Experience with Holter monitoring during

propranolol therapy for infantile hemangiomas

Stephanie K. Jacks, MD,a,b Naomi J. Kertesz, MD,a Patricia M. Witman, MD,a and
Esteban Fernandez Faith, MDa
Columbus, Ohio, and Jackson, Mississippi
Background: Although adverse events in children treated with propranolol have proven rare, the
appropriate methods of assessing cardiovascular risk and monitoring for toxicity when the medication is
used for infantile hemangiomas remain unclear.
Objective: We sought to analyze Holter monitor reports of otherwise healthy patients on propranolol for
infantile hemangiomas to determine the incidence of sustained arrhythmias and to evaluate the utility of
Holter monitoring in the outpatient setting.
Methods: We retrospectively reviewed the charts of patients with infantile hemangioma who underwent
24-hour Holter monitoring after initiation or dose escalation of propranolol between 2011 and 2014.
Results: In all, 43 patients aged 1.8 to 36.2 months, with 44 Holter monitor reports, were included in the
study. No sustained arrhythmias were revealed. The treatment plan was not altered in any patient based on
the Holter monitor report.
Limitations: This was a retrospective study design.
Conclusion: Our study suggests that Holter monitoring may be unnecessary in otherwise healthy patients
with infantile hemangioma older than 12 weeks who are treated with propranolol in the outpatient setting.
( J Am Acad Dermatol 2015;73:255-7.)
Key words: infantile hemangiomas; medication safety; pediatric dermatology; propranolol; systemic
therapies; vascular lesions.

ince 2008, propranolol has gained widespread

acceptance as first-line treatment for infantile
hemangiomas and, in 2014, a pediatric formulation received Food and Drug Administration
approval.1 Although cardiovascular adverse events
have proven rare, the appropriate methods of
assessing cardiovascular risk and monitoring for
toxicity remain unclear.
Our protocol for initiation of propranolol includes
cardiac monitoring in hospital for children younger
than 12 weeks (corrected chronological age), patients with PHACE (posterior fossa malformations,
hemangioma, arterial lesions, cardiac abnormalities,

eye abnormalities) syndrome, or when a suboptimal

social situation warrants hospitalization for close
monitoring and caregiver education. For otherwise
healthy infants older than 12 weeks (corrected
chronological age), propranolol is initiated with
monitoring of vital signs including heart rate and
blood pressure at baseline and 1 hour after the first
dose in the outpatient setting. A screening electrocardiogram (ECG) is obtained on all patients before
initiation of the medication. Evaluation by pediatric
cardiology is performed in patients with a history of
cardiovascular disease, ECG abnormalities, or at risk
for PHACE syndrome. A 24-hour Holter monitor

From the Nationwide Childrens Hospital, Columbus,a and University of Mississippi Medical Center.b
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication May 10, 2015.
Reprints not available from the authors.

Correspondence to: Esteban Fernandez Faith, MD, Nationwide

Childrens Hospital, 700 Childrens Dr, Columbus, OH 43205.
E-mail: Esteban.fernandezfaith@nationwidechildrens.org.
Published online June 5, 2015.
0190-9622/$36.00
2015 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2015.05.015

255

256 Jacks et al

J AM ACAD DERMATOL

AUGUST 2015

propranolol. Mean age at the time of Holter monitor

report is obtained at approximately 48 hours after the
placement was 7.9 months. The majority (37, 84%) of
first dose of propranolol in children older than
the Holter monitor studies were obtained in patients
12 weeks or after a significant dose increase.
taking propranolol at a dose of 2 mg/kg/d, whereas 1
Recent pharmacokinetic studies confirm that the
patient was on a dose of 1 mg/kg/d, 3 patients on a
medication reaches a steady state after about
dose of 2.5 mg/kg/d, and 3 patients on a dose of
48 hours in neonates.2
3 mg/kg/d. The dosage was divided 3 times daily.
Because of the lack of data surrounding the use of
The results of 24-hour
Holter monitoring in this
Holter monitoring obtained
setting, we examined our reCAPSULE SUMMARY
at 48 hours after propranolol
cords to determine its utility.
initiation or dose increase
The utility of Holter monitoring in infants
did not affect the treatment
METHODS
treated with systemic propranolol for
plan in any of our patients.
After obtaining approval
infantile hemangioma is unclear.
No patient was referred to a
from
the
institutional
Holter monitoring in an outpatient
cardiologist based on the
review board at Nationwide
setting did not reveal cardiac
result of the Holter monitor
Childrens
Hospital
in
abnormalities that would impact the
report. The average heart
Columbus, OH, we examtreatment course.
rate ranged from 96 to 148
ined the charts of patients
beats per minute (bpm), with
with a diagnosis of infantile
Our study suggests that routine Holter
a mean average heart rate of
hemangioma who undermonitoring is unnecessary for children
119 bpm. The minimum
went 24-hour Holter monitor
with infantile hemangioma treated with
heart rate ranged from 60 to
testing between July 2011
propranolol.
99 bpm, with a mean miniand May 2014 at approximum heart rate of 72 bpm.
mately 48 hours after initiaThere were no cases of sustained arrhythmia or
tion or dose increase of propranolol. Holter monitor
atrioventricular block. No reason to discontinue the
reports obtained for other indications were excluded
medication or adjust the dose was revealed with
from the study. All Holter monitor studies were
Holter monitoring.
interpreted by a pediatric electrophysiologist.
d

RESULTS

DISCUSSION

In all, 43 patients were included in the study, with

44 Holter monitor reports examined (1 patient
underwent Holter monitoring after both the initial
dose and after a subsequent dose increase). Eight
(19%) patients were referred to a cardiologist before
starting propranolol because of abnormal ECG
findings: left ventricular hypertrophy (3), biventricular hypertrophy (3), biventricular hypertrophy and
premature ventricular contractions (1), and left
ventricular hypertrophy and right interventricular
conduction delay (1). Several other patients were
evaluated by a cardiologist before starting the
medication because of concerns raised from the
history or clinical examination: possible PHACE
syndrome (2), innocent murmur (2), and a known
history of patent ductus arteriosus (1). All patients,
including the 8 with ECG abnormalities, were
cleared by the cardiologist to start the medication.
In all, 36 (84%) were female. They ranged in age from
1.8 to 36.2 months (1 patient aged \12 weeks
underwent outpatient Holter monitoring for a dose
increase, while the initial doses of the medication
were given during hospitalization). No episodes
of bradycardia were uncovered by vital signs
monitoring either before or 1 hour after starting

Propranolol has been used off-label for at least

40 years to treat cardiac rhythm disturbances, hypertension, and structural heart defects in children, and
has been observed to have a favorable safety profile.
Events involving serious cardiovascular morbidity or
mortality in children from either chronic use or
accidental overdose of propranolol are exceedingly
rare.3,4 Adverse events documented during treatment of infantile hemangioma include bradycardia,
hypotension, wheezing, hypoglycemia, sleep disturbance, somnolence, cool or mottled extremities,
diarrhea, and gastrointestinal upset.4 Changes in
blood pressure and heart rate after propranolol
initiation are infrequent and, when present, are
usually asymptomatic.5 The recent interest regarding
appropriate cardiovascular screening and monitoring of otherwise healthy infants undergoing
propranolol initiation may be attributed to the rapid
rise in its use by dermatologists, who previously had
minimal experience with the medication.
A consensus statement released in 2013 recommends that all infants starting treatment with
propranolol for infantile hemangioma should undergo a complete history and physical examination
that includes evaluation of the cardiovascular and

J AM ACAD DERMATOL
VOLUME 73, NUMBER 2

pulmonary systems, and vital signs assessment

including blood pressure and heart rate.4 ECG is
recommended when bradycardia is present, when
there is a family history of congenital heart
conditions or arrhythmias, when there is a maternal
history of connective tissue disease, and when there
is a history of arrhythmia or an arrhythmia
is auscultated during examination. Routine echocardiography is not considered necessary in the
absence of abnormal clinical findings. The
consensus conference statement recommended
that propranolol can safely be initiated in the
outpatient setting for infants older than 8 weeks,
with measurement of heart rate and blood pressure
at baseline and at 1 and 2 hours after the first dose,
and with repeated monitoring for subsequent
significant dose increases ([0.5 mg/kg/d).4
The group was unable to reach a consensus
regarding the need for Holter monitoring, although
the consensus statement notes that most of the
centers represented at the conference do not
perform Holter monitoring on a routine basis.4
Published data on the use of Holter monitors in the
outpatient setting are limited. To our knowledge,
only 1 study, a case series of 57 patients treated with
oral propranolol for infantile hemangioma,
comments on their use. In this study, a Holter
monitor was placed 10 days after starting
propranolol. Results showed that none of the
24-hour Holter monitor reports revealed abnormal
findings.6
In our study, no significant abnormalities impacting the treatment plan were discovered as a result of
the Holter monitor studies. Accepted lower limits of
normal heart rate for different age groups (\70 bpm
for neonates \1 month of age, \80 bpm for infants
aged 1-12 months, and \70 bpm for children
[12 months of age) are based on ECG measurements.4 According to these limits, a majority of our
patients (39, 89%) would be considered to have had
episodes of sinus bradycardia, whereas the
remainder showed normal sinus rhythm. However,
the limits for normal heart rate on a Holter monitor
study differ from that on an ECG, as Holter monitors
include data from both sleeping and awake periods.
By Holter monitor parameters, short periods of sinus
bradycardia with a heart rate as low as 60 bpm are

Jacks et al 257

considered normal in newborns, and the lower limit

continues to decrease with age.7,8 According to
Holter monitor parameters, none of our patients
were considered to have heart rate abnormalities.
This study adds to previous literature suggesting
that there is no clinically significant impact on
cardiovascular rhythm when propranolol is
used for treatment of infantile hemangioma in the
outpatient setting.
Although our study does have limitations,
including small sample size and retrospective design,
the results suggest that Holter monitoring is unnecessary in otherwise healthy infants with hemangioma
who are older than 12 weeks and have been
screened for other risk factors before initiation of
propranolol. At our institution the cost of placement
and interpretation of a Holter monitor study is
approximately $980. We perform ECG screening
before the initiation of propranolol to assess for
atrioventricular block. Holter monitoring may prove
to be of value when ECG rhythm disturbances are
noted or when recommended by a consulting
cardiologist. Avoidance of routine placement of
Holter monitors in otherwise healthy children is
likely to reduce costs and minimize inconvenience
to families.
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