International Journal of Pediatric Otorhinolaryngology 73 (2009) 1168–1172

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International Journal of Pediatric Otorhinolaryngology

journal homepage: www.elsevier.com/locate/ijporl

Case report

Role of Propranolol in the therapeutic strategy of infantile laryngotracheal

hemangioma
Françoise Denoyelle a,b,c, Nicolas Leboulanger a,b,c,*, Odile Enjolras d, Robert Harris a,
Gilles Roger a,b,c, Eréa-Noël Garabedian a,b,c
a
Armand-Trousseau Children Hospital, Pediatric ENT Department, AP-HP, 75012 Paris, France
b
UPMC Univ. Paris VI, France
c
INSERM U-587 Paris, France
d
Armand-Trousseau Children Hospital, Maxillo-Facial and Plastic Surgery Department, AP-HP, 75012 Paris, France

A R T I C L E I N F O A B S T R A C T

Article history: There are recent reports of effective treatment of cutaneous hemangiomas with Propranolol. The current
Received 18 February 2009 study aims to assess efficacy of systemic Propranolol for subglottic hemangiomas and to discuss its place
Received in revised form 16 April 2009 among the other available therapies. We report 2 infants with subglottic hemangiomas, which were
Accepted 20 April 2009
resistant to other established medical treatments. One infant presented with PHACES association, the
Available online 29 May 2009
other with widespread cutaneous congenital hemangiomas. Both were subsequently treated with
systemic Propranolol. Both patients’ subglottic hemangiomas responded dramatically to systemic
Keywords:
Propranolol. No side effects of the therapy occurred, and a safety protocol previously designed for
Subglottic hemangioma
Propranolol prescribed for other indications was applied to our patients. Propranolol appears to be an
Propranolol
Children effective treatment for subglottic hemangiomas and should now be used as a first-line treatment in
subglottic hemangiomas when intervention is required.
ß 2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Subglottic and/or tracheal infantile hemangiomas are poten-
tially life-threatening tumors, despite their spontaneous regres-
sion typically beginning after 18–24 months of age. Many types of
treatment have been proposed, some of them aiming to wait for
spontaneous regression (tracheotomy), and some aiming to
partially or totally reduce or destroy the hemangioma (corticos-
teroids, Interferon or Vincristine therapy, LASER, cryotherapy, local
steroid therapy with intubation, open surgery) [1–5].
The adverse effects of these various types of therapies are
potentially severe. Tracheotomy in infants has a high mortality/
severe morbidity rate, 1–3% [6]. Long-term steroid therapy
induces Cushing syndrome with growth retardation, typical
appearance, hirsutism, arterial hypertension, hypertrophic
cardiomyopathy, delayed wound healing, immunosuppression,
and an infectious risk [7]. Interferon a2A and 2B are associated
* Corresponding author at: Armand-Trousseau Children Hospital, Pediatric ENT
Department, AP-HP, 75012 Paris, France. Tel.: +33 144736923; fax: +33 144736108.
E-mail addresses: f.denoyelle@trs.aphp.fr (F. Denoyelle),
nicolas.leboulanger@trs.aphp.fr (N. Leboulanger), bertieharris@yahoo.com
(R. Harris), gilles.roger@trs.aphp.fr (G. Roger), noel.garabedian@trs.aphp.fr
(E.-N. Garabedian).
with many various side effects (flu type malaises, spastic
diplegia, neutropenia, liver enzymes abnormalities) [8–10].
Vincristine therapy has been described in extensive life-
threatening cases [1]. Side effects such as constipation,
abdominal pain, and parasthaesia due to the peripheral
neuropathy have been reported. Although there is resolution
of symptoms after cessation of treatment, this last neurological
side effect may impose a premature arrest of therapy. Local
injections of steroids associated with intubation leads to
prolonged hospitalization on the intensive care unit (ICU)
(mean duration 19 days [3]). The main side effect of cryotherapy
and LASER is pathological scarring with secondary laryngeal
stenosis [11] and many teams only use LASER in small unilateral
hemangiomas to limit this risk. The use of open surgery in
bilateral or circumferential hemangiomas offers an effective
therapeutic strategy. However, there is a risk of severe
complications with this surgery, as in all open airway surgery.
The spectacular effect of Propranolol therapy on hemangiomas,
described for the first time in 2008 by Leaute-Labreze [12] is
dramatically changing the therapeutic strategies used to date.
Here we report the cases of two children presenting severe
subglottic hemangioma successfully treated with Propranolol.
This study received the approval of the Institutional Review
Board of our hospital. Informed consent for publication was
obtained from the parents of both children.

0165-5876/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijporl.2009.04.025
 F. Denoyelle et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 1168–1172 1169

2. Clinical observations

2.1. Case No. 1

A 2-month-old girl was referred to our department for a

PHACES syndrome with upper airway obstruction. The PHACES
syndrome associates posterior fossa malformations, hemangio-
mas, arterial anomalies, coarctation of the aorta and other cardiac
defects, eye abnormalities, and sternal defects. Usually, a single
structural anomaly is associated with hemangiomata.
The child had a large sternal cleft (Fig. 1) diagnosed by antenatal
ultrasonography, and a supra umbilical median raphe, which had
partly healed at birth. A complex malformation of both renal and
hepatic vessels (arteries and veins) was detected by angio-CT.
Ophthalmological examination, cardiac ultrasonography, and
cerebral MRI were normal.
A few weeks after birth, numerous cutaneous infantile
hemangiomas appeared, located on the lower lip, the chest (at
the upper part of the abdominal raphe) and both parotid areas. The
soft-tissue involvement corresponded to the S3 newly described
facial segmentation of infantile hemangiomas, and there was no
S1, S2 or S4 [13]. She was first treated with high doses of steroids
(Betamethasone, 0.5 mg/day), but with no effect on the cutaneous Fig. 2. Patient No. 1, endoscopic view, with both steroids and Vincristine treatments.
Subglottic hemangioma with narrowed lumen.
hemangiomas.
She developed, over a period of a few weeks, a noticeable
laryngeal dyspnea and a painful necrosis of the inferior lip with because of progression of the laryngeal symptoms. After consulta-
feeding difficulties. At this stage she was referred to our institution tion between the different pediatric subspecialties, the decision
aged 8 weeks. The initial endoscopic examination under general was made to avoid, for as long as possible, external laryngeal
anesthesia showed a circumferential subglottic hemangioma with surgery because of the sternal cleft associated with mediastinal
an 80% stenosis. Surprisingly, this high grade stenosis was hernia. In total, the child received 35 injections of Vincristine.
relatively well tolerated (Fig. 2). Due to the subglottic growth, Eventually the corticosteroid therapy could be stopped. The
and necrosis of the cutaneous hemangiomas, Vincristine treatment endoscopic examination at this time showed a residual stenosis
(0.15 mg once a week) was commenced. of 60% but the patient was almost asymptomatic (intermittent
We planned to simultaneously reduce daily steroid dose from wheezing without dyspnea, tracheal tug or intercostal recession).
0.75 mg/day to 0.05 mg/day over a 3-month period. The child was Treatment with Propranolol was started (3 mg/kg/day, i.e.
also kept on a proton pump inhibitor (Lansoprazole, 1 mg/kg/day)). 20 mg/day) when she was 11 months, following another cardiac
We planned to wait to assess the outcome of this treatment before assessment. It was given concomitantly with the Vincristine.
considering endoscopic or open removal of the subglottic Endoscopy was performed 1 month after the initiation of the
hemangioma. The repeat endoscopy after 3 weeks showed a slight therapy which showed a spectacular regression of the heman-
improvement of the airway with a 70% stenosis. We, therefore, gioma, with a subglottic stenosis less than 10% and normal mucosa
continued to gradually reduce the corticosteroid to 0.125 mg/day (Fig. 3). The treatment was also significantly effective on the
of Betamethasone for a 5 kg child, but it had to be re-increased twice cutaneous lesions (Fig. 4).

Fig. 1. Patient No. 1 at admission: hemangiomas on the inferior lip, face, and chest. Fig. 3. Patient No. 1, endoscopic view, 4 months after initiating the Propranolol
Note the sternal retraction caused by both airway obstruction and sternal cleft. treatment. Subnormalization of the airway.
1170 F. Denoyelle et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 1168–1172

Fig. 5. Patient No. 2, facial aspect at birth.

surgery with an external approach could not be performed because

of the severe Cushing syndrome. After 5 more days, we planned a
final extubation attempt, with tracheotomy if unsuccessful.
However, the endoscopic assessment showed a massive
reduction of the subglottic hemangioma, allowing successful
extubation. A further examination 2 weeks later showed an upper
Fig. 4. Patient No. 1, 4 months after initiating the Propranolol treatment. airway with a normal diameter and complete disappearance of the
Major improvement of the facial lesions. lesion (Fig. 8). There has been no recurrence of the lesion so far
with continued 2 mg/kg/day Propanolol, and a decreasing steroid
The Vincristine therapy was stopped and the next endoscopic dose. The Cushing syndrome has significantly decreased (Fig. 9).
examination 4 months after initiating the Propranolol treatment The tolerance of the Propranolol treatment was good in both
showed a subnormal airway with a narrowing of 10%. A further cases with neither cardiological nor bronchial side effects.
follow-up showed no recurrence of laryngeal symptoms or
subglottic hemangioma. The 3 mg/kg/day Propranolol therapy 3. Discussion
was stopped at the age of 18 months, without recurrence so far.
The sternal surgery is scheduled in a few months. Due to their variation of size, shape, and behavior, subglottic
and/or tracheal infantile hemangiomas in children may present
2.2. Case No. 2 with a broad spectrum of clinical features, from a well-tolerated
non-symptomatic tumor to a life-threatening lesion. Long-term
A female infant was referred to our department with congenital
infantile hemangiomas including a corticoresistant subglottic
hemangioma. At birth there were multiple cutaneous hemangio-
mas in a widespread distribution (face corresponding to a full right
S1 segment, partial bilateral S3, and partial S4, neck, mouth, and
chest) (Fig. 5) and a subglottic circumferential lesion leading to a
60% stenosis, which was treated with high doses of corticosteroids
from the age of 1 month.
At the age of 4 months, she displayed a major Cushing
syndrome (Fig. 6) and, although the cutaneous lesions appeared to
have responded, there was an increase of the obstructive
respiratory symptoms requiring endotracheal intubation, soon
after which the patient was referred to our institution.
Our initial endoscopic assessment showed multiple mucosal
hemangiomas (floor of mouth, epiglottis, valleculae) and a
subglottic localization leading to a 50% stenosis (Fig. 7a and b).
Due to a concomitant sepsis, the child was kept intubated for a few
days, but the Propranolol treatment (2 mg/kg/day) was initiated
immediately after a satisfactory cardiac evaluation. Steroid doses
were gradually decreased.
After 1 week, the tube was removed for another endoscopic
examination. The hemangioma was unchanged with the same
morphological characteristics. LASER was performed on two
intubation-induced laryngeal granulomas. The child did not Fig. 6. Patient No. 2 at admission, severe Cushing syndrome (first extubation
tolerate extubation and was, therefore, re-intubated. Laryngeal attempt).
 F. Denoyelle et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 1168–1172
Fig. 7. Patient No. 2, endoscopic view, aspect during the first extubation attempt.
Subglottic granulomas (a) associated to a 2–3 mm more distal circumferential
hemangioma (65% stenosis) (b).
Fig. 8. Patient No. 2, endoscopic view, 3 weeks after Propanolol introduction.
Subnormal lumen diameter.
1171
Fig. 9. Patient No. 2, aspect after 2 months of Propranolol therapy and reduced doses
of steroids.
complications, like increased pulmonary arterial pressure, may
also occur in children with a chronic upper airway obstruction [14].
The use of tracheotomy in symptomatic lesions has been
proposed as a ‘‘wait-and-see’’ treatment, to wait for the
spontaneous regression of the hemangioma and thus avoiding
the risks of an excision surgery. However, tracheotomy has its own
complications including potentially lethal ones, such as an
accidental decannulation leading to asphyxia.
Since the first description of surgical excision in 1949 [15],
various surgical treatments have been proposed to manage
subglottic hemangiomas, with an external or endoscopic approach.
The medical treatments aim to reduce the size of the tumor. Two or
more treatments may be necessary, and the clinical parameters
leading to the choice of treatment regimen are not discussed here.
What many of these treatments have in common is that they can
expose the child to potentially severe complications. Pathological
scarring with secondary stenosis may occur after both external
approach and endoscopic surgery. High levels of corticosteroids over
a long period of time induce a Cushing syndrome with dangerous
metabolic consequences (as in case No. 2); prolonged endotracheal
intubation requires a long stay in ICU, etc.
Finally, the response to medical treatments differs from one
child to another and partial regression or non-stabilizations are not
rare.
Whatever the goal of these treatments may be (to remove the
lesion or wait for spontaneous regression), all of them expose the
child to potentially severe complications.
Recently, the use of Propranolol, a non-selective b blocker, has
been described on 11 children with cutaneous hemangiomas, with
a spectacular efficacy in all cases [12]. Proposed mechanisms of
action of Propranolol on hemangiomas include control of hypoxic
stress with up regulated HIF-1a, apoptosis induction, and
decreased production of endothelial vascular and fibroblastic
growth factors (VEGF and FGFb) [12]. Beta-2 receptors for
Propranolol are expressed in hemangioma endothelial cells.
Because potential side effects of Propranolol include bradycar-
dia, hypotension, bronchoconstriction, and reduced physiological
1172 F. Denoyelle et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 1168–1172
responses to hypoglycemia, a protocol was designed to use this
treatment with maximum safety. It includes baseline cardiac
ultrasonography, cardiologic examination (specifically including
blood pressure and heart rate) and a monitoring of blood glucose
levels during the first 48 h of treatment [16]. This precise protocol
was applied to our patients: Propranolol at 0.16 mg/kg/8 h,
increased to a maximum of 0.67 mg/kg/8 h (2 mg/kg/day) while
monitoring vital signs and glucose blood levels [16].
The two clinical cases reported here illustrate that Propanolol
may be a new powerful tool in the management of subglottic and
tracheal localized hemangiomas. It seemed to have a quick and
intense effect on subglottic hemangiomas, as was previously
described in the cutaneous localizations, and allowed both
children to be weaned from Vincristine (No. 1), steroids and
endotracheal tube (No. 2). The two children did not present any
side effects of the therapy.
A drawback of Propranolol is that currently in many countries, it
is not available in a pharmaceutical formulary dose appropriate for
newborns, infants, and children below 6 years old. For now, the
drug has to be prepared from tablets to suitable smaller dosages,
given dissolved into a liquid food, which complicates dose
adaption and drug administration. However, an oral solution
directly suitable for children is available in northern America [17].
To date, most of the pediatric otolaryngology team’s first-line
treatment is long-term steroid therapy for hemangiomas localized
to the subglottis. The use of LASER is common for unilateral
hemangiomas, and for surgery through an external approach for
circumferential or extensive hemangiomas. Some children receive
a systemic therapy (Interferon, Vincristine) because of associated
extensive cutaneous hemangiomas. What is the residual place for
these therapies now?
The preliminary results suggest that Propranolol should now be
used as a first-line treatment in subglottic hemangiomas which
require intervention. If the efficacy of Propranolol therapy on
subglottic infantile hemangiomas is confirmed, the need for
surgical procedures will be dramatically reduced.
However, in small unilateral subglottic hemangiomas, the
benefit–risk ratio of one or two laser endoscopic removals has to be
compared to the potential adverse effects of several months of
Propranolol therapy and should be evaluated in a large series.
Surgery, by either external or endoscopic approach, may have a
role to play in iatrogenic post-intubation stenosis or granulomas in
neonates, as in our second case. Because Propranolol does not
interfere with the healing process, its use does not prohibit a
concomitant surgical procedure or corticosteroid therapy.
How long should be children treated? In the first case,
Propranolol therapy could be stopped after 7 months of treatment,
at the age of 18 months, without recurrence of the subglottic
stenosis. We currently do not know if this b blocker therapy could
be stopped before the age of spontaneous regression of the
hemangiomas, but further studies will have to confirm this
hypothesis because we have, indeed, observed in other patients,
without subglottic localization, a conspicuous rebound growth of
some superficial infantile hemangiomas, rapidly developing in
children who received the Propranolol up to 1 year of age, and even
in one case up to 2 years of age. In these children, re-introduction of
the treatment was successful.
Finally, the use of Propranolol should be studied on a larger
population to confirm its efficacy on obstructive subglottic
infantile hemangiomas, balancing its tolerance, for this indication
on a very young pediatric population, with the known adverse
effects resulting from other therapeutic procedures. Those future
studies may also indicate if the cutaneous localization could act as
markers for subglottic response to Propranolol treatment, and
whether there are some hemangiomas that are, perhaps, non-
responsive to Propranolol.
In addition the benefit/risk compared to one or two endoscopic
procedures has to be evaluated in small unilateral hemangiomas.
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