JAMA Pediatrics Journal Club Slides:
Treatment of Acute Cough in
Infants and Toddlers
Paul IM, Beiler JS, Vallati JR, Duda LM, King TS. Placebo effect in
the treatment of acute cough in infants and toddlers: a randomized
clinical trial. JAMA Pediatr. Published online October 27, 2014.
doi:10.1001/jamapediatrics.2014.1609.
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Introduction
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Background
– Cough is a frequent symptom in infants and toddlers and is one of the
most common reasons children visit a health care provider.
– Little evidence supports use of over-the-counter medicines for acute
cough, particularly in younger children.
– Several studies have demonstrated the effectiveness of honey for
treatment of acute cough, but honey cannot be safely consumed by
children younger than 1 year.
– Agave nectar has physical properties similar to honey but without known
risk of infantile botulism.
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Study Objective
– To compare the effect of a novel formulation of pasteurized agave nectar
vs placebo and no treatment on nocturnal cough and the sleep difficulty
associated with nonspecific acute cough in infants and toddlers.
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Methods
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Study Design
– Partially double-blinded, randomized trial comparing a single nighttime
dose of agave nectar plus grape flavoring, placebo (grape-flavored water),
and no treatment.
– Surveys were administered to parents on 2 consecutive days:
• Day 1: day of presentation, following no treatment the prior night.
• Day 2: following agave nectar, placebo, or no treatment on previous
night.
– Agave and placebo dosing stratified by age:
• 3 mL for ages 2-5 months, 4 mL for ages 6-23 months, 5 mL for ages
24-47 months.
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Setting
– Two outpatient, general pediatric practices.
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Methods
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Patients
– 119 children aged 2 to 47 months with nonspecific acute cough, nocturnal
symptoms, and illness duration of 7 days or less.
– Patients were excluded if they had signs or symptoms of a more treatable
disease or a history of asthma, chronic lung disease, or other severe
chronic diseases.
– Sample size calculations indicated that 120 participants (40 per arm)
would have 80% power to detect a 0.5-point difference between treatment
groups incrementally for the primary efficacy measure of change in cough
frequency between the first night and the end of the second night.
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Outcomes
– Cough frequency, cough severity, bothersome nature of cough, rhinorrhea
severity, congestion severity, and child and parent sleep quality.
– Parental assessments of outcomes were assessed through a version of
previously used and validated questions using a 7-point ordinal scale.
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Methods
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Limitations
– Each child had a physician visit between the 2 nights of the study, which
may explain some of the improvement in all of the groups, including the no
treatment group.
– Upper respiratory infections naturally improve with time, making it more
difficult to detect treatment effects.
– No objective outcome measures were used.
– Compliance with treatment administration could not be guaranteed.
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Results
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119 children completed the trial (mean [SD] age, 22.9 [14.0] months), with
a mean (SD) cough duration of 4.0 (1.5) days prior to enrollment.
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No demographic or baseline symptom severity differences were observed
between the study groups.
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For all outcomes except for cough bothersomeness to the child, both the
agave nectar and placebo groups had significant improvement compared
with the no treatment group, but no differences were detected for any
outcome between the agave nectar and placebo groups.
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A combined symptom score was calculated using all study outcomes,
including cough frequency, cough severity, congestion severity, rhinorrhea
severity, and cough effect on child and parent sleep. Again, both agave
nectar and placebo were superior to no treatment, but no significant
differences were detected between the agave nectar and placebo groups.
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Results
Between-Night Treatment Effects of
Agave Nectar, Placebo, and No
Treatment on Study Outcomes Using
a Likert-Type Scale
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Results
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Secondary Analyses
– No effect of illness duration was observed on treatment effect.
– No significant differences were found between the study groups for
other remedies given (eg, acetaminophen, ibuprofen).
– Subgroup analysis for 30 participants younger than 1 year:
• For all outcomes, the agave nectar did result in more than a 0.5point greater improvement than for the placebo (the a priori
definition of a clinically meaningful difference), a finding limited by
the small subgroup sample size and the reduced power to detect a
statistically significant finding.
– Adverse effects were rare; no significant differences were found
between the study groups for any individual adverse event.
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Comment
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A significant placebo effect exists in the treatment of young children with
nonspecific acute cough because the agave nectar and placebo both
resulted in perceived improvement of child symptoms by parents compared
with no treatment.
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The common clinical advice of watchful waiting with no treatment may not
be the best advice for parents whose infants and toddlers are struggling
with cough and its associated sleep disruption.
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These findings strengthen the validity of prior studies suggesting that honey
is effective for acute cough given that similar methods were used in the
current study with only a placebo effect demonstrated.
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The intriguing (although not statistically significant) findings among children
younger than 1 year suggest that further evaluation of agave nectar among
a larger cohort in this age group may be warranted as this group is the most
germane to therapeutic measures for nonspecific acute cough.
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Contact Information
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If you have questions, please contact the corresponding author:
– Ian M. Paul, MD, MSc, Department of Pediatrics, Penn State College of
Medicine, Mail Code HS83, 500 University Dr, Hershey, PA 17033-0850
(ipaul@psu.edu).
Funding/Support
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This study was funded by an unrestricted grant to the Penn State College of
Medicine by Zarbee’s Inc.
Conflict of Interest Disclosures
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Dr Paul reported serving as a paid consultant to Zarbee’s Inc in 2012, with a
total income of $1350; this consulting relationship was discontinued upon
discussions of performing a clinical trial. Dr Paul’s relationship was
evaluated and supervised by the Penn State College of Medicine Conflict of
Interest System Committee. No other disclosures were reported.
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