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Current Best Evidence: Translating Best Evidence into Best
Care
EDITORS NOTE: Studies for this issue were identified using
alerts fromArchives of Disease in Childhood-Education
and Practice, Archives of Disease in Childhood-Fetal and
Neonatal, Archives of Disease in Childhood, British Med-ical
Journal, Journal of the American Medical Association, New England
Journal of Medicine, Pediatric Infectious
Disease Journal, Pediatrics, The Journal of Pediatrics, and The
Lancet. Search terms were paediatrics [All Fields]
OR pediatrics [All Fields] OR pediatrics [MeSH Terms]. In
addition, studies also were identified using the Clinical
Queries feature of PubMed. Cleo Pappas, MLIS, Library of the
Health Sciences, University of Illinois at Chicago,
contributed to the review and selection of this months
abstracts.
Jordan Hupert, MD
EVIDENCE-BASED MEDICINE PEARL: LONGITUDINAL LATENT CLASS
ANALYSIS: Longitudinal latent class anal-ysis, as it applies to
medicine, is a method that detects subgroups among a large group.
Each subgroup (or sub-
class) is defined by a set of characteristics (signs/symptoms),
the probabilities of which statistically relate to one
another. An example can be found in the article by Lodge et al
(see piece by Collins on page 207 regarding article
Lodge et al; J Pediatr2014;164:289-94). The authors applied this
type of analysis to early-life risk factors (eg,
parental asthma, parental smoking, pets in the home) and the
subsequent development of childhood wheezingin a large birth
cohort. Although the probability of each of the risk factors for
the overall birth cohort was easily
measured over time, it was not known whether there were
subclasses, each with a unique set of risk-factor prob-
abilities. The statistical analysis was able to identify 5
subclasses of that birth cohort. The authors reviewed the sub-
class risk-factor-probability sets and they defined wheezing
phenotypes for each: never/infrequent, transient,
intermediate, late, and persistent wheezing. This type of
analysis is termed latent as the subclasses (wheezing
phenotypes) are present but not apparent (a definition of
latent). The analysis was longitudinal, as patients
were followed for wheezing patterns at discreet time points from
4 weeks until 7 years of age.
Jordan Hupert, MD
LIBRARIAN PEARL: ALERTS:Alerts are tools that allow you to
develop a search strategy, enter it into a database, andthen have
the database email you results on a regular basis. Alerts are
useful for quality improvement initiatives,
chronic illnesses, orphan illnesses, and long-term projects such
as research articles or white papers. The first
step in creating an alert is to set up a free email account that
you will remember to check regularly. You may use
any internet browser. To create an alert in Google, go to
www.google.com/alerts. Enter your search query and
examine the sample result to determine if your query is specific
to your topic. Create the alert by entering your email
address, the sources you want checked, and the frequency that
you wish to receive results. For a tutorial, visit www.
wikihow.com/Use-Google-Alerts.
Cleo Pappas, MLIS
Identication of early-life risk factor proles forwheeze
phenotypesLodge CJ, Zaloumis S, Lowe AJ, Gurrin LC, Matheson
MC,Axelrad C, et al. Early-life risk factors for childhood
wheeze
phenotypes in a high-risk birth cohort. J Pediatr
2014;164:289-94.
QuestionAmong infants at high risk of allergy who are fol-lowed
longitudinally, which early-life factors are associatedwith
wheezing?
DesignObservational birth cohort.
SettingMelbourne, Australia.
Participants620 infants at high risk of allergy followed up
to
7 years of age.
OutcomesRisk factors associated with 5
longitudinal-latent-class-analysis (LLCA)-identified wheeze
classes: never/
infrequent, transient, intermediate, late, and persistent
phe-notypes.
Main Results Lower respiratory tract infection (LRTI) and
childcare by 1 year of age were associated with risk of
tran-
sient wheeze. LRTI and aeroallergen sensitization increasedthe
risk of early persistent wheeze. LRTI, eczema,
aeroallergensensitization, and food sensitization increased the
risk of in-termediate-onset wheeze. Heavy parental smoking at
birthincreased the risk of late-onset wheeze. Breastfeeding was
protective in transient and late-onset wheeze.
Conclusions These findings provide distinct early-life
riskfactor profiles for each wheeze phenotype.
CommentaryLLCA has allowed researchers to expand upon
original 4 group classification of childhood wheeze by Marti-nez
et al1 and better differentiate wheezing phenotypes.2
Lodge et al applied LLCA to 7 years of wheeze data from
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620 children in the Melbourne Atopy Cohort Study (MACS)and their
23 data points far exceed most previous LLCAstudies. The
identification of a 5-class model, noted above,
largely agrees with previous studies, as do the identified
asso-ciations. The intermediate-onset phenotype is strongly
linkedto atopy. The increased prevalence of significant wheeze
inthis high risk birth cohort (60% MACS vs 41% The Avon
Lon-gitudinal Study of Parents an Children3) is almost entirely
ac-counted for by intermediate-onset wheeze (20.7% MACS vs
3% The Avon Longitudinal Study of Parents an Children).The
conclusions are hampered by the lack of a
standardizedquestionnaire. For example, cough was included under
2
years and episodes of asthma from 3 to 7 years. However,the
findings remain consistent with previous studies. The au-
thors also postulate some causative mechanismsfor their
phe-notypes but fail to take account of the crucial role that
early-
life lung function has been showntoplay in the classificationof
pre-school wheeze phenotypes.1,2
Samuel A. Collins, BA, MA, MBBS, MRCPCH
University of SouthamptonSouthampton, United Kingdom
References
1. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen
M,
Morgan WJ. Asthma and wheezing in the first six years of life.
The Group
Health Medical Associates. N Engl J Med 1995;332:133-8.
2. Collins SA, Pike KC, Inskip HM, Godfrey KM, Roberts G,
Holloway JW,
et al. Validation of novel wheeze phenotypes using longitudinal
airway
function and atopic sensitization data in the first 6 years of
life: evidence
from the Southampton Womens survey. Pediatr Pulmonol
2013;48:
683-92.
3. Savenije OE, Granell R, Caudri D, Koppelman GH, Smit H, Wijga
A, et al.
Comparison of childhood wheezing phenotypes in 2 birth
cohorts:
ALSPAC and PIAMA. J Allergy Clin Immunol 2011;127:1505-12.
Topical antibiotics are superior to oral antibioticsin children
with acute tympanostomy tubeotorrheavan Dongen TM, van der Heijden
GJ, Venekamp RP, RoversMM, Schilder AG. A trial of treatment for
acute otorrhea in
children with tympanostomy tubes. N Engl J Med
2014;370:723-33.
Question Among children with acute tympanostomy tubeotorrhea
(TTO), what is the efficacy of topical intra-aural an-
tibiotics, compared with oral antibiotics, in resolution
ofTTO?
DesignRandomized, controlled, 3-group trial.
Setting Utrecht, Amsterdam, and Nijmegen in TheNetherlands.
ParticipantsChildren, 110 years of age, with up to 1 weekof
TTO.
Intervention Hydrocortisone-bacitracin-colistin eardrops
or oral amoxicillin-clavulanate suspension or observation.
Outcomes Presence of otorrhea after 2 weeks of
treatment,assessed otoscopically.
Main Results2 weeks after treatment, 5% of children treated
with antibioticglucocorticoid eardrops had otorrheacompared with
44% of those treated with oral antibiotics(number needed to treat,
3; 95% CI, 2 to 4) and 55% of thosetreated with initial observation
(number needed to treat, 2;
95% CI, 2 to 3).ConclusionsAntibioticglucocorticoid eardrops
were moreeffective than oral antibiotics and initial observation in
chil-dren with TTO.
CommentaryThe benefits of topical antibiotic therapy foracute
TTO have been recently reviewed, leading to a recom-
mendation that clinicians should prescribe topical antibi-otic
eardrops only, without oral antibiotics, for childrenwith
uncomplicated acute TTO.1 The trial by van Dongenet al bolsters
this recommendation with high quality evidenceand a placebo control
group. Although 55% of the placebogroup had otorrhea by otoscopy 2
weeks after treatment,
there was no difference in generic quality of life amonggroups
and differences in otitis-specific quality of life weresmall,
suggesting a potential role for observation and auraltoilet (eg,
cleaning otorrhea from the ear canal with a nasal
aspirator) in some children with mild discharge,
minimalsymptoms, and good quality of life. Children with
persistentor more symptomatic TTO are best treated with topical
anti-biotic drops, approved for use in the middle ear, as
recom-mended in the previously cited clinical practice
guideline1
and reinforced in the Choosing Wisely campaign2 from theAmerican
Board of Internal Medicine.
Richard M. Rosenfeld, MD, MPHState University of New York
Downstate Medical Center
Brooklyn, New York
References
1. Rosenfeld RM, Schwartz SR, Pynnonen MA, Tunkel DE, Hussey
HM,
Fichera JS, et al. Clinical practice guideline: tympanostomy
tubes in chil-
dren. Otolaryngol Head Neck Surg 2013;149(Suppl 1):S1-35.
2. American Academy of OtolaryngologyHead and Neck Surgery.
Choosing Wisely: Five things physicians and patients should
question.
Available
at:http://www.choosingwisely.org/doctor-patient-lists/american-
academy-of-otolaryngology-head-and-neck-surgery-foundation/ .
Accessed
March 3, 2014.
Transcranial magnetic stimulation may improvesymptoms of
hemiparesisGillick BT, Krach LE, Feyma T, Rich TL, Moberg K,
ThomasW, et al. Primed low-frequency repetitive transcranial
mag-
netic stimulation and constraint-induced movement therapyin
pediatric hemiparesis: a randomized controlled trial. Dev
Med Child Neurol2014;56:44-52.
Question Among children with congenital hemiparesis, what
is the therapeutic efficacy of repetitive transcranial
magnetic
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stimulation (rTMS), compared with sham rTMS, inenhancing
function of the affected limb?
DesignRandomized, controlled trial.
SettingGillette Childrens Specialty Healthcare, Saint
Paul,Minnesota.
ParticipantsChildren with congenital hemiparesis.
InterventionrTMS or sham rTMS; all patients also
receivedconstraint-induced movement therapy (CIMT).
OutcomesPrimary outcome was spontaneous performancein bimanual
functional activities as evaluated with the Assist-
ing Hand Assessment (AHA) test.
Main Results Improvement in AHA differed significantly
between groups (P= .007). Eight of 10 participants in
therTMS/CIMT group showed improvement greater than the
smallest detectable difference, but only 2 of 9 in the
shamrTMS/CIMT group showed such improvement (numberneeded to treat,
2; 95% CI, 2-5).
Conclusions Primed, low-frequency rTMS combined with
CIMT is efficacious in pediatric hemiparesis.Commentary This
study combines a validated behavioralintervention with an augmented
form of inhibitory rTMS.It adds to the growing consensus on both
techniques, butdoes not demonstrate superiority of primed rTMS or
showwhether the treatments are synergistic or merely additive.
IfrTMS temporarily relieves the injured hemisphere from
competition so it can learn new outputs (my belief), then
itshould be done right before CIMT. If it remodels the brainon its
own, it does not matter. Susceptibility to TMS changeswith
development1 and varies significantly between individ-uals.
Therefore, response variables (eg, motor evoked poten-
tial threshold and the degree of inhibition from rTMS) mighthave
been reported and tested as covariates to strengthen andbetter
interpret the results. rTMS has existed for 25 years,
andsubstantial preliminary data on the effectiveness of
contrale-sional inhibition have been published,2 yet there have
been
neither large trials nor apparent interest in commercializa-tion
for the treatment of hemiparesis. Results such as thesemust be
followed-up aggressively if they are to provide a
just return on investment.
Eric Wassermann, MDNational Institutes of Health
Bethesda, Maryland
References
1. Garvey MA, Mall V. Transcranial magnetic stimulation in
children. Clin
Neurophysiol 2008;119:973-84.
2. Wassermann EM, Zimmermann T. Transcranial magnetic brain
stimula-
tion: therapeutic promises and scientific gaps. Pharmacol Ther
2012;133:
98-107.
Acetaminophen: a possible alternative to
ibuprofen in patent ductus arteriosus closure
Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS,et al.
Oral paracetamol versus oral ibuprofen in the manage-ment of patent
ductus arteriosus in preterm infants: a ran-
domized controlled trial. J Pediatr2014;164:510-4.
QuestionAmong premature infants with a patent ductus ar-
teriosus (PDA), what is the therapeutic efficacy of
acetamin-ophen, compared with ibuprofen, on the PDA closure
rate?
DesignRandomized, controlled trial.SettingNeonatal intensive
care unit, Ankara, Turkey.
Participants Preterm infants < 30 weeks gestational
age,birthweight < 1250 g, and postnatal age 48 to 96 hourswho
had echocardiographically confirmed significant PDA.
InterventionOral acetaminophen versus oral ibuprofen.
OutcomesPDA closure rate.
Main ResultsThe PDA closed in 31 (77.5%) of the patientsassigned
to the oral ibuprofen group vs 29 (72.5%) of thoseenrolled in the
acetaminophen group (absolute risk reduc-tion [ARR] 5%, 95% CI,
-13.95% to 23.95%, not significant).
The reopening rate was higher in the acetaminophen groupthan in
the ibuprofen group, but not statistically different(ARR 6%, 95%
CI, -9.48% to 25.48%, not significant).
Conclusions Acetaminophen may be a medical alternative inthe
management of PDA.
Commentary Despite intense study, indecision surrounds
treatment of the preterm infant with a PDA. Who shouldbe
treated, when, and with what? Oncel et al provide pilot ev-idence
suggesting a role for oral acetaminophen to close thePDA.
Interestingly, the most premature infantsthose athighest risk for
complications secondary to a PDA
appeared to have the highest rates of ductal closure with
acet-
aminophen when compared to oral ibuprofen. This trial waspowered
to detect an unrealistic 25% difference in PDAclosure rates between
the two therapies, and found an insig-nificant difference of merely
5%. Additionally, the trial wasfar too small to detect important
yet uncommon adverse ef-
fects of acetaminophen. Finally, eligibility was based
primar-ily on echocardiographic evidence of significant PDA. It
isincreasingly clear that many PDAs close spontaneously,
andexpectant management is safe.1 Routine screening
echocardi-ography, asperformed in this study, will likely lead to
over-treatment.2 One can hope that oral acetaminophen will
prove to have higher efficacy and less toxicity than
indometh-
acin or ibuprofen. Such novel therapies are crucially impor-tant
because the ultimate decision about which infants willbenefit most
from treatment of the PDA hinges completelyon the risk:benefit of
the available therapies.
Sara B. DeMauro, MD, MSCEUniversity of Pennsylvania
PhiladelphiaPennsylvania
Clyde J. Wright, MDUniversity of Colorado School of Medicine
Aurora, Colorado
July 2014 CURRENT BEST EVIDENCE
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References
1. Sosenko IR, Fajardo MF, Claure N, Bancalari E. Timing of
patent ductus
arteriosus treatment and respiratory outcome in premature
infants: a
double-blind randomized controlled trial. J Pediatr
2012;160:929-35.e1.
2. DeMauroSB, Cohen MS,RatcliffeSJ, AbbasiS, Schmidt B.
Serialechocar-
diography in very preterm infants: a pilot randomized trial.
Acta Paediatr
2013;102:1048-53 .
Prophylactic use of probiotics amelioratesinfantile colicIndrio
F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corva-
glia L, et al. Prophylactic use of a probiotic in the
preventionof colic, regurgitation, and functional constipation: a
ran-domized clinical trial. JAMA Pediatr2014;168:228-33.
Question Among newborns, what is the prophylactic efficacy
of probiotics, compared with placebo, in
preventing/amelio-rating infantile colic?
DesignRandomized, controlled trial.
Setting9 neonatal units in Italy.
ParticipantsFull-term babies.
Intervention Lactobacillus reuteri Diagnostic and
StatisticalManual(DSM) 17938 or placebo.
OutcomesReduction of daily crying time, regurgitation,
andconstipation during the first 3 months of life.
Main Results At 3 months of age, the mean duration of
crying time (38 vs 71 minutes; P< .01), the mean numberof
regurgitations per day (2.9 vs 4.6; P < .01), and themean number
of evacuations per day (4.2 vs 3.6; P< .01)for theL reuteriDSM
17938 and placebo groups, respectively,
were significantly different.
Conclusions Prophylactic use ofL reuteriDSM 17938 during
the first 3 months of life reduced the magnitude of crying
andfunctional gastrointestinal disorders.
CommentaryInfantile colic, though self-resolving, increases
healthcare and emotional costs. Those with infantile colic
are
at a significantly increased risk for developing
recurrentabdominal pain, allergic diseases, and psychological
disor-ders.1 Though the etiology is unknown, evidence suggests
the gut microbiome may play a role in the generation
ofsymptoms.2 Indrio et al employed a double blind,
placebo-controlled multicenter prophylactic strategy for infant
cryingusing the probiotic L reuteri DSM 17938. Interpretation ofthe
beneficial effects of the probiotic is limited by the fewdetails
regarding randomization among the centers, how
study material was supplied to each center and subjects,and the
use of a nonvalidated diary. Despite these limitations,this study
lends increasing support for the use ofL reuteriDSM 17938 for
infantile colic. However, at least two impor-tant questions remain.
First, what is the mechanism of action
ofL reuteri DSM 17938, asit does not appear to change
gutmicrobiome composition?3 Answering this question may
lead to therapies without the need for administration oflive
organisms. Second, what, if any, are the long-term
healthconsequences of using this (or any) probiotic in
infancy?Future studies will ideally re-examine children several
years
after treatment.
Bruno P. Chumpitazi, MD, MPHRobert J. Shulman, MD
Baylor College of MedicineHouston, Texas
References
1. Savino F, Castagno E, Bretto R, Brondello C, Palumeri E,
Oggero R. A
prospective 10-year study on children who had severe infantile
colic.
Acta Paediatr Suppl 2005;94:129-32.2. de Weerth C, Fuentes S, de
Vos WM. Crying in infants: On the possible
role of intestinal microbiota in the development of colic. Gut
Microbes
2013;4:416-21.
3. Roos S, Dicksved J, Tarasco V, Locatelli E, Ricceri F,
Grandin U, et al. 454
pyrosequencing analysis on faecal samples from a randomized DBPC
trial
of colicky infants treated withLactobacillus reuteriDSM 17938.
PLoS One
2013;8:e56710.
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