International Journal of Pediatric Otorhinolaryngology 84 (2016) 5254

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International Journal of Pediatric Otorhinolaryngology

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

Case Report

Use of intravenous propranolol for control of a large cervicofacial

hemangioma in a critically ill neonate
Shanik J. Fernando a,b,1,*, Sabra Leitenberger c, Matt Majerus c, Alfons Krol c,
Carol J. MacArthur a
a
Department of Otolaryngology Head and Neck Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, PV01, Portland,
OR 97239, USA
b
School of Medicine, Vanderbilt University, 201 Light Hall, 2215 Garland Avenue, Nashville, TN 37232, USA
c
Department of Dermatology, Oregon Health & Science University, Center for Health & Healing, Mail code: CH16D, 3303 SW Bond Avenue, Portland,
OR 97239, USA

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 24 December 2015
Accepted 6 February 2016
Available online 12 February 2016

Cervicofacial segmental infantile hemangiomas (IH) may result in airway obstruction requiring use of
propranolol to induce hemangioma regression and reestablish the airway. We present the rst case using
intravenous (IV) propranolol for control of airway obstruction and rapid expansion of cervicofacial IH in
the setting of necrotizing enterocolitis (NEC) impaired gastrointestinal function. Intravenous dosing of
propranolol was tolerated well in a critically ill neonate with multisystem complications of prematurity.
2016 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Segmental infantile hemangioma
Propranolol
Vascular anomaly
Necrotizing enterocolitis
Airway

1. Introduction
Segmental hemangiomas are a subtype of infantile hemangioma (IH). The segmental forms of infantile hemangiomas are often
extensive, and can present with complications of IH, including
airway compromise.
We present a case report of our experience using intravenous
propranolol in an attempt to expediently alleviate airway
obstruction secondary to a segmental hemangioma involving
the upper aerodigestive tract including the oor of mouth in an
infant with active NEC.
2. Case description
The baby was born at 27 and 6/7 weeks, weighing 0.645 kg with
respiratory insufciency secondary to prematurity. On physical
exam the infant was noted to be morphologically normal. There

* Corresponding author at: Department of Otolaryngology Head and Neck

Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Road,
PV01, Portland, OR 97239, USA. Tel.: +1 9712263959.
E-mail address: Shanik.fernando@vanderbilt.edu (S.J. Fernando).
1
Present address: Vanderbilt University School of Medicine, 201 Light Hall, 2215
Garland Avenue, Nashville, TN 37232, USA.
http://dx.doi.org/10.1016/j.ijporl.2016.02.005
0165-5876/ 2016 Elsevier Ireland Ltd. All rights reserved.

was noted to be adequate perfusion of the skin without rash or

petechiae or palpable lesions. On day of life (DOL) 11 it was rst
noted that there was a salmon-colored macule noted over the
left cheek, eye and forehead. There was progression of the lesion
and on DOL 13, a new ecchymotic area beneath the right chin line
with scattered lacy dark pink macules on the right side of the neck
was noted.
Dermatology and Pediatric Otolaryngology services were
consulted and on DOL 14 noted a left V1 segmental vascular
patch extending from the left nasal sidewall up onto left upper
eyelid and left forehead. In addition there was a right V3 segmental
reticulated vascular patch on the right cheek extending onto the
right lower vermilion lip, and right neck. Finally, an erythematous
patch was noted to be present on the right tip of tongue. With the
presence of extensive segmental hemangiomas, the team considered a diagnosis of PHACE (S) (Posterior fossa malformations,
Hemangioma, Arterial abnormalities, Cardiac abnormalities, Eye
abnormalities, Sternal Cleft/Supraumbilical raphe). Initiation of
oral propranolol was considered to halt growth of this extensive IH
but given that PHACE (S) may be accompanied by narrowed or
absent segments of major vessels in the neck and brain, this was
held until a diagnostic MRI could be performed. A non-sedated MRI
showing grossly normal cervical and intracranial vasculature,
along with lack of other diagnostic features, made the diagnosis of

S.J. Fernando et al. / International Journal of Pediatric Otorhinolaryngology 84 (2016) 5254

PHACE (S) highly unlikely. Airway evaluation with rigid laryngoscopy and bronchoscopy was negative at that time for airway
involvement. Shortly thereafter, the patient had a bloody stool
with an abdominal X-ray demonstrating pneumatosis consistent
with NEC.
Given the concern for developing NEC, the patient was not
treated with propranolol. Following resolution of the NEC on DOL
41, the patient was started on oral propranolol at 0.2 mg/kg/day
divided TID. However, the IH had grown signicantly in the
interval with components involving the neck, oor of mouth, facial
and periorbital areas which continued to enlarge (Figs. 1 and 2).
Shortly following starting oral propranolol, the patient gradually
developed upper airway obstruction and required intubation
following episodes of respiratory distress. Over the following days,
the dosage was gradually increased to 0.4 mg/kg/day divided TID.
However the intraoral components continued to enlarge and
painful ulceration of the lower lip and tongue developed. The
hemangioma continued to rapidly enlarge with the IH involving
the FOM resulting in posteriorsuperior tongue displacement and
impingement on the airway.
Despite gradual increases in the dosage of the PO propranolol
(0.2 mg/kg/day to 1.6 mg/kg/day divided TID) the IH continued to
enlarge. It was then hypothesized that due to the NEC, the enteral
propranolol was not being made bioavailable via the patients
gastrointestinal tract given the lack of response to medication. At 8
weeks of age, she was switched to IV propranolol for 3 weeks. IV
propranolol was initially dosed at 0.3 mg/kg/day divided TID and
titrated up over the following period to 0.5 mg/kg/day which was
determined by the Pharmacology service to be the IV equivalent of
2 mg/kg/day given enterally.
Within 4 days of starting IV propranolol, there was signicant
decrease in the tongue and oor of mouth swelling and the
softening of the hemangioma over the mandible (Fig. 3). Subsequent direct laryngoscopy conrmed the absence of airway
obstruction secondary to hemangioma and noted continued
improvement of tongue and oor of mouth swelling. The patient
was successfully extubated and transitioned back to oral
propranolol. She has continued to improve on outpatient
propranolol at age 7.5 months continuing on a dosage of 2 mg/
kg/day divided TID (Fig. 4).

Fig. 1. Patient with cervicofacial segmental hemangioma at 4 weeks of age.

53

Fig. 2. Evidence of segmental hemangioma in V3 distribution on the right at 4 weeks

of age.

3. Discussion
The use of propranolol for inducing regression of infantile
hemangiomas has been well established in the literature since the
initial discovery of the utility of the non-selective beta blocker in
promoting regression [1]. Following this discovery, propranolol
has become a primary treatment for infantile hemangiomas and is
considered to be standard of care [2,3]. The mechanism of action of
propranolol in causing regression of infantile hemangiomas
remains unclear. Hypotheses around its mechanism of action
include down-regulation of proangiogenic factors and apoptosis of
capillary cells [4]. The drug is typically completely absorbed from
the gastro-intestinal tract and is highly protein bound (8095%)
systemically [5]. In addition, the drug experiences a high rate of

Fig. 3. Evidence of regression of infantile hemangioma following initiation of

intravenous propranolol.

54

S.J. Fernando et al. / International Journal of Pediatric Otorhinolaryngology 84 (2016) 5254

describing the use of intravenous propranolol for infantile

hemangioma, the lesion being located within the orbit [18]. The
case presented here describes the novel use of intravenous
propranolol as an effective treatment of airway obstruction
secondary to a segmental hemangioma in the setting of NEC.

4. Conclusion
The use of IV propranolol, in the setting of a premature infant
with severe NEC, controlled a rapidly expanding IH with airway
impingement quickly within a matter of several days of treatment.
The dosing was tolerated well in a critically ill neonate with
multisystem complications of prematurity.

References

Fig. 4. Six month follow-up after initiation of propranolol therapy.

rst pass metabolism (up to 90% of oral dose is eliminated) [5].

Unfortunately, there are no studies which describe the pharmacokinetic data specic to the infant and child population [6].
Our patient presented with a segmental hemangioma, involving
the lower face. Segmental hemangiomas in this distribution, as
found in our patient, have been previously described to involve the
airway at a high rate [7]. Several case reports in which propranolol
has been used for treating airway hemangiomas have demonstrated success [8,9]. Meta-analyses and larger cohort studies have
further demonstrated the efcacy of using propranolol in resolving
airway hemangiomas [5,10]. While the use of propranolol in
resolving airway hemangiomas has been previously described
with relation to oral dosing, use of intravenous propranolol has not
been previously been reported.
The pharmacokinetics of propranolol have previously articulated in the literature [11,12]. Propranolol is cleared almost
exclusively by hepatic metabolism and as such oral propranolol is
subject to high rst pass effect wherein the effective dose to reach
systemic availability is low [12]. The intravenous dosage is also
quickly cleared by hepatic metabolism, with hepatic blood ow
being the main determinant of metabolism [13]. However, given
the avoidance of the rst pass effect much lower dosages of
intravenous propranolol are able to achieve systemic concentrations comparable to that of oral dosages [14]. For the purposes of
this case, intravenous drug delivery was chosen given concern for
NEC and the questionable absorption of the orally administered
propranolol in light of continued IH progression.
Propranolol is transported via the transcellular pathway across
the gastrointestinal cellular barrier [15]. It has been demonstrated,
in the healthy adult human, that propranolol is efciently
transported transcellularly to become highly bioavailable
[16,17]. In disease states such as NEC, the cellular transport
mechanisms that regulate gastrointestinal permeability are widely
understood to be altered, which may help to explain our
experience in having issues with the effectiveness of orally
administered propranolol. There is only one other case report

[1] C. Leaute-Labre`ze, E. Dumas de la Roque, T. Hubiche, F. Boralevi, J.-B. Thambo, A.

Taeb, Propranolol for severe hemangiomas of infancy, N. Engl. J. Med. 358 (2008)
26492651, http://dx.doi.org/10.1056/NEJMc0708819.
[2] C. Leaute-Labre`ze, P. Hoeger, J. Mazereeuw-Hautier, L. Guibaud, E. Baselga, G.
Posiunas, et al., A randomized, controlled trial of oral propranolol in infantile
hemangioma, N. Engl. J. Med. 372 (2015) 735746, http://dx.doi.org/10.1056/
NEJMoa1404710.
[3] X. Liu, X. Qu, J. Zheng, L. Zhang, Effectiveness and safety of oral propranolol versus
other treatments for infantile hemangiomas: a meta-analysis, PLOS ONE 10
(2015) e0138100, http://dx.doi.org/10.1371/journal.pone.0138100.
[4] T. Itinteang, A.H.J. Withers, P.F. Davis, S.T. Tan, Biology of infantile hemangioma,
Front. Surg. 1 (2014) 38, http://dx.doi.org/10.3389/fsurg.2014.00038.
[5] P.V. Vlastarakos, G.X. Papacharalampous, M. Chrysostomou, E.-F. Tavoulari, A.
Delidis, D. Protopapas, et al., Propranolol is an effective treatment for airway
haemangiomas: a critical analysis and meta-analysis of published interventional
studies, Acta Otorhinolaryngol. Ital. 32 (2012) 213.
[6] L.P. Lawley, E. Siegfried, J.L. Todd, Propranolol treatment for hemangioma of
infancy: risks and recommendations, Pediatr. Dermatol. 26 (2009) 610614,
http://dx.doi.org/10.1111/j.1525-1470.2009.00975.x.
[7] T.M. O, R.E. Alexander, T. Lando, N.N. Grant, J.A. Perkins, A. Blitzer, et al., Segmental
hemangiomas of the upper airway, Laryngoscope 119 (2009) 22422247, http://
dx.doi.org/10.1002/lary.20666.
[8] L. Buckmiller, U. Dyamenahalli, G.T. Richter, Propranolol for airway hemangiomas: case report of novel treatment, Laryngoscope 119 (2009) 20512054, http://
dx.doi.org/10.1002/lary.20633.
[9] S. Maturo, C. Hartnick, Initial experience using propranolol as the sole treatment
for infantile airway hemangiomas, Int. J. Pediatr. Otorhinolaryngol. 74 (2010)
323325, http://dx.doi.org/10.1016/j.ijporl.2009.12.008.
[10] L.M. Buckmiller, P.D. Munson, U. Dyamenahalli, Y. Dai, G.T. Richter, Propranolol
for infantile hemangiomas: early experience at a tertiary vascular anomalies
center, Laryngoscope 120 (2010) 676681, http://dx.doi.org/10.1002/lary.20807.
[11] L. Borgstrom, C.-G. Johansson, H. Larsson, R. Lenander, Pharmacokinetics of
propranolol, J. Pharmacokinet. Biopharm. 9 (1981) 419429, http://dx.doi.org/
10.1007/BF01060886.
[12] R. Gomeni, G. Bianchetti, R. Sega, P.L. Morselli, Pharmacokinetics of propranolol in
normal healthy volunteers, J. Pharmacokinet. Biopharm. 5 (2015) 183192,
http://dx.doi.org/10.1007/BF01065394.
[13] P.A. Routledge, D.G. Shand, Clinical pharmacokinetics of propranolol, Clin. Pharmacokinet. 4 (1979) 7390.
[14] E. Cid, F. Mella, L. Lucchini, M. Carcamo, J. Monasterio, Plasma concentrations and
bioavailability of propranolol by oral, rectal and intravenous administration in
man, Biopharm. Drug Dispos. 7 (1986) 55566, http://dx.doi.org/10.1002/
bdd.2510070605.
[15] N. Takamatsu, L.S. Welage, N.M. Idkaidek, D.-Y. Liu, P.I.-D. Lee, Y. Hayashi, et al.,
Human intestinal permeability of piroxicam, propranolol, phenylalanine, and PEG
400 determined by jejunal perfusion, Pharm. Res. 14 (1997) 11271132, http://
dx.doi.org/10.1023/A:1012134219095.
[16] G. Venkatesh, S. Ramanathan, S.M. Mansor, N.K. Nair, M.A. Sattar, S.L. Croft, et al.,
Development and validation of RP-HPLC-UV method for simultaneous determination of buparvaquone, atenolol, propranolol, quinidine and verapamil: a tool for
the standardization of rat in situ intestinal permeability studies, J. Pharm. Biomed.
Anal. 43 (2007) 15461551, http://dx.doi.org/10.1016/j.jpba.2006.11.013.
[17] G. Krishna, K. Chen, C. Lin, A.A. Nomeir, Permeability of lipophilic compounds in
drug discovery using in-vitro human absorption model, Caco-2, Int. J. Pharm. 222
(2001) 7789, http://dx.doi.org/10.1016/S0378-5173(01)00698-6.
[18] A. Fay, J. Nguyen, F.A. Jakobiec, L. Meyer-Junghaenel, M. Waner, Propranolol for
isolated orbital infantile hemangioma, Arch. Ophthalmol. 128 (2010) 256258,
http://dx.doi.org/10.1001/archophthalmol.2009.375.