2; corticoids, N=2; other form
of oral propranolol, N=9; surgery, N=11), 20 (10.6\%) cases received no
drug to treat their IH, and 8 (4.2\%) cases had significant missing data
(lost to follow-up). Therefore, a total of 94 children (75\% female)
with IH treated with Hemangiol(r) were included in this study. All parents
or legal guardians gave their informed consent.

The most common IH localisation was the head (59.6\%), especially the
periocular (N=23) and nasal (N=11) regions. Rare cases of syndromic
(PHACES syndrome, N=2; LUMBAR syndrome, N=2), hepatic haemangioma (N=2),
and miliary IH (N=1) were identified.

Hemangiol(r) was initiated at a median age of 4 {[}0; 21{]} months,
including 2 children \textless{}5 weeks and 29 children \textgreater{}5
months old. The main indication for IH treatment with Hemangiol(r) was
functional threat (N=36; 38.3\%) and mainly concerned facial IH,
predominantly for periocular (N=19) and nasal (N=6) localisations.
Ulcerated IH were treated with Hemangiol(r) in 29 (30.9\%) children,
especially in perineal localisations (N=7). Life-threatening forms of IH
required treatment with Hemangiol(r) for 5 children (hepatic haemangioma,
N=2; miliary, N=1; subglottic haemangioma, N=2). Patients' clinical
characteristics were reported in Table 1.

Paediatric cardiology consultation

The systematic paediatric cardiology consultation diagnosed a cardiac
murmur in 8 (8.5\%) subjects, of which four innocent murmurs and four
congenital heart diseases: one case of minimal pulmonary valve stenosis,
one case of coarctation of the aorta in a 4-month-old child with PHACES
syndrome, one case of atrial septal defect, and one case of ventricular
septal defect. Systematic echocardiography reported increased cardiac
output for the two subjects with hepatic haemangiomas and 2 cases of
patent ductus arteriosus (PDA) in a neonate with IH and non-sustained
ventricular tachycardia (spontaneous PDA closure), and in a
six-month-old infant born at 30 weeks gestation with PIK3CA mutation and
subglottic haemangioma, who underwent percutaneous PDA closure.

The systematic echocardiography performed in the 86 remaining patients
without any cardiac symptom or neonatal condition found 19 cases of
non-significant cardiac features: patent foramen ovale (N=16), moderate
flow acceleration in the pulmonary artery branches (N=1), small
aorto-pulmonary collateral (N=1), and trivial pulmonary regurgitation
(N=1). No further follow-up was indicated by the paediatric cardiologist
in those 19 children.

The systematic ECG was normal in 93 (98.9\%) cases and diagnosed
Wolff-Parkinson-White syndrome in one patient with no family history.

Overall, none of the findings observed during the paediatric cardiology
consultation resulted in any contraindication for Hemangiol(r).

Hemangiol(r) initiation protocol

The conventional Hemangiol(r) initiation protocol was the most commonly
used (N=76; 80.9\%). The rapid Hemangiol(r) initiation protocol concerned
children with ulcerated IH (N=11), life-threatening IH (N=4), as well as
the neonate with non-sustained ventricular tachycardia associated with
IH of the cheek, the case of coarctation of aorta associated with IH of
the arm and PHACES syndrome and a two month old child with parotid IH
with a risk of compression. In children with ulcerated IH, the rapid
Hemangiol(r) protocol included the prescription of strong analgesics and
local treatment during hospitalisation.

Hospital monitoring at the initiation of the treatment showed a
significant decrease in heart rate one hour after treatment initiation,
especially in stage 1 (from mean 140.3+-18.1 bpm to mean 127.1+-16.1 bpm,
P\textless{}0.01). Then the heart rate remained stable during the
monitoring. In stage 2, one hour after treatment increase, a less marked
than in stage 1 but significant heart rate decrease was observed (from
mean 128.1+-19.0 bpm to mean 121.7+-17.0 bpm, P=0.02). No significant
decrease in heart rate was observed in stage 3. Overall, no significant
bradycardia was observed. We found a significant but non-symptomatic
decrease in diastolic blood pressure at stage 2 and stage 3, without
requiring any drug discontinuation. No change was observed in the
systolic blood pressure (Table 2).

We found no significant difference in terms of heart rate and blood
pressure change, between the two conventional and rapid initiation
protocols.

Follow-up of children under Hemangiol(r)

The maintenance therapeutic dose of Hemangiol(r) was 2.7+-0.8 mg/kg/day.
The first follow-up consultation with an IH expert occurred at 1
{[}0.5;6{]} month, and the second one at 6 {[}2;13{]} months after
Hemangiol(r) initiation.

The first follow-up cardiology consultation occurred at 3 {[}1;7{]}
months.

The median overall treatment duration was 7 {[}1.5;19{]} months.

Adverse events (AEs)

No AE was observed during the initiation of treatment, in both
conventional and rapid protocols.

We did not find any significant change in the ECG before the initiation
and 3 months after the initiation of Hemangiol(r) with a PR interval at
115.3+-17.6 ms vs. 110.3+-19.6 ms (P=0.1), QRS interval at 69.6+-11.5 ms
vs. 68.8 ms+-12.1 ms (P=0.68), corrected QT interval at 378+-20 ms vs.
381+-26 ms (P=0.37). No case of atrioventricular block or any other
cardiac adverse event was reported.

During the follow-up, after the initiation period, 25 (26.6\%) patients
experienced one or more adverse events. Among these patients, 8 (8.5\%)
children presented a SAE: 5 cases of uncontrolled bronchial
hyperreactivity (one associated with pneumopathy and diarrhoea) and 3
cases of serious hypoglycaemia. SAEs led to permanent treatment
discontinuation in 6 cases, temporary discontinuation in one case, and
dose reduction in one case. For all SAEs, causality scores ranged from 2
to 5 out of 6, suggesting possible to strong association between SAEs
and propranolol (Table 3). As recommended by drug agencies, all cases of
SAEs were reported to the national pharmacovigilance centre.

A total of 24 non-serious AEs were reported in 19 (20.2\%) patients
(including 2 patients with SAEs and a non-serious AE, and 5 patients
with 2 non-serious AEs): sleep disturbances (N=9), primarily nightmares;
respiratory disorders, especially acute bronchiolitis with temporally
discontinuation of treatment (N=5); and digestive disorders (N=6) with
benign diarrhoea, constipation, vomiting and anorexia. We also found one
suspected case of hypoglycaemia, one case of asthenia, one skin rash,
and one case of repeated disabling sneezing. No non-serious AE required
hospitalization or prolonged drug discontinuation.

\textbf{Discussion}

This study investigated the current use of Hemangiol(r) in 94 children
with proliferating IH. It provided new tolerance data on this treatment
and the value of systematic cardiac screening before treatment.
Moreover, the safety of a rapid initiation protocol was evaluated.

Overall, the population treated with Hemangiol(r) in this study is similar
to previous reports\textsuperscript{8} and our cohort is representative
of the usually described population of IH, with a predominant female
representation\textsuperscript{21}. However, more subjects with preterm
birth and low birth weight were present in our cohort, considering they
were previously described as risk factors for IH\textsuperscript{2,22}.
The cases with PHACES or LUMBAR syndromes included in the study
underwent screening evaluation of clinical and radiological associated
anomalies, as recommended in children with large segmental haemangiomas
of the upper and lower body\textsuperscript{10,12}. The main indications
for treatment of our cohort were IH with a functional threat, ulcerated
haemangiomas and IH with an aesthetic prognosis, as recommended in the
current guidelines\textsuperscript{13}. Children of our study were
treated for an average of 7 months, which is moderately longer than in
the initial trial (e.g. 6 months)\textsuperscript{18}. However, recent
studies have suggested treatment for 6 to 12 months due to a greater IH
rebound growth in shorter treatment duration\textsuperscript{23,24}.
Indeed, treatment duration is mostly dependent on clinical complete
lesion regression\textsuperscript{25}. Off-label use of Hemangiol(r) was
rare in this study. Two neonates \textless{}5 weeks of age were treated
with a good tolerance during initiation and no reported adverse event
during follow-up, which confirms a previous study on the safety of oral
propranolol for IH in the neonatal period \textsuperscript{26}. Late
Hemangiol(r) initiations \textgreater{}5 months of age concerned 29
subjects in our study. Usually, late treatment initiations are related
to a delayed referral to the specialist, especially for superficial
IH\textsuperscript{27}.

The safety analysis found AEs in 26.6\% patients, which is consistent
with previous studies on oral propranolol, which reported AEs rates from
19.6\%\textsuperscript{28} to 38.2\%\textsuperscript{29}. Sleep
disturbances, wheezing and digestive side effects were the most
frequently reported AEs in our cohort, as described in the previous
studies, however peripheral coldness was not reported in our
cohort\textsuperscript{28,29}. SAEs were found in 8.5\% patients,
exclusively severe hypoglycaemia and uncontrolled bronchial
hyperreactivity, which is higher than previous reported SAEs rates,
ranging from 2.6\%\textsuperscript{30} to 4.8\%\textsuperscript{29}.
Cardiac SAEs, such as atrioventricular block, bradycardia and
symptomatic hypotension, were not found in our cohort, as opposed to
previous studies\textsuperscript{29,30} and despite a systematic
paediatric cardiology pretherapeutic and follow-up assessment.
Nevertheless, the causality of propranolol for cardiovascular SAEs in
the literature remains unclear and suggests pre-existing conditions or
incidental discovery\textsuperscript{29,31}. Of note, SAEs occurred in
two prematurely born children, who may be more prone to hypoglycaemia
and bronchial hyperreactivity as previously
reported\textsuperscript{32}. Therefore, low dose of Hemangiol(r)
(2mg/kg/day) could be of interest in such high-risk
children\textsuperscript{23,28}, however the dosage of 3mg/kg/day has
been more investigated in pharmacokinetics and pharmacodynamics
studies\textsuperscript{33,34} based on the manufacturer's clinical
trial\textsuperscript{18}.

For all SAEs, causality scores concluded to possible to strong relation
to Hemangiol(r). As severe hypoglycaemia and uncontrolled bronchial
hyperreactivity are well known SAEs, variability of causality scores
came from intrinsic causation with variable chronological criteria (time
to onset after taking the treatment, or evolution after lowering the
dosage or stopping treatment) and the presence of confounding factors
(i.e. infectious for bronchospasms). As a result, SAEs with high
causality scores (4 or 5) in our study were patients with complete
description of the event, compatible time to onset, regression of AE
after stopping treatment, and no confounding factor. Previous studies
did not provide any details on the causality between such SAEs and
treatment with Hemangiol(r).

From a general perceptive, those findings emphasize the importance of
parental therapeutic education about these potential risks and how to
manage them. During the treatment initiation period, oral information
supported by an educational pack should be provided to parents, in order
to identify symptoms potentially related to SAEs\textsuperscript{35}.
For example, parents should be fully aware that Hemangiol(r) needs to be
temporarily suspended in case of food intolerance or limited food intake
in their child, in order to avoid hypoglycaemia\textsuperscript{36}.
Similarly, bronchial hyperreactivity reactions were often related to
respiratory tract infections and therefore require appropriate parental
supervision\textsuperscript{29,37}.

Overall, the cardiac tolerance was good. No AE, serious or not, was
reported during drug initiation at the hospital, whatever the protocol
used, as well as during the follow-up. No significant decrease in
systolic blood pressure was observed, and the initial decrease in heart
rate and diastolic blood pressure was moderate and not clinically
relevant, as in the literature\textsuperscript{38--40}. Similarly,
previous studies have reported the safety of oral propranolol for the
treatment of IH\textsuperscript{41} and suggested not to extend cardiac
monitoring beyond initiation period except for heart rate during
following consultations\textsuperscript{42}. In light of these results,
an outpatient Hemangiol(r) initiation protocol could be considered in
selected and non-at risk patients, as suggested by Puttgen and
al.\textsuperscript{43}.

This study supports the absence of relevance for a systematic
pre-therapeutic paediatric cardiology consultation. Indeed, all cardiac
findings observed in this cohort were mostly non-significant and did not
result in any contraindication for betablockers. Therefore, a simple
physical examination made by the IH expert seems sufficient to identify
patients at risk. Based on our cohort, children with IH requiring
cardiological assessment are those with clinical symptoms (cardiac
murmur), abnormal blood pressure or heart rate, syndromic forms
(PHACES), high risk of heart failure (hepatic, military haemangiomas),
or off-label use (preterm birth, neonate period). These results are
consistent with previous studies reporting that systematic
echocardiography\textsuperscript{44,45} or
ECG\textsuperscript{40,46}before propranolol initiation are not relevant
in terms of contraindication assessment and correlation with SAE
occurrence\textsuperscript{47}.

Most patients (81\%) underwent a conventional initiation protocol with a
3-week titration phase in day care hospital. This protocol seems safe
and adapted to most children with IH, as reported in cost-effectiveness
studies\textsuperscript{48}. Nevertheless, a 3-week delay to reach the
maintenance dose of 3 mg/kg/day may not be appropriate in a therapeutic
emergency situation, such as in IH involving any vital risk,
uncontrolled bleeding, ulceration, pain or infectious risk. In our
study, nearly 20\% of patients with severe proliferative IH underwent a
rapid initiation protocol, with a 48-hour dose escalation in
conventional hospitalization in paediatric cardiology. This rapid
protocol was well tolerated and facilitated the prescription of strong
analgesics and local treatment, as in ulcerated IH. In both conventional
and rapid protocols, Hemangiol(r) was well tolerated in terms of blood
pressure and heart rate adaptation.

\textbf{Study limitation~}

Despite the collection of AEs during patients' follow-up at the
hospital, as well as through parent's call to the 24-hour hotline, the
existence of missing data may be inherent to the retrospective design of
the study. Moreover, 54 children with IH and treated with other forms of
betablockers (acebutolol, propranolol) during the study period were not
included in the analysis.

\textbf{Conclusion}

In children treated with Hemangiol(r) for proliferative IH, this
post-marketing surveillance drug study reported an AE incidence rate of
26.6\%, of which 8.5\% non-fatal SAEs, supporting the importance of
parental therapeutic education. The pre-therapeutic paediatric
cardiology consultation should not be systematic but only indicated on
selected at-risk patients. In addition to the conventional initiation
protocol with a 3-week titration phase in day care hospital, we suggest
using a rapid initiation protocol with a 48-hours dose escalation in
conventional hospitalization when treatment is urgent.

\textbf{Acknowledgement}

We thank our patients for their participation.

\textbf{Declarations of interest:} the authors have no competing
interests to declare.

\textbf{Financial support:} This research did not receive any specific
grant from any funding agency in the public, commercial or
not-for-profit sector.

\textbf{Data availability statement} : the data that support the
findings of this study are available from the corresponding author upon
reasonable request.



\textbf{References}

1. Mulliken JB, Glowacki J. Hemangiomas and Vascular Malformations in
Infants and Children: A Classification Based on Endothelial
Characteristics. \emph{Plast Reconstr Surg} . 1982;69(3):412-420.
doi:10.1097/00006534-198203000-00002

2. Anderson KR, Schoch JJ, Lohse CM, Hand JL, Davis DM, Tollefson MM.
Increasing Incidence of Infantile Hemangiomas over the Past 35-years:
Correlation with Decreasing Gestational Age at Birth and Birth
Weight.\emph{J Am Acad Dermatol} . 2016;74(1):120-126.
doi:10.1016/j.jaad.2015.08.024

3. Kilcline C, Frieden IJ. Infantile Hemangiomas: How Common Are They? A
Systematic Review of the Medical Literature. \emph{Pediatr Dermatol} .
2008;25(2):168-173. doi:10.1111/j.1525-1470.2008.00626.x

4. Wassef M, Blei F, Adams D, et al. Vascular Anomalies Classification:
Recommendations From the International Society for the Study of Vascular
Anomalies. \emph{Pediatrics} . 2015;136(1):e203-e214.
doi:10.1542/peds.2014-3673

5. Tollefson MM, Frieden IJ. Early Growth of Infantile Hemangiomas: What
Parents' Photographs Tell Us. \emph{Pediatrics} . 2012;130(2):e314-e320.
doi:10.1542/peds.2011-3683

6. Chang LC, Haggstrom AN, Drolet BA, et al. Growth Characteristics of
Infantile Hemangiomas: Implications for Management. \emph{PEDIATRICS} .
2008;122(2):360-367. doi:10.1542/peds.2007-2767

7. Bauland CG, Luning TH, Smit JM, Zeebregts CJ, Spauwen PHM. Untreated
Hemangiomas: Growth Pattern and Residual Lesions. \emph{Plast Reconstr
Surg} . 2011;127(4):1643-1648. doi:10.1097/PRS.0b013e318208d2ac

8. Leaute-Labreze C, Harper JI, Hoeger PH. Infantile
haemangioma.\emph{The Lancet} . 2017;390(10089):85-94.
doi:10.1016/S0140-6736(16)00645-0

9. Cheng CE, Friedlander SF. Infantile hemangiomas, complications and
treatments. \emph{Semin Cutan Med Surg} . 2016;35(3):108-116.
doi:10.12788/j.sder.2016.050

10. Garzon MC, Epstein LG, Heyer GL, et al. PHACE Syndrome:
Consensus-Derived Diagnosis and Care Recommendations. \emph{J Pediatr} .
2016;178:24-33.e2. doi:10.1016/j.jpeds.2016.07.054

11. Rotter A, Samorano LP, Rivitti-Machado MC, Oliveira ZNP, Gontijo B.
PHACE syndrome: clinical manifestations, diagnostic criteria, and
management. \emph{An Bras Dermatol} . 2018;93(3):405-411.
doi:10.1590/abd1806-4841.20187693

12. Iacobas I, Burrows PE, Frieden IJ, et al. LUMBAR: Association
between Cutaneous Infantile Hemangiomas of the Lower Body and Regional
Congenital Anomalies. \emph{J Pediatr} . 2010;157(5):795-801.e7.
doi:10.1016/j.jpeds.2010.05.027

13. Krowchuk DP, Frieden IJ, Mancini AJ, et al. Clinical Practice
Guideline for the Management of Infantile Hemangiomas.\emph{Pediatrics}
. 2019;143(1). doi:10.1542/peds.2018-3475

14. Bennett ML, Fleischer AB, Chamlin SL, Frieden IJ. Oral
corticosteroid use is effective for cutaneous hemangiomas: an
evidence-based evaluation. \emph{Arch Dermatol} . 2001;137(9):1208-1213.
doi:10.1001/archderm.137.9.1208

15. Janmohamed SR, Madern GC, de Laat PCJ, Oranje AP. Educational paper:
therapy of infantile haemangioma---history and current state (part
II).\emph{Eur J Pediatr} . 2015;174(2):259-266.
doi:10.1007/s00431-014-2404-5

16. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo
J-B, Taieb A. Propranolol for severe hemangiomas of infancy. \emph{N
Engl J Med} . 2008;358(24):2649-2651. doi:10.1056/NEJMc0708819

17. Leaute\selectlanguage{english}-Labreze C, Roque ED de la, Nacka F, et al. Double-blind
randomized pilot trial evaluating the efficacy of oral propranolol on
infantile haemangiomas in infants \textless{} 4 months of age. \emph{Br
J Dermatol} . 2013;169(1):181-183. doi:10.1111/bjd.12217

18. Leaute-Labreze C, Hoeger P, Mazereeuw-Hautier J, et al. A
Randomized, Controlled Trial of Oral Propranolol in Infantile
Hemangioma. \emph{N Engl J Med} . 2015;372(8):735-746.
doi:10.1056/NEJMoa1404710

19. Begaud B, Evreux JC, Jouglard J, Lagier G. {[}Imputation of the
unexpected or toxic effects of drugs. Actualization of the method used
in France{]}. \emph{Therapie} . 1985;40(2):111-118.

20. Arimone Y, Bidault I, Dutertre J-P, et al. Reactualisation de la
methode francaise d'imputabilite des effets indesirables des
medicaments. \emph{Therapie} . 2011;66(6):517-525.
doi:10.2515/therapie/2011073

21. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective Study of
Infantile Hemangiomas: Demographic, Prenatal, and Perinatal
Characteristics. \emph{J Pediatr} . 2007;150(3):291-294.
doi:10.1016/j.jpeds.2006.12.003

22. Munden A, Butschek R, Tom WL, et al. Prospective study of infantile
haemangiomas: incidence, clinical characteristics and association with
placental anomalies. \emph{Br J Dermatol} . 2014;170(4):907-913.
doi:10.1111/bjd.12804

23. Yang H, Hu D-L, Shu Q, Guo X-D. Efficacy and adverse effects of oral
propranolol in infantile hemangioma: a meta-analysis of comparative
studies. \emph{World J Pediatr} . 2019;15(6):546-558.
doi:10.1007/s12519-019-00285-9

24. Baselga E, Dembowska-Baginska B, Przewratil P, et al. Efficacy of
Propranolol Between 6 and 12 Months of Age in High-Risk Infantile
Hemangioma. \emph{Pediatrics} . 2018;142(3):e20173866.
doi:10.1542/peds.2017-3866

25. Chang L, Gu Y, Yu Z, et al. When to stop propranolol for infantile
hemangioma. \emph{Sci Rep} . 2017;7:43292. doi:10.1038/srep43292

26. Ji Y, Chen S, Xiang B, Yang Y, Qiu L. Safety and tolerance of
propranolol in neonates with severe infantile hemangiomas: a prospective
study. \emph{Sci Rep} . 2017;7(1):1-8. doi:10.1038/s41598-017-01321-2

27. Onnis G, Dreyfus I, Mazereeuw-Hautier J. Factors associated with
delayed referral for infantile hemangioma necessitating
propranolol.\emph{J Eur Acad Dermatol Venereol JEADV} .
2018;32(9):1584-1588. doi:10.1111/jdv.14842

28. Wedgeworth E, Glover M, Irvine AD, et al. Propranolol in the
treatment of infantile haemangiomas: lessons from the European
Propranolol In the Treatment of Complicated Haemangiomas (PITCH)
Taskforce survey. \emph{Br J Dermatol} . 2016;174(3):594-601.
doi:10.1111/bjd.14233

29. Leaute-Labreze C, Boccara O, Degrugillier-Chopinet C, et al. Safety
of Oral Propranolol for the Treatment of Infantile Hemangioma: A
Systematic Review. \emph{PEDIATRICS} . 2016;138(4):e20160353-e20160353.
doi:10.1542/peds.2016-0353

30. Prey S, Voisard J-J, Delarue A, et al. Safety of Propranolol Therapy
for Severe Infantile Hemangioma. \emph{JAMA} . 2016;315(4):413-415.
doi:10.1001/jama.2015.13969

31. Droitcourt C, Kerbrat S, Rault C, et al. Safety of Oral Propranolol
for Infantile Hemangioma. \emph{Pediatrics} . 2018;141(6).
doi:10.1542/peds.2017-3783

32. Ji Y, Chen S, Wang Q, et al. Intolerable side effects during
propranolol therapy for infantile hemangioma: frequency, risk factors
and management. \emph{Sci Rep} . 2018;8(1):1-7.
doi:10.1038/s41598-018-22787-8

33. Frari LD, Leaute\selectlanguage{english}-Labreze C, Guibaud L, et al. Propranolol
pharmacokinetics in infants treated for Infantile Hemangiomas requiring
systemic therapy: Modeling and dosing regimen
recommendations.\emph{Pharmacol Res Perspect} . 2018;6(3):e00399.
doi:10.1002/prp2.399

34. Takechi T, Kumokawa T, Kato R, Higuchi T, Kaneko T, Ieiri I.
Population Pharmacokinetics and Pharmacodynamics of Oral Propranolol in
Pediatric Patients With Infantile Hemangioma. \emph{J Clin Pharmacol} .
2018;58(10):1361-1370. doi:10.1002/jcph.1149

35. Martin K, Bleib F, Chamlin SL, et al. Propranolol Treatment of
Infantile Hemangiomas: Anticipatory Guidance for Parents and
Caretakers.\emph{Pediatr Dermatol} . 2013;30(1):155-159.
doi:10.1111/pde.12022

36. Holland KE, Frieden IJ, Frommelt PC, Mancini AJ, Wyatt D, Drolet BA.
Hypoglycemia in Children Taking Propranolol for the Treatment of
Infantile Hemangioma. \emph{Arch Dermatol} . 2010;146(7):775-778.
doi:10.1001/archdermatol.2010.158

37. Shepherd D, Adams S, Wargon O, Jaffe A. Childhood wheeze while
taking propranolol for treatment of infantile hemangiomas. \emph{Pediatr
Pulmonol} . 2012;47(7):713-715. doi:10.1002/ppul.21603

38. Petrovic J, Trifunovic B, Vukomanovic G, Topalovic M, Trajkovic G,
Parezanovi\selectlanguage{polish}ć \selectlanguage{english}V. Oral propranolol for infantile hemangiomas: a prospective
study on the role of 48-hour Holter monitoring in additional safety
assessment. \emph{J Dermatol Treat} . 2017;28(6):554-558.
doi:10.1080/09546634.2016.1277177

39. Hengst M, Oelert M, Hoeger PH. Blood Pressure Monitoring During the
Induction and Maintenance Period of Propranolol Therapy for Complicated
Infantile Hemangiomas: A Prospective Study of 109 Infants. \emph{Pediatr
Dermatol} . 2015;32(6):802-807. doi:10.1111/pde.12681

40. Raphael MF, Breugem CC, Vlasveld FAE, et al. Is cardiovascular
evaluation necessary prior to and during beta-blocker therapy for
infantile hemangiomas? \emph{J Am Acad Dermatol} . 2015;72(3):465-472.
doi:10.1016/j.jaad.2014.12.019

41. Xu D-P, Cao R-Y, Xue L, Sun N-N, Tong S, Wang X-K. Treatment of
Severe Infantile Hemangiomas With Propranolol: An Evaluation of the
Efficacy and Effects of Cardiovascular Parameters in 25 Consecutive
Patients. \emph{J Oral Maxillofac Surg} . 2015;73(3):430-436.
doi:10.1016/j.joms.2014.09.010

42. Hoeger P, Harper J, Baselga E, et al. Treatment of infantile
haemangiomas: recommendations of a European expert group. \emph{Eur J
Pediatr} . 2015;174. doi:10.1007/s00431-015-2570-0

43. Puttgen KB, Summerer B, Schneider J, Cohen BA, Boss EF, Bauman NM.
Cardiovascular and blood glucose parameters in infants during
propranolol initiation for treatment of symptomatic infantile
hemangiomas. \emph{Ann Otol Rhinol Laryngol} . 2013;122(9):550-554.
doi:10.1177/000348941312200903

44. Frongia G, Byeon J-O, Arnold R, Mehrabi A, G\selectlanguage{ngerman}ünther P. Cardiac
diagnostics before oral propranolol therapy in infantile hemangioma:
retrospective evaluation of 234 infants. \emph{World J Pediatr} .
2018;14(3):254-258. doi:10.1007/s12519-018-0137-7

45. Erdo\selectlanguage{polish}ğ\selectlanguage{english}an I. Cardiac evaluation in children with
hemangiomas.\emph{Turk Kardiyol Dernegi Arsivi-Arch Turk Soc Cardiol} .
January 2016. doi:10.5543/tkda.2016.65171

46. Yarbrough KB, Tollefson MM, Krol AL, Leitenberger SL, Mann JA,
MacArthur CJ. Is Routine Electrocardiography Necessary Before Initiation
of Propranolol for Treatment of Infantile Hemangiomas? \emph{Pediatr
Dermatol} . 2016;33(6):615-620. doi:10.1111/pde.12972

47. Tang LY, Hing JW, Tang JY, et al. Predicting complications with
pretreatment testing in infantile haemangioma treated with oral
propranolol. \emph{Br J Ophthalmol} . 2016;100(7):902-906.
doi:10.1136/bjophthalmol-2015-307284

48. Chaturvedi K, Steinberg JS, Snyder CS. Cost-effectiveness of
treating infantile haemangioma with propranolol in an outpatient
setting. \emph{Cardiol Young} . 2018;28(10):1105-1108.
doi:10.1017/S1047951118000987

\selectlanguage{ngerman}\textbf{Table 1. Patient clinical presentation at Hemangiol® initiation}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Patients included} (n)\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
94\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Gender}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Girls\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
70 (74.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Boys\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
24 (25.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Age} (median {[}min;max{]}); months\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
4 {[}0; 21{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Height} (median~{[}min;max{]}); cm\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
63.8 {[}45.5; 84{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Weight} (median {[}min;max{]}); Kg\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
6.5 {[}3.6; 11{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Medical history}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
None (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
82 (87.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Preterm birth (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
5 (5.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Birth weight \textless{}2500 g (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1 (1.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Congenital abnormalities\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
4 (4.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Other\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
2 (2.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Type of IH}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Superficial (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
35 (37.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Deep (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
8 (8.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Mixt (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
51 (54.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Multifocal IH} (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
23 (24.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Location of IH}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Head (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
56 (59.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Periocular (n, \%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{23 (24.5)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Nose (n,\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{11 (11.7)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Lips (n,\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{5 (5.3)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Parotid (n,\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{5 (5.3)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Other (n,\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{12 (12.8)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Cervical (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
5 (5.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Cutaneous (n,\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{3 (3.2)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Subglottic (n,\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{2 (2.1)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Thoracic and dorsal (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
12 (12.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Abdomen and pelvis (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
12 (12.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Hepatic (n,\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{2 (2.1)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Perineal (n,\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{7 (7.4)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{Other (n,\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\emph{3 (3.2)}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Limbs (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
8 (8.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Miliary (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1 (1.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Syndromic association}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
PHACES syndrome (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
2 (2.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
LUMBAR syndrome (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
2 (2.1)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Indication for treatment}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Functional (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
36 (38.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Ulceration (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
29 (30.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Aesthetic (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
24 (25.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Life threatening (n,\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
5 (5.3)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Legends: IH, infantile haemangioma; PHACES, posterior fossa anomalies,
haemangioma, arterial lesions, cardiac abnormalities, eye anomalies,
sternal defects; LUMBAR, lower body haemangioma, urogenital, myelopathy,
bones, anorectal/arterial, and renal anomalies.

\selectlanguage{ngerman}\textbf{Table 2. Patient cardiac monitoring during Hemangiol®
initiation}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
Dose & & Monitoring time & Monitoring time & Monitoring time &
Monitoring time\tabularnewline
\midrule
\endhead
& Cardiac monitoring & H0 & H1 & H2 & H3\tabularnewline
0.5mg/kg & SBP (mean \selectlanguage{ngerman}± SD) & 94.8 \selectlanguage{ngerman}± 12.5 & 93.3 \selectlanguage{ngerman}± 12.7 & 90.8 \selectlanguage{ngerman}± 14.4 &
91.0 \selectlanguage{ngerman}± 13.3\tabularnewline
& DBP (mean \selectlanguage{ngerman}± SD) & 57.5 \selectlanguage{ngerman}± 14.2 & 54.8 \selectlanguage{ngerman}± 13.4 & 54.2 \selectlanguage{ngerman}± 14.0 & 53.7 \selectlanguage{ngerman}±
12.7\tabularnewline
& BPM (mean \selectlanguage{ngerman}± SD) & 140.3 \selectlanguage{ngerman}± 18.1 & 127.1 \selectlanguage{ngerman}± 16.1* & 129.3 \selectlanguage{ngerman}± 15.0* & 125.8
\selectlanguage{ngerman}± 16.4*\tabularnewline
1 mg/kg & SBP (mean \selectlanguage{ngerman}± SD) & 91.8 \selectlanguage{ngerman}± 13.0 & 90.8 \selectlanguage{ngerman}± 15.2 & 88.2 \selectlanguage{ngerman}± 12.9 &
91.0 \selectlanguage{ngerman}± 12.2\tabularnewline
& DBP (mean \selectlanguage{ngerman}± SD) & 59.7 \selectlanguage{ngerman}± 15.6 & 54.3 \selectlanguage{ngerman}± 15.1* & 48.9 \selectlanguage{ngerman}± 14.3* & 54.6 \selectlanguage{ngerman}±
13.7*\tabularnewline
& BPM (mean \selectlanguage{ngerman}± SD) & 128.1 \selectlanguage{ngerman}± 19.0** & 121.7 \selectlanguage{ngerman}± 17.0* & 119.6 \selectlanguage{ngerman}± 15.7* &
120.3 \selectlanguage{ngerman}± 14.2*\tabularnewline
1.5 mg/kg & SBP (mean \selectlanguage{ngerman}± SD) & 91.3 \selectlanguage{ngerman}± 14.7 & 88.9 \selectlanguage{ngerman}± 15.3 & 89.0 \selectlanguage{ngerman}± 15.0 &
90.7 \selectlanguage{ngerman}± 12.2\tabularnewline
& DBP (mean \selectlanguage{ngerman}± SD) & 58.1 \selectlanguage{ngerman}± 13.5 & 52.6 \selectlanguage{ngerman}± 15.4* & 51.7 \selectlanguage{ngerman}± 13.6* & 52.8 \selectlanguage{ngerman}±
11.1*\tabularnewline
& BPM (mean \selectlanguage{ngerman}± SD) & 125.9 \selectlanguage{ngerman}± 20.1** & 123.4 \selectlanguage{ngerman}± 15.8 & 120.7 \selectlanguage{ngerman}± 14.8 & 118.7
\selectlanguage{ngerman}± 14.5*\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

Legends: H0, before Hemangiol® initiation; H1, one hour after Hemangiol®
initiation; H2, two hours after Hemangiol® initiation; H3 three hours
after Hemangiol® initiation; SBP, systolic blood pressure; DBP,
diastolic blood pressure; BPM, beats per minute (heart rate); SD,
standard deviation.

* Significant statistical difference between H0 and H1 or H2 or H3
during the same hospitalization (P-value \textless{}0.05); **
Significant statistical difference between H0 at 0.5mg/kg initiation and
H0 at 1mg/kg or 1.5mg/kg initiations (P-value \textless{}0.05).

\textbf{Table 3. Serious adverse events}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{Case}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{1}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{2}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{3}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{4}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{5}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{6}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{7}\strut
\end{minipage} & \begin{minipage}[b]{0.08\columnwidth}\raggedright\strut
\textbf{8}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
SAE\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Uncontrolled bronchial hyper reactivity\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Hypoglycaemia without risk factor\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Hypoglycaemia without risk factor\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Hypoglycaemia after limited food intake\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Uncontrolled bronchial hyper reactivity\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Uncontrolled bronchial hyper reactivity\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Uncontrolled bronchial hyper reactivity\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Uncontrolled bronchial hyper reactivity\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
medical history\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Preterm 35 WA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Preterm 34 WA\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
age at initiation (months)\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
11 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
7 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5 months\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Hemangiol\selectlanguage{ngerman}® dosage during SAE\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3 mg/kg/day\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Time between SAE and Hemangiol\selectlanguage{ngerman}® initiation\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.5 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
7 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5 months\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
11 months\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Decision after SAE\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Treatment suspended\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Treatment suspended\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Treatment suspended\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Dose reduced under 2 mg/kg/day\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Treatment suspended\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Treatment reinitiated 3 months later\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Treatment suspended\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Treatment suspended\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
IH outcome after decision\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Rebound growth Surgery\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Involution\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Involution\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Rebound growth\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Involution\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Rebound growth\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Involution\strut
\end{minipage} & \begin{minipage}[t]{0.11\columnwidth}\raggedright\strut
Involution\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
Causality score\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2/6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5/6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3/6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2/6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2/6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5/6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2/6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4/6\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Legends: SAE, serious adverse event; WA, weeks of amenorrhea.

\textbf{Figure legends}

\textbf{Supplementary Figure. Rapid initiation protocol}

\selectlanguage{english}
\FloatBarrier
\end{document}

