cardiovascular and blood glucose monitoring

8/16/2019 Cardiovascular and Blood Glucose Monitoring

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Annals of Otology, Rhinology Laryngology 122(9):550-554.

© 2 013 Annals Publishing Company. All rights reserved.

Cardiovascular and Blood Glucose Parameters in Infants

During Propranolol Initiation for Treatment of

Symptomatic Infantile Hemangiomas

Katherine B. Puttgen, M D; Barbara Sum merer, MD ; Jeremy Schneider, M D;

Bernard A. Cohen, MD ; Emily F. Boss, M D, MPH ; Nancy M. Baum an, MD

Objectives We sought to determine the effect of propranolol on cardiovascular and blood glucose parameters in infants

with symptom atic infantile hem angiom as w ho were hospitalized for initiation of treatmen t, and to analyze adverse effects

of propranolol throughout the course of inpatient and outpatient treatment.

Methods

A retrospective cohort analysis was performed on 50 infants (age less than 12 months) with symptomatic in-

fantile hemangiomas who were hospitalized for propranolol initiation between 2008 and 2012, Demographic data and

disease characteristics were re corded. Systolic and diastolic blood pressures, heart rate, blood glucose values, and adverse

events recorded during hospitalization were analyzed. An additional cohort of 200 consecutively treated children was

also assessed for adverse events associated with outpatient propranolol use .

Results The median age among the inpatient cohort was 3.4 months (range, 0,8 to 12,0 months). Infants older than 6

months were more likely to exhibit bradycardia than were younger infants (p < 0.001). Hypotensive and/or bradycardic

periods were infrequent and were not associated with observable clinical symptoms. The mean systolic and diastolic

blood pre ssures and the mean he art rate decrease d significantly from day 1 of hospita lization to day 2 (p = 0,004 ; p =

0,008; p < 0,001), but not from day 2 to day 3, when the propranolol dose was increased to target, Hypoglycemia was

rare (0,3% incidence,) Among the 250 outpatients, 2 infants developed lethargy and hypoglycemia during a viral illness

and recovered without sequelae. One infant experienced recurrent bronchospasm with viral illnesses and required con-

comitant bronchodilator therapy.

onclusions

Frequent d eviations from normal ranges of blood pressure and heart rate occur upon initiation of propran-

olol, but are clinically asymptomatic. These findings support that outpatient initiation of propranolol in healthy, nor-

motensive infants appears to be a relatively safe altemative to inpatient initiation, Hypoglycemia is rare, but can occur

throughout the treatment period; parent counseling is of paramount importance.

Key Words: blood pressure, cardiovascular system, heart rate, infantile hemangioma, propranolol.

INTRODUCTION

Propranolol has redefined the treatment of symp-

tomatic infantile hemangiom a (I H) .' Since the seren-

dipitous discovery of propranolol's usefulness for IH

5 years ago, its use for this indication has surpassed

that of oral corticosteroids. Am ong prop ranolol's at-

tributes is its long-standing history of relatively safe

use in children with cardiovascular conditions. De-

spite this duration of use, little is known about the

cardiovascular effects in infants. Likewise, few re-

ports have defined what constitutes hypotension and

bradycardia in the population under 12 months of

age .2 ^ Given the rapid adoption of propranolol as

first-line treatment for symptomatic IH, we sought

to determine its effect on cardiovascular and blood

glucose parameters in infants with symptomatic IH

who were admitted to our institution for initiation of

therapy. We also sought to assess the adverse effects

of propranolol throughout the course of inpatient

and outpatient treatment for IH among a population

of children followed at two institutions.

METHODS

The Johns Hopkins and Children's National Med-

ical Center Institutional Review Boards approved

this study.

Cardiovascular and Blood Glucose Monitoring

During Inpatient Treatment. A retrospective cohort

analysis was performed on 50 infants (age less than

12 months) with symptomatic IH who were hospi-

From the Departments of Dermatology (Puttgen, Summerer, Schneider, Cohen) and Otolaryngology (Boss), Johns Hopk ins University

School of Medicine, Baltimore, Maryland, and the Department of Otolaryngology, Children's National Medical Center, Washington,

DC (Bauman), This work was supported by NIH grant 5R21HD062959-02,

Correspondence: Katherine B, Puttgen, MD, Johns Hopkins University School of Medicine, Dept of Dermatology, 200 N Wolfe St,

Uni t 2107, Bal timore , MD 21287,


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Puttgen et al. C ardiovascular Parameters in Propranolol T reated Infants

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Hemangioma

551

talized for propranolol initiation between 2008 and

2012 and whose complete records were available

for review. From 2008 to 2011, it was our institu-

tional practice to admit all children younger than 12

months of age for initiation of propranolol. Begin-

ning in 2012 , infants less than 2 months of age w ere

routinely admitted for initiation of propranolol ther-

apy and infants older than 2 months were admitted

only if a comorbidity existed.

The demographic data obtained included gen-

der, race, presence or absence of prematurity, and

age at initiation, along with characteristics of the

hemangiomas necessitating treatment, including lo-

cation, presence or absence of ulcération, and exis-

tence of PHACE(S) syndrom e. Systolic blood pres-

sure (SBP), diastolic blood pressure (DBP), heart

rate (HR ), and blood glucose (BG ) values were the

main outcome measures of interest. These values

were obtained on the day of admission before ini-

tiation of propranolol (baseline), on the first day of

propranolol therapy (day 1), and on the next 2 days

after dose escalation (days 2 and 3).

The initial dosing of propranolol was mg/kg per

day divided every 8 hours. If

3

doses were tolerated,

the dose was escalated to the target dose of

2

mg/kg

per day divided every 8 hours for doses 4, 5, and 6.

The patients' SBP, DBP, HR, and BG values were

recorded

hour after each dos e. The SBP, DBP, and

HR were also recorded every 4 hours according to

the monitoring protocol of the inpatient infant unit.

If a low BP or HR was recorded, nursing staff were

instructed to repeat the measurements immediately,

and if the reading remained low, to repeat them in 1

hour. The BP and HR were measured by automat-

ed oscillometric devices or by manual oscillometry

with an appropriate-size infant

cuff

Ranges of nor-

mal were taken from age-specific published data.^-^

The BG level was measured by fingerstick or heel

stick technique using an automated StatStrip glu-

cometer (Nova Biomédical, Waltham, Massachu-

setts). A BG value of less than 60 mg/dL was con-

sidered to indicate hypoglycemia.-^

Assessment of Adverse Events During Outpa

tient Treatment. In addition to the inpatient analy-

sis described, adverse events associated with pro-

pranolol were assessed in the 50 inpatients and in

an additional cohort of 200 consecutively treated

children with IH, ranging in age from 0.8 month to

5 years, regardless of inpatient or outpatient drug

initiation. Infants were selected for analysis of sig-

nificant adverse events if they were receiving pro-

pranolol therapy for IH at either of two reg ional ter-

tiary children's centers (Johns Hopkins, Baltimore,

Maryland, or Children's National Medical Center,

TABLE 1. DEMOGRAPHIC AND DISEASE

CHARACTERISTICS

Patients

Characteristics

Sex

Female

Male

Age


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Puttgen et al. Cardiovascular Parameters in Propranolol T reated Infants

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Hemangioma

TABLE 2. BLOOD PRESSUR E AND HEART RATE (MEAN ± SD) AT BASELINE AND

OVER PROPRANOLOL INITIATION PERIOD

Baseline

Day I

Day 2

Day 3

Systolic blood pressure (mm Hg) 96.1 ± 13.5

Diastolic blood pressure (mm Hg) 52.4 ± 11.5

Heart rate (beats per minute) 135.0 ± 14.3

97.8 ± 16.3

53.3 ± 12.6

123.2 ±16.7

90.5 ±11.7

49.1 ±11.2

122.7 ±13.4

90.1 ± 10.7

48.5 ± 10.3

120.2 ±13.0

had at least recording of simultaneously low SBP,

DBP,

and HR , so that there were 11 total occurrenc-

es of concomitant hypotension and bradycardia.

The decrease in mean SPB from day 1 to day 2

was signiflcant (97.8 ±16.3 versus 90.5 ± 11.7 mm

Hg;

p = 0.004). Likewise, a significant decrease in

mean DB P occurred from day to day 2 (53.3 ± 12.6

versus 49.1 ± 11.2 mm Hg; p = 0.008). Changes in

mean SBP and DBP values from day 2 to day 3 —

during dose escalation — were not significant (day

3 SBP, 90.1 ± 10.7 mm Hg [p = 0.46]; day 3 DBP,

48.5 ± 10.3 mm Hg [p = 0.61]; Table 2). Similarly,

the change in mean HR from day to day 2 (123.2 ±

16.7 beats per minute versus 122.7 ± 13.4 beats per

minute) achieved significance (p < 0.001), but that

from day 2 to day 3 did not (p = 0.06; Fig

1).

The ma-

jority of children remained normotensive at all time

points (baseline to discha rge), but during each day of

hospitalization an increasing percentage of patients

exhibited hypotension at various time points. This

effect was magnified for DBP as compared to SBP

(Fig 2). Bradycardia was noted on at least

record-

ing in 24% of patients and was noted on 5.3% of

all recorded H R v alues. At all time points, the oldest

group of patients — those 6 months of age or older

— were more likely to exhibit bradycardia than were

younger patients (p <

0.001;

Fig 3).

A BG level of 50 mg/dL was recorded at 1 time

in 1 inpatient, corresponding to a 0.3% incidence

of hypoglycemia among the 340 BG recordings

for the 50 patients. No patient required a decrease

in the dose of propranolol due to cardiovascular or

BG changes. Despite the abnormal BP, HR , and BG

160 ;

140

120

100

8

60

40-

20-

Baseline Day Day 2 Day 3

• Heart rate • Systolic blood pressure s Diastolic blood pressure

Fig 1. Heart rate (beats per minute) and blood pressure

(mm H g; mean ± SD ) at baseline and over initiation pe-

riod. Difference between day

and day 2 was significant

(p < 0.05) for all 3 parameters.

JL

J

values recorded, the patients remained clinically

asymptomatic per physician, nursing, and parent as-

sessments. One patient with congestive heart fail-

ure and multifocal he patic IHs required a prolonged

dose escalation because of asymptomatic bradycar-

dia, but was able to be discharged on the target dose

of 2 mg/kg per day.

Adverse Events During Outpatient Treatment.

Of

the 250 patients followed, 2 infants (0.8%) devel-

oped lethargy during a viral illness and were hypo-

glycémie on arrival to the emergency department.

Both recovered without sequelae and continued pro-

pranolol until completion of therapy. One patient

(0.4%) experienced recurrent bronchospasm with

viral illnesses that required bronchodilator therapy,

but he also completed therapy. No caretakers de-

scribed significant concerns with eating, sleeping,

or mood changes.

DISCUSSION

This study is the first to document in detail the

cardiovascular effects of propranolol administered

for treatment of symptomatic IH in a cohort of

healthy infants who were otherwise hemodynami-

cally normal (w ith the exception of 1 patient with

congestive heart failure). Our findings show that

asymptomatic deviations from normal ranges of BP

and HR occur with reasonable frequency du ring ini-

tiation of propranolol, confirming that beta block-

ade is occurring. The most pronounced decrease in

BP from baseline occurs at infants' first exposure

to propranolol, during initiation at mg/kg per day.

Reassuringly, no significant decrease in BP oc-

curred during esca lation to target dosing of

2

mg/kg

per day. These findings suggest that changes in vital

signs are more likely to occur during initiation than

during dose escalation of propranolol. Compared to

alterations in BP, deviations from normal ranges of

HR were less frequent. This finding is reassuring,

as infants less than 12 months of age are dependent

on HR to maintain cardiac output.^ The changes in

HR from baseline to day 2 and from day 1 to day 2

were not statistically significant. The fact that only

a single baseline measurement was m ade may have

influenced this finding.

Hypoglycemia in these otherwise healthy inpa-

tients was rare, occurring in 1 asymptomatic pa-


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Puttgen et ai Cardiova scular Param eters in Propranolol-Treated Infants Witii Hem angioma

553

Systolic blood pressure

100%

-

90% -

80% -

70% -

60% -

50 %

-

40% -

30 %

-

20 % -

10%

-

0%

H

1 1

• •

1 1 1 1

Am—•—n—

1

70

-H

6e.4

—

1 , 1

• m

1 .

72.3

20.2

L_J

68.8

— n

23.8

1 1

1 100% -1

90%

-

o n A

4U/u

,,

2 0 % •

~~l

H

58

1 1

1

w r

67.2

¡

j 1 1

r —y

ran ^ 1

1

f - [

1 IH

0% -

mu

1 ^

Diastolic blood pressure

5 9 {5 21

45.8

Baseline

Day 1

Day 2

ay 2 Day 3 Baseline Day 1

•

hypertensive D normotensive • hypotensive

Fi g

2. Patient systolic and diastolic blood pressure measurements as they relate to normal values.

Day 3

tient at 1 time point. In the outpatient follow-up, 2

of 250 patients (0.8 ) had hypo glycem ia during a

viral illness that resulted in lethargy severe enough

to prompt evaluation in the emergency department.

However, it is not our practice to measure BG lev-

els during routine o utpatient follow-up visits, so this

may be an underestimation of asymptomatic hypo-

glycemia that could have occurred. Hypoglycemia

is a known side effect of beta blockers, although a

rare one.^'^ In a systematic review of

4

studies on

the use of propranolol for treatmen t of IH in 1,264

patients between June 2008 and June 2012, hypogly-

cemia was noted in 4 patients,

of whom presented

with hypoglycémie seizures.^ Despite the rarity of

this adverse event, it is a significant concern, and

it is prudent to counsel parents on the importance

of regular feeding while infants are on propranolol

for treatment of IH. We advise families to contact

their treating physician if oral intake is decreased

as a result of illness or perioperative fasting so that

Fig 3 .

Heart rate measu rements by age group as they relate to nor-

mal value s. Light shaded area — nonnal heart rate; dark shaded

area

—

bradycardia. Numbers are percentages of patients. A) Day

l . B ) D a y 2 . C ) D a y 3 .


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Puttgen et al. C ardiovascular Parameters in Propranolol Treated Infants

ith

Hemangioma

propranolol dosing can be temporarily adjusted or

held. The risk of significant rebound hypertension

with sudden cessation of propranolol is negligible

in infants with normal cardiac function (J. Brenner,

personal comm unication).

To our knowledge, this is the first study to doc-

ument in detail the cardiovascular effects of pro-

pranolol administered to hemodynamically nor-

mal infants with symptomatic IH. There were sev-

eral limitations worthy of discussion, including the

retrospective nature of the study. The BP and HR

measurements were obtained by nursing staff on the

hospital floor, but variability in technique may have

occurred. Oscillometry, the most frequently used

method of obtaining BP and HR in infants, is not as

reliable as arterial monitoring; howe ver, the morbid-

ity associated with arterial lines is well know n.' We

do not have data on whe ther the infants were aw ake,

sleeping, calm, or agitated at the time of BP and

HR monitoring, although we have noted anecdot-

ally that lower BP and HR values are typically re-

corded while infants are asleep . Fleming et aH stated

that although HR does decrease during infant sleep,

these decreases are not statistically significant. The

BG level was checked hour after e ach dose of pro-

pranolol, and although we counsel parents to feed

infants around the time of medication dosing, our

data do not include information about the exact tim-

ing of the last feeding relative to the time of BG

measurement. Our comparisons did not adjust for

individual patient demographics such as gender,

body mass index, race or ethnicity, or hemangioma

size characteristics, and it is possible that these fac-

tors could also influence the hem odynam ic respon se

to propranolol therapy. Last, because adverse even ts

were not recorded prospectively, the incidence of

mild adverse events may be underreported.

Despite these limitations, this analysis provides

important data regarding propran olol's effect on car-

diovascular and BG parameters in infants with IH.

Our findings support that outpatient initiation of pro-

pranolol in otherwise healthy infants appears to be

a relatively safe alternative to inpatient monitoring

and that the greatest decrease in BP occurs at the ini-

tiation of therapy. Moreover, even these statistically

significant decreases did not result, in our cohort,

in observable sym ptoms, and this finding further in-

creases our comfort in pursuing outpatient initiation

for the majority of infants. The current practice in

our institutions, based on interdisciplinary decision-

making, has evolved such that we admit all infants

under 8 weeks of corrected age and all patients with

significant medical comorbidities or limited care-

taker support. We pursue outpatient initiation of pro-

pranolol for the majority of patients over 8 weeks of

corrected age and monitor vital signs for the first 2

hours after initiatio n. This study will contribute to

a collaborative literature database that will be used

to establish formal practice guidelines for the treat-

ment of IH with propranolol.

Acknowledgments: The authors thank Joel Brenner, MD, Professor of Pediatrics and Director of the Taussig Heart Center at the

Bloomberg Children's C enter. Johns H opkins H ospital , for his expertise in reviewing the manusciipt and offering guidanc e, and Albert

K. Oh . MD . Phill ip C. Guzzetta, MD , and Elizabeth A. Greene, M D. for their contributions in developing treatment protocols for pa-

tients with vasculai- anomalies.

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C o p y r i g h t o f A n n a l s o f O t o l o g y , R h i n o l o g y & L a r y n g o l o g y i s t h e p r o p e r t y o f A n n a l s

P u b l i s h i n g C o m p a n y a n d i t s c o n t e n t m a y n o t b e c o p i e d o r e m a i l e d t o m u l t i p l e s i t e s o r p o s t e d

t o a l i s t s e r v w i t h o u t t h e c o p y r i g h t h o l d e r ' s e x p r e s s w r i t t e n p e r m i s s i o n . H o w e v e r , u s e r s m a y

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cardiovascular and blood glucose monitoring

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