TM

FEBRUARY 2020 • VOL. 43 NO. 2 • PAGES 13-24 aapgrandrounds.org

Statin Use in Children With

Familial Hypercholesterolemia

Hypertrophic Cardiomyopathy:
Sudden Death After Exercise

UTI Relapse in Children With

Resistant Uropathogens

Getting Specific About Urine

Specific Gravity
 Table of Contents
MEDICINE/PEDIATRICS
Editorial Board Benjamin Doolittle, New Haven, CT
Mike Dubik, Portsmouth, VA p15 Statin Use in Children With Familial Hypercholesterolemia
EDITOR Patricia Fechner, Seattle, WA
James A. Taylor, Seattle, WA William L. Hennrikus, Hershey, PA GENERAL PEDIATRICS
DEPUTY EDITOR Gloria Higgins, Columbus, OH p16 Hypertrophic Cardiomyopathy: Sudden Death After Exercise
Leslie L. Barton, Tucson, AZ Mary-Jane Staba Hogan,
New Haven, CT NEPHROLOGY
ASSOCIATE EDITOR
Douglas J. Opel, Seattle, WA
Daniel Lesser, San Diego, CA
p17 
UTI Relapse in Children With Resistant Uropathogens
Jonathan Mintzer, Montclair, NJ
CME QUESTION EDITOR Philip Rosenthal, San Francisco, CA EMERGENCY MEDICINE
Robert Wittler, Wichita, KS Cheryl Sanchez-Kazi, Loma Linda, CA
p18 
Getting Specific About Urine Specific Gravity
EDITORIAL BOARD David Spar, Cincinnati, OH

Kirsten Bechtel, New Haven, CT Jeffrey Winer, Memphis, TN GENERAL PEDIATRICS

Charlene Wong, Philadelphia, PA
Rebecca Brady, Cincinnati, OH p19 
Safe Infant Sleep Practices
Susan L. Bratton, Salt Lake City, UT
Esther K. Chung, Seattle, WA ADOLESCENT MEDICINE
Daniel Doherty, Seattle, WA
p20 
Oral HPV and Vaccination Among Female Adolescents
HEMATOLOGY/ONCOLOGY
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critiques of important new studies relevant to pediatric practice, p21 Late Infections in Survivors of Childhood Leukemia
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CARDIOLOGY
p22 
Brain Injury and Critical Congenital Heart Disease
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14 aapgrandrounds.org
MEDICINE/PEDIATRICS
Statin Use in Children With Familial
Hypercholesterolemia
Source: Luirink IK, Wiegman A, Kusters DM, et al. 20-year follow-up of
statins in children with familial hypercholesterolemia. N Engl J Med.
2019;381(16):1547–1556; doi: 10.1056/NEJMoa1816454
Investigators from Amsterdam University Medical Centers,
Amsterdam, and Imagelabonline and Cardiovascular, Erichem,
both in the Netherlands, conducted a study assessing long-term
outcomes in children treated with statins for familial hypercholes-
terolemia with elevated low-density lipoprotein (LDL) cholesterol.
Study participants were children with familial hypercholesterol-
emia (98% genetically confirmed) and their unaffected siblings
who had originally participated in a randomized controlled trial
on the efficacy and safety of pravastatin, with enrollment between
1997 and 1999. These individuals were recontacted and asked to
complete a questionnaire detailing subsequent medical history,
lifestyle habits, medication use, and family history. In addition,
study participants had carotid intima-media thickness assessed
with ultrasonography at baseline and follow-up. Primary study
outcomes included change in carotid intima-media thickness and
cardiovascular disease (including myocardial infarction, angina
pectoris, peripheral artery disease, stroke, or coronary revascu-
larization procedure) or death from cardiovascular causes. Vital
records were reviewed to determine outcomes in participants not
returning for follow-up. Differences between participants with
familial hypercholesterolemia and unaffected siblings were com-
pared with linear mixed methods, with adjustment for confound-
ers. In addition, data on cardiovascular disease and death prior
to the age of 40 years were collected in affected parents of study
participants, and outcomes were compared to those of study par-
ticipants with familial hypercholesterolemia.
Among 214 children with familial hypercholesterolemia and 95
unaffected siblings participating in the original study, follow-up
data were obtained in 184 (86%) and 77 (81%), respectively. Mean
ages at baseline were 13.0 years for those with familial hyper-
cholesterolemia and 12.9 for unaffected siblings; mean ages at
follow-up were 32 years for both groups. Among those with fol-
low-up data, 22% of those with familial hypercholesterolemia
and 34% of siblings were current smokers. Of those with hyper-
cholesterolemia, 79% were using lipid-lowering medications at
follow-up. At baseline, carotid intima-media thickness was sig-
nificantly greater in participants with familial hypercholester-
olemia than in unaffected siblings (mean, 0.446 and 0.439 mm,
respectively). However, after adjusting for confounders, the rate
of increase in carotid intima-media thickness per year was not
significantly different between the 2 groups. At follow-up, one
participant with familial hypercholesterolemia had cardiovascu-
lar disease, and there were no deaths related to cardiovascular
disease in either group. However, among 156 parents with famil-
ial hypercholesterolemia, for whom statin therapy was available
only later in life, 26% had had a cardiovascular event, and 7%
died of cardiovascular causes before the age of 40 years.
• February 2020
TM
The authors conclude that initiation of statin therapy during
childhood in patients with familial hypercholesterolemia slowed
the progression of carotid intima-media thickness and reduced
the risk of cardiovascular disease in adulthood.
COMMENTARY BY
Benjamin R. Doolittle, MD, M Div, FAAP, FACP, Internal Medicine
and Pediatrics, Yale School of Medicine, New Haven, CT
Dr Doolittle has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.
The authors of the current study address a vexing question
regarding pediatric patients with familial hypercholesterolemia.
Do statins really make a difference over the long term? Prior
studies had been of shorter duration—only 5 and 10 years—with
higher dropout and lower target LDL rates.1,2 Luirink et al also
elegantly address an important barrier. A 20-year randomized
controlled trial is neither feasible nor ethical in this population.
Instead, they have used the parents of affected children as the
ersatz control arm. For these parents, statins were unavailable
until much later in life. Furthermore, these children were com-
pared to their unaffected siblings.
The study findings suggest that long-term use of statins reduces
both cardiovascular events and mortality. Furthermore, even
though target LDL levels were achieved among only 20% of the
participants, the progression of carotid intima-media thickness
was similar to that of their siblings. Statin use—regardless of LDL
levels—appears to inhibit the formation of plaque on the endo-
vascular lining.3 Among adults, statin use is recommended based
on risk factors such as age, diabetes, smoking, systolic blood
pressure, and lipid levels, rather than lipid levels alone.4
The study findings raise a broader question: Are there other pop-
ulations, such as children with obesity or diabetes, who might
benefit from statin therapy in childhood? For example, ele-
vated lipid levels have been found in children who are obese.5
Similarly, accelerated atherosclerosis has been noted in children
with type 1 diabetes.6 Among children with familial hypercholes-
terolemia followed up for >20 years in the current study, there
was a dramatic benefit with no apparent side effects.
Bottom Line: Among children with familial hypercholesterolemia
who are at high risk, treatment with statins is associated with
reduced cardiovascular events and death compared to findings
in their parents.
References
1. 
Langslet G, et al. J Clin Lipidol. 2015;9(6):778–785; doi: 10.1016/j.jacl.2015.08.008
2. Carreau V, et al. Paediatr Drugs. 2011;13(4):267–275; doi:
10.2165/11591650-000000000-00000
3. 
Stancu C, et al. J Cell Mol Med. 2001;5(4):378–387
4. Eckel R, et al. J Am Coll Cardiol. 2014;63(25 PtB):2960–2984; doi: 10.1016/j.
jacc.2013.11.003
5. 
Freedman DS, et al. Pediatrics. 1999;103(6):1175–1182; doi: 10.1542/peds.103.6.1175
6. 
Margeirsdottir HD, et al. Diabetologia. 2008;51(4):554; doi: 10.1007/s00125-007-0921-8
15
GENERAL PEDIATRICS
Hypertrophic Cardiomyopathy:
Sudden Death After Exercise
Source: Weissler-Snir A, Allan K, Cunningham K, et al. Hypertrophic car-
diomyopathy-related sudden cardiac death in young people in Ontario.
Circulation. 2019;140(21):1706–1716; doi: 10.1161/CIRCULATIONAHA.119.040271
Investigators from the University of Toronto, Ontario, Canada,
conducted a retrospective study to determine the incidence
of sudden cardiac death (SCD) in young people with hypertro-
phic cardiomyopathy (HCM) and evaluate the role of exercise
in HCM-SCD. For the study, they identified cases of HCM-SCD in
Ontario, Canada, occurring between 2005 and 2011 among indi-
viduals 10–45 years old, as confirmed by means of autopsy at the
Office of the Chief Coroner for Ontario (OCCO). OCCO maintains
a centralized database and includes information about all sud-
den deaths attended by the coroner in the province. A diagnosis
of HCM as the cause of SCD was considered definite when the
autopsy findings included marked cardiomyocyte hypertrophy
with pleomorphic to bizarre nuclei and myofiber disarray. Cases
with other findings consistent with HCM, but no myofiber dis-
array, were classified as possible HCM-SCD. Sudden deaths in
individuals with known HCM, but in whom no autopsy was per-
formed, were categorized as probable HCM-SCD. The incidence of
HCM-SCD among the at-risk population was estimated by using
Ontario census data and assuming a prevalence of HCM of 1:500.1
To assess the role of exercise in HCM-SCD, the authors reviewed
the death investigation review conducted by the coroner in each
autopsied case and categorized the activity level at the time
of death as being during sleep, at rest, during light activity, or
during moderate or vigorous exercise.
During the study period, 44 definite, 3 probable, and 6 possible
cases of HCM-SCD were identified. Based on an estimate of the
population at risk, the incidence of definite HCM-SCD was cal-
culated as 0.31 per 1,000 HCM person years (95% CI, 0.24–0.44).
Including probable and possible cases increased the estimated
incidence to 0.38 per 1,000 HCM person years (95% CI, 0.28–
0.49). The median age of individuals with HCM-SCD confirmed
by means of autopsy was 35.5 years (interquartile range, 26–42
years), and 83% were male; 70% of cases occurred in individuals
without prior diagnosed HCM. Overall, 34% of cases occurred at
rest, 30% during sleep, 17% during light activity, and 17% during
or immediately after moderate or vigorous activity. However,
among those ≤20 years, 77.4% of cases of HCM-SCD were asso-
ciated with moderate or vigorous activity versus 4.8% in older
victims.
The authors conclude that HCM-SCD is uncommon in the popula-
tion at risk and infrequently related to exercise, at least in older
individuals.
16
COMMENTARY BY
Esther K. Chung, MD, MPH, FAAP, Pediatrics, University of
Washington School of Medicine and Seattle Children’s Hospital,
Seattle, WA
Dr Chung has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.
Every summer, general pediatric offices await the influx of sports
physical examination forms that document the preparticipation
physical examination (PPE) required by most states.2 The pedi-
atrician who signs the bottom of a PPE form, even if only for a
fleeting second, bears the burden of wondering whether this will
be the rare child who experiences SCD from undiagnosed HCM
while participating in sports.
The current investigators sought to describe the incidence of HCM-
SCD and its association with exercise in a large, unselected eth-
nically diverse “young” population, ranging from 10–45 years old.
In comparison to HCM-SCD occurring in those >20 years, HCM-SCD
occurring in those ≤20 years was much more likely to be associated
with exercise (77.8% vs 4.8%; P <.001). Although the authors con-
clude that HCM-SCD was infrequently related to exercise in older
patients, it was frequently related to exercise in young patients.
The authors found that the annual HCM-SCD incidence for the
study population was low. Pediatricians should take heart know-
ing that most deaths occurred in those with previously undi-
agnosed HCM, a diagnosis that is often difficult to make in the
absence of a positive family history.3 Only 25.1% of those with
HCM, a prevalent autosomal dominant disorder,1 have a known
affected first- or second-degree relative, according to recent
findings from an international registry.3 Promising advances in
recent years, including cascade screening, make it increasingly
easier to diagnose and treat HCM.4,5
Bottom Line: The overall incidence of HCM-SCD in individuals
10–45 years old is low. Although HCM-SCD is infrequently asso-
ciated with exercise in patients >20 years, nearly 80% of HCM-
related SCDs among those ≤20 years are associated with exercise.
EDITORS’ NOTE
Previous studies, specifically in young athletes, also reveal a
low incidence of SCD. (See AAP Grand Rounds. 2018;40[5]:58.6)
Although HCM is the predominant cause, anomalous origin of
the coronary arteries, myocarditis, and arrhythmogenic right
ventricular cardiomyopathy have been reported.6
References
1. Maron BJ, et al. Circulation. 1995;92(4):785–789
2. Caswell SV, et al. Pediatrics. 2015;135(1):26–32; doi: 10.1542/peds.2014-1451
3. Neubauer S, et al. J Am Coll Cardiol. 2019;74(19):2333–2345; doi: 10.1016/j.
jacc.2019.08.1057
4. Houston BA, et al. Clin Med Insights Cardiol. 2015;8(suppl 1):53–65; doi: 10.4137/CMC.
S15717
5. Knight LM, et al. Heart Rhythm. 2020;17(1):106–112; doi: 10.1016/j.hrthm.2019.06.015
6. Malhotra A, et al. N Engl J Med. 2018;379(6):524-534; doi: 10.1056/NEJMoa1714719
aapgrandrounds.org
NEPHROLOGY
UTI Relapse in Children With Resistant Uropathogens
Source: Hyun HS, Kim JH, Cho MH, et al. Low relapse rate of urinary tract
infections from extended-spectrum beta-lactamase-producing bacteria
in young children. Pediatr Nephrol. 2019;34(11):2399–2407; doi: 10.1007/
s00467-019-04298-4
Investigators from multiple Korean institutions conducted a ret-
rospective cohort study to identify risk factors for and outcomes
with extended-spectrum β-lactamase (ESBL) UTIs among children.
Children ≤24 months of age who presented to the study hospital
between 2010 and 2016 and received a diagnosis of a febrile UTI
caused by gram-negative bacteria were eligible. Febrile UTI was
defined as fever, pyuria, and a single pathogen titer of >50,000 col-
ony-forming units per milliliter obtained via urinary catheteriza-
tion. Child demographic and clinical characteristics (eg, presence
of underlying disease such as urinary tract abnormalities, history
of hospitalization or UTI, antibiotic use within previous 3 months,
and technetium 99m dimercaptosuccinic acid [DMSA] scan results)
were obtained from the medical record.
The primary exposure variable was antibiotic susceptibility, clas-
sified as ESBL (ie, resistant to β-lactam antibiotics) or non-ESBL
(ie, susceptible to β-lactam antibiotics). The primary outcome
was UTI relapse, defined as a UTI caused by the same patho-
gen as a previous infection within 2 weeks of the completion of
treatment. Demographic and clinical characteristics were com-
pared between ESBL and non-ESBL groups. Multivariable regres-
sion analyses were used to assess the independent associations
between ESBL status, clinical characteristics, and the primary
outcome after controlling for potential confounders.
There were 845 participants who met eligibility criteria. Overall,
17.3% (n=146) had ESBL-producing bacteria, and 1% (n=12) had a
UTI relapse. Among the ESBL group, 75% (n=109) received initial
antibiotic therapy to which the causative agent was not suscepti-
ble. Among these, 49 were switched to susceptible therapy, with
some (n=11) switched because of persistent fever (>48 hours).
Among all participants, a history of antibiotic use (adjusted haz-
ard ratio [aHR], 2.9; 95% CI, 1.9–4.5) and underlying disease (aHR,
1.6; 95% CI, 1.0–2.7) were associated with development of ESBL
UTI. Among those who had UTI relapse, a history of hospitaliza-
tion (aHR, 4.0; 95% CI, 1.2–12.9) and the presence of a cortical
defect on DMSA scans (aHR, 8.6; 95% CI, 1.1–70.3) were associ-
ated with UTI relapse. There was no significant difference in UTI
relapse rates among participants with ESBL UTI who received ini-
tial or eventual susceptible therapy (2.3%) and participants with
ESBL UTI who continued with nonsusceptible therapy (3.3%).
The investigators conclude that nearly 20% of UTIs in children
≤24 months were caused by ESBL-producing bacteria that may
necessitate switching to different antibiotic therapy from what
was initially prescribed.
• February 2020
TM
COMMENTARY BY
Cheryl P. Sanchez-Kazi, MD, FAAP, FASN, CCD, Pediatric
Nephrology, Loma Linda University Children’s Hospital, Loma
Linda, CA
Dr Sanchez-Kazi has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.
The global spread of multidrug-resistant UTI due to ESBL-producing
gram-negative organisms is increasing.1 Previous reports and the
current study show that the risk factors for ESBL UTI in children
include recent antibiotic use or hospitalization within 1–3 months,
previous history of UTI, urinary tract abnormalities, clean intermit-
tent catheterization, and long history of antibiotic prophylaxis.2–6
A strength of the current study is the selection of children 0–24
months old. Bowel and bladder dysfunction, which is common in
children with UTI, does not yet play a significant role in this age
group. Participants in the study came from one geographic loca-
tion, which may limit the generalization of the authors’ findings.
However, multiple retrospective studies in different countries also
reported similar risk factors for ESBL UTI, including the most com-
mon ESBL pathogens, Escherichia coli and Klebsiella species.4
There were no differences in UTI relapse between children with and
those without ESBL UTI, even if there was a change in antibiotic
because of resistance or persistent fever. It would have been help-
ful if the authors also had included the length of hospitalization
in their report; other studies have shown a longer stay in patients
with ESBL UTI, thereby increasing the cost of treatment.2,4 In the cur-
rent study, overall clinical symptoms did not differ, including time
to defervescence or degree of pyuria. An independent risk factor to
relapse in both ESBL and non-ESBL UTI is the presence of acute cor-
tical defects on DMSA scans, which may suggest that parenchymal
involvement may require longer therapy. It is reassuring to know
that development of renal scars was similar in both groups.
Bottom Line: The risk of UTI relapse in ESBL infection is low
with appropriate antibiotic therapy. (See AAP Grand Rounds.
2019;42[5]:53.7)
EDITORS’ NOTE
This study is a sober reminder of the ubiquitous threat of ESBL-
producing bacteria. Moreover, the paucity of follow-up DMSA
scans in study patients does not induce complacency regarding
ultimate renal outcome.
References
1. Mahony M, et al. Pediatr Nephrol. Published online ahead of print August 15, 2019;
doi: 10.1007/s00467-019-04316-5
2. Albaramki JH, et al. Pediatr Int. 2019;61(11):1127–1132; doi: 10.1111/ped.1391
3. Uyar Aksu N, et al. Pediatr Int. 2017;59(2):176–180; doi: 10.1111/ped.13112
4. Flokas ME, et al. J Infect. 2016;73(6):547–557; doi: 10.1016/j.jinf.2016.07.014
5. Hanna-Wakim RH, et al. Front Cell Infect Microbiol. 2015;5:45; doi: 10.3389/
fcimb.2015.00045
6. Madhi F, et al. PLoS One. 2018;13(1):e0190910; doi: 10.1371/journal.pone.0190910
7. Shaikh N, et al. JAMA Pediatr. Published online ahead of print August 5, 2019; doi:
10.1001/jamapediatrics.2019.2504
17
EMERGENCY MEDICINE
Getting Specific About Urine Specific Gravity
Source: Shaikh N, Shope MF, Kurs-Lasky M. Urine specific gravity and
the accuracy of urinalysis. Pediatrics. 2019;144(5):e20190467; doi: 0.1542/
peds.2019-0467
Investigators from the University of Pittsburgh conducted a ret-
rospective analysis to determine whether urine specific gravity
(SG) affects the accuracy of other components of the urinalysis.
Children <24 months of age with a visit to the study ED between
2007 and 2013 were eligible if they underwent bladder catheter-
ization and had an automated urinalysis and urine culture per-
formed within 3 hours of each other. Children with genitourinary
anomalies were excluded.
Investigators evaluated the accuracy of urinalysis components
used for diagnosis of UTI by comparing the positive likelihood
ratios (LRs) in dilute versus concentrated urine samples. Dilute
urine samples were defined as those with an SG <1.015, and con-
centrated samples were defined as those with an SG ≥1.015. UTI
was defined as ≥100,000 colony-forming units (CFUs) per millili-
ter of a uropathogen from specimens obtained via clean catch
or ≥50,000 CFU/mL from specimens obtained via catheterization.
Urinalysis components evaluated included leukocyte esterase
(LE; a positive test defined as ≥1), nitrite, white blood cell count
(WBC) per high-power field (hpf; a positive test defined as ≥5),
WBC/mm3 (a positive test defined as ≥10), bacteria/hpf (a posi-
tive test defined as ≥ few), and bacteria on Gram-stain (a positive
test defined as ≥ any). Investigators also used predictive models
to calculate how many children would be overtreated or missed
with and without SG being used in the interpretation of other
urinalysis components.
There were 10,078 children included in analysis. Of these, 39.4%
(n=3,966) had concentrated urine, and, overall, 6.1% had a UTI
(n=617). The positive LRs for LE and bacteria/hpf (ie, their abil-
ity to rule in UTI) were similar in dilute and concentrated urine.
However, WBC/hpf and WBC/mm3 had lower LRs in concentrated
(vs dilute) urine, and nitrite and bacteria on Gram stain had
higher LRs. Despite this finding, there was no change in predic-
tive models for the number of children overtreated or missed
with or without inclusion of SG in combination with urinalysis
components.
The investigators conclude that SG influences the accuracy of
some components of the urinalysis but that inclusion of SG in
decision-making would result in little change to clinical practice.
18
COMMENTARY BY
Kirsten A. Bechtel, MD, FAAP, Pediatric Emergency Medicine, Yale
School of Medicine, New Haven, CT
Dr Bechtel has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.
UTIs are common bacterial infections in the pediatric population.1
An uncontaminated sample of urine for urinalysis and culture is
generally required before starting any presumptive antimicro-
bial treatment. The urinalysis serves as the necessary screening
test to determine the need to start empiric antibiotics, espe-
cially if pyuria and bacteriuria are present.2 Despite the wide-
spread use of urinalyses by clinicians to make the presumptive
diagnosis of UTI, urine SG has not previously been incorporated
into their interpretation. For example, the urine SG has not been
considered during the evaluation of febrile infants who are at
the highest risk for UTI.3 (See AAP Grand Rounds. 2018;39[4]:39.4)
The urinalysis alone is sensitive and specific for infants <60 days,
irrespective of urine concentration. The UTI Calculator (https://
uticalc.pitt.edu/) uses a combination of demographic informa-
tion, the presence of LE and nitrites, and degree of pyuria and
bacteriuria to determine the likelihood of a UTI.5 Urine SG is not
used in this diagnostic model.
The results of a recent study suggested that the diagnostic test
characteristics of the urine dipstick and microscopic pyuria for
the diagnosis of UTI may vary substantially by urine concentra-
tion.6 The clinical significance of these findings, such as how they
might affect clinical decision-making regarding the likelihood
of a UTI based on urine SG, was not a focus of this study. The
current study, however, does address this question. Shaikh et al
demonstrate that although urine SG may affect test characteris-
tics of components of the urinalysis such as LE and the degree
of pyuria, it does not affect the overall clinical decision-making
for the presence of a UTI for children >3 months.
Bottom Line: One can rely on the positivity of LE and nitrites, or
the degree of pyuria and bacteriuria, irrespective of the urine
concentration, when considering the likelihood of a UTI in young
children.
References
1. Korbel L, et al. Paediatr Int Child Health. 2017;37(4):273–279; doi:
10.1080/20469047.2017.138204
2. AAP Subcommittee on Urinary Tract Infection. Pediatrics. 2016;138(6):e20163026; doi:
10.1542/peds.2016-3026
3. Shaw KN, et al. Pediatr Clin North Am. 1999;46(6):1111–1124, vi
4. Tzimenatos L, et al. Pediatrics. 2018;141(2):e20173068; doi: 10.1542/peds.2017-3068
5. Shaikh N, et al. JAMA Pediatr. 2018;172(6):550–556; doi: 10.1001/
jamapediatrics.2018.0217
6. Chaudhari PP, et al. Ann Emerg Med. 2017;70(1):63–71.e8; doi: 10.1016/j.
annemergmed.2016.11.042
aapgrandrounds.org
GENERAL PEDIATRICS
Safe Infant Sleep Practices
Source: Hirai AH, Kortsmit K, Kaplan L, et al. Prevalence and factors asso-
ciated with safe infant sleep practices. Pediatrics. 2019;144(5):e20191286;
doi: 10.1542/peds.2019-1286
Investigators from several federal agencies conducted a study
to assess compliance with AAP safe sleep recommendations
among US infants. Study data were abstracted from the 2016
Pregnancy Risk Assessment Monitoring System (PRAMS) survey.
PRAMS is a population-based survey conducted by the CDC of
mothers with recent live births from 39 states. Only data from
states with a 55% response rate were included in the analyses.
Results are weighted to provide representative data from the
included states. For the current study, maternal responses on
4 specific infant safe sleep practices recommended by the AAP
were assessed: (a) back sleep position, (b) separate approved
sleep surface, (c) room sharing without bed sharing, and (d) no
soft objects or loose bedding. Responses from several questions
were used to derive outcomes for each of these items. In addi-
tion, respondents were asked if they received advice on each of
these sleep practices from a doctor, nurse, or other health care
professional. Regression analysis was used to assess the effect
of receipt of health care professional advice on sleep practices.
Data on mother-infant dyads from 29 states met the 55%
response rate criterion and were included in the analyses. The
weighted mean age of study infants was 4.1 months, and 97.4%
were ≤6 months at the time of the survey. Overall, the weighted
estimate of back sleeping was 78.0% (95% CI, 77.3%–78.7%);
57.1% (95% CI, 56.2%–57.9%) reported room sharing without bed
sharing, 42.4% (95% CI, 41.6%–43.3%) of infants had no soft or
loose bedding, and 31.8% (95% CI, 30.9%–32.6%) always or often
slept on approved surfaces. Maternal report of receiving advice
for specific safe sleep practices from health care professionals
were 92.6% (95% CI, 92.1%–93.0%) for back sleeping, 83.5% (95%
CI, 82.8%–84.2%) for sleeping on recommended surfaces, 85.0%
(95% CI, 84.3%–85.6%) for not sleeping with soft objects or loose
bedding, and 48.8% (95% CI, 47.9%–49.7%) for room sharing with-
out bed sharing. Maternal report of receiving advice on each of
these practices was associated with increased likelihood that
the safe sleep practice was used by the mother.
The authors conclude that rates of use of safe sleep practices are
suboptimal. Advice from health care professionals is important
in increasing use of these sleep practices.
• February 2020
TM
COMMENTARY BY
Mike Dubik, MD, FAAP, Pediatrics, Portsmouth, VA
Dr Dubik has disclosed no financial relationship relevant to this commentary. This commentary does
not contain a discussion of an unapproved/investigative use of a commercial product/device.
Infants should be put to sleep on their backs, on firm surfaces,
without any soft bedding, and in the same room but not the
same bed as their parents or other caregivers.1
Sociodemographic variation in the current study was interesting.
For example, back sleep position was highest among non-His-
panic American Indians or Alaska natives (85.3%), and room
sharing without bed sharing was highest among Hispanic care-
givers (61.8%). As if smoking alone were not enough of a risk fac-
tor, current maternal smoking was associated with 23% reduced
use of separate approved sleep surfaces. Current breastfeeding
mothers were also less likely to use approved sleep surfaces
(22%).
Variation by state has been noted previously1: The highest
rate of back sleep position was in Iowa (87.7%) and the lowest
in Louisiana (67.4%), and room sharing without bed sharing
was highest in Delaware (65.5%) and lowest in Alaska (46.8%).
However, the study was limited to 29 states, leaving out California
and the entire Southeastern United States, which has some of
the highest sudden unexpected infant death rates.2
Consistent with findings from other studies,3 it is clear that safe
sleep practices are suboptimal and that there are plenty of—as
the authors put it—“improvement opportunities,” including bet-
ter clinician advice.
Bottom Line: Remember to recommend the AAP guidelines for
safe infant sleeping.
References
1. AAP Task Force on Sudden Infant Death Syndrome. Pediatrics. 2016;138(5):e20162938;
doi: 10.1542/peds.2016-2938
2. Erck Lambert AB, et al. Pediatrics. 2016;141(3):e20173519; doi: 10.1542/peds.2017-3519
3. Colson ER, et al. JAMA Pediatr. 2013;167(11):1032–1037; doi: 10.1001/
jamapediatrics.2013.2560
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19
ADOLESCENT MEDICINE
Oral HPV and Vaccination Among
Female Adolescents
Source: Schlecht NF, Masika M, Diaz A, et al. Risk of oral human papillo-
mavirus infection among sexually active female adolescents receiving the
quadrivalent vaccine. JAMA Netw Open. 2019;2(10):e1914031; doi: 10.1001/
jamanetworkopen.2019.14031
Investigators from multiple institutions in New York state con-
ducted a prospective study to assess the prevalence of oral HPV
among sexually active female adolescents and evaluate the
effect of quadrivalent HPV vaccine on oral HPV. Study partici-
pants were sexually active female adolescents, 13–21 years old,
receiving care at a large adolescent clinic in New York City. Study
participants completed a questionnaire detailing their sexual
history, including age at initiation of sexual activity, number
of partners, and types of sexual activity. The participants pro-
vided an oral rinse sample that was tested for >40 HPV types.
Study outcomes included the presence of any type of HPV in oral
samples, prevalence of oncogenic HPV types, and prevalence of
HPV types included in the quadrivalent vaccine (HPV-6, HPV-11,
HPV-16, and HPV-18). A Fisher exact test was used to compare the
prevalence of vaccine HPV types among participants who had
received ≥1 dose of vaccine to that of those who were unvac-
cinated; an additional logistic regression analysis was used to
adjust for confounders. Regression analysis was also used to
assess the association between oral HPV and time since first
sexual activity.
Oral rinse samples were collected in 1,259 female adolescents
with a median age of 18 years (age range, 13–21 years). Overall,
50.7% of participants were African American and 45.2% were of
Hispanic ethnicity. At the time of enrollment, 69.7% reported
having ≥3 sexual partners; the median age of first sexual activity
among participants was 14.8 years, and 92.2% reported having
oral sex. HPV was detected in oral rinse samples from 78 par-
ticipants (6.2%; 95% CI, 4.9%–7.7%), with an oncogenic HPV type
detected in 21 (1.7%; 95% CI, 1.0%–2.5%) and an HPV vaccine type
detected in 8 (0.6%; 95% CI, 0.3%–1.3%). The rate of oral HPV
decreased with increasing time since first sexual activity (OR,
0.45; 95% CI, 0.21–0.96, when comparing rates of oral HPV in par-
ticipants who engaged in sex for ≥4 years to those whose first
sexual activity was <1 year before testing). At enrollment, 15.3%
of participants had not received any doses of the quadrivalent
HPV vaccine. Rates of vaccine type HPV were detected in 2 of 192
female adolescents who were not vaccinated versus 1 of 1,067 in
those with ≥1 vaccine doses (P=.06). After adjusting for age and
years since first sexual activity, receipt of HPV vaccine was inde-
pendently associated with a decreased risk of vaccine type oral
HPV (OR, 0.20; 95% CI, 0.04–1.00).
The authors conclude that oral HPV is not uncommon in sexu-
ally active female adolescents and that HPV vaccination reduces
detection of vaccine type HPV in oral samples.
20
COMMENTARY BY
Charlene Wong, MD, FAAP, Duke Children’s Health and Discovery
Initiative, Duke-Margolis Center for Health Policy, Duke University,
Durham, NC
Dr Wong has disclosed no financial relationship relevant to this commentary. This commentary does
not contain a discussion of an unapproved/investigative use of a commercial product/device.
Most sexually active people become infected with HPV at least
once in their lifetime.1 The current investigators identified a
prevalence of 6.2% for oral HPV in a large urban clinic site. They
also linked cervical HPV infection with oral HPV infection, the lat-
ter of which can progress to precancerous conditions and even-
tually invasive squamous cell carcinoma of the head and neck.2
HPV can be cleared, with the current study demonstrating that
almost no oral HPV remained for >12 months.
At least 1 dose of the quadrivalent HPV vaccine was associated
with lower rates of vaccine type oral HPV. Current vaccine rec-
ommendations are for 2 HPV vaccine doses if the first dose is
administered before age 15 years, though national rates of HPV
vaccine coverage remain suboptimal, with only approximately
one-half of adolescents being up to date on this vaccine.3
Strengths of the current study include a study population of
minority girls and women, who are underrepresented in epidemi-
ological and vaccine studies, and the pragmatic and longitudinal
study design. A key limitation is that almost all recruited partici-
pants (84.7%) had received at least 1 dose of the quadrivalent HPV
vaccine, resulting in poorly balanced vaccinated versus unvacci-
nated groups. Additionally, men were not recruited, and the can-
cer consequences of oral HPV are greater for men than for women.4
Generalizability is also limited by recruitment at a single clinical
site that provides care at no out-of-pocket cost to patients.
Bottom Line: Oral HPV is not uncommonly detected in sexually
active female adolescents. Adolescents with at least 1 dose of
the quadrivalent HPV vaccine have lower rates of oral HPV infec-
tion. (See AAP Grand Rounds. 2019;41[4]:47.5)
EDITORS’ NOTE
If, as we suspect, the study findings are duplicated in male ado-
lescents, it will “provide yet another reason to vaccinate adoles-
cent boys and young men against HPV.”6
References
1. Satterwhite CL, et al. Sex Transm Dis. 2013;40:187–193; doi: 10.1097/
OLQ.0b013e318286bb53
2. Chaturvedi A, et al. J Clin Oncol. 2011;29(32):4294–4301; doi: 10.1200/JCO.2011.36.4596
3. Walker TY, et al. MMWR Morb Mortal Wkly Rep. 2019;68:718–723; doi: 10.15585/mmwr.
mm6833a2
4. American Cancer Society. Cancer Facts & Figures 2019. https://www.cancer.org/
content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-
and-figures/2019/cancer-facts-and-figures-2019.pdf. Accessed January 2020
5. Dixon BE, et al. Pediatrics. 2019;143(1):e20181457; doi: 10.1542/peds.2018-1457
6. Katzenellenbogen RA, et al. JAMA Netw Open. 2019;2(10):e1914038; doi: 10.1001/
jamanetworkopen.2019.14038
aapgrandrounds.org
HEMATOLOGY/ONCOLOGY
Late Infections in Survivors of
Childhood Leukemia
Source: Pelland-Marcotte MC, Pole JD, Hwee J, et al. Long-term risk of infec-
tions after treatment of childhood leukemia: a population-based cohort
study using administrative health data. J Clin Oncol. 2019;37(29):2651–
2660; doi: 10.1200/JCO.19.00570
Investigators from the University of Toronto and The Hospital for
Sick Children, Toronto, Canada, conducted a retrospective cohort
study to assess the rate of infections in survivors of childhood leu-
kemia. Study participants were Ontario, Canada, residents <18 years
old with acute lymphoblastic leukemia (ALL) or acute myeloid leu-
kemia (AML) diagnosed between 1992 and 2015 who survived with-
out relapse at least 30 days beyond the completion of treatment.
Data on these children were identified using the Pediatric Oncology
Group of Ontario Networked Information System registry. Using
Ontario Health Insurance Plan databases, the authors matched
each leukemia survivor 5:1 on year of birth, sex, and location of res-
idence (rural or urban) to control subjects. Provincial and national
databases were used to identify diagnoses of infectious diseases,
hospitalizations for infections, and deaths related to infections in
survivors of leukemia and their matched controls beginning 30 days
after last treatment for ALL or AML (index date). Regression analyses
were used to determine the adjusted relative risk (aRR) for infec-
tions, or hospitalization for infection, among children who were
treated for leukemia; age, sex, location of residence, family income,
and presence of Down syndrome were included in the models. The
hazard ratio (HR) for deaths related to infection was also calculated.
Subgroup analyses including those with ALL or AML, with or with-
out hematopoietic stem cell transplantation (HSCT), and time from
index date (<1 year, 1–4.99 years, 5+ years) were also conducted.
Data were analyzed on 2,204 survivors of leukemia and 11,020
controls. The median age of study participants at the index date
was 8 years, and median follow-up was 7.2 years for survivors of
leukemia and 9.7 years for controls. The rate of infections was
significantly higher in survivors of leukemia than in controls
(aRR, 1.50; 95% CI, 1.44–1.56) and was significantly higher during
each time period. For the entire study period, rates of blood and
central nervous system infections were the most common types
of infections in subjects compared to controls (aRR, 4.06; 95% CI,
3.09–5.33). Rates of infection were significantly higher in patients
with either ALL or AML than in controls (aRR, 1.46; 95% CI, 1.40–
1.53 and aRR, 1.54; 95% CI, 1.39–1.71, respectively) and in those
with or without treatment with HSCT. Rate of hospitalization for
infections was also significantly higher in survivors of leukemia
than in controls at <1 year and 1–4.99 years after the index date
but not after 5+ years (RR, 1.56; 95% CI, 0.55–2.56). There were 28
deaths from infection in the study cohort; the risk of death from
infection was significantly higher in all survivors of leukemia
than in controls (HR, 149.3; 95% CI, 20.4–1,091.9) and in survivors
who did not receive HSCT (HR, 92.7; 95% CI, 12.4–609.7).
The authors conclude that children surviving after treatment for
ALL and AML are at long-term increased risk for infections.
• February 2020
TM
COMMENTARY BY
Mary-Jane Staba Hogan, MD, MPH, FAAP, Pediatric Hematology/
Oncology, Yale School of Medicine, New Haven, CT
Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.
Immune dysfunction resulting from persistently decreased T
cells or lymphocyte subsets after leukemia treatment comple-
tion lasts for up to 6 months or longer.1 In the United States and
Canada, survivors of childhood cancer are approximately 2 times
more likely to be hospitalized for infection than are age- and
sex-matched controls.2 Types of infections encountered in survi-
vors of leukemia include respiratory tract infections in 9.9%–72%
and UTIs in 2.9%–19.8%.3 Identified organisms include bacteria
in 3.9%–38.5%, fungi in 16.1%–66.7%, and viruses in 16.1%–66.7%,
with viral hepatitis affecting 0.8%–75.4% of survivors of leuke-
mia.3 Associated risk factors for infectious complications con-
tributing to morbidity and mortality during survivorship from
any cancer include exposure to total body irradiation, HSCT,
graft-versus-host disease, splenectomy, and splenic radiation.4
Limitations of the current study include selection bias of a pre-
dominantly white and urban cohort in which comorbidities and
vaccination rates or seroconversion statuses5 were not investi-
gated. To date, there are still unknown immunologic late effects
of more recent treatment protocols involving immunotherapy
and a reduction of irradiation. The Children’s Oncology Group
Long-Term Follow-Up Guidelines for Survivors of Childhood,
Adolescent, and Young Adult Cancers recommends that all survi-
vors receive pneumococcal, meningococcal, Haemophilus influ-
enzae, HPV,5 and hepatitis A and B vaccinations based on various
studies.6
Bottom Line: Survivors of childhood leukemia are at signifi-
cant risk for infections years after completion of therapy and
may benefit from more prompt intervention when febrile and
ill-appearing.
References
1. Perkins JL, et al. Cancer. 2014;120(16):2514–2521; doi: 10.1002/cncr.28763
2. Kurt BA, et al. Pediatr Blood Cancer. 2012;59:126–132; doi: 10.1002/pbc.24017
3. Pelland-Marcotte MC, et al. Leuk Lymph. 2019;60(9):2104–2114; doi:
10.1080/10428194.2019.1573369
4. Weil BR, et al. J Clin Onc. 2018;36(16):1571–1578; doi: 10.1200/JCO.2017.76.1643
5. Klosky JL, et al. J Clin Onc. 2017;35(31):3582–3590; doi: 10.1200/JCO.2017.74.1843
6. Children’s Oncology Group. Long-Term Follow-Up Guidelines for Survivors of
Childhood, Adolescent, and Young Adult Cancers. www.survivorshipguidelines.org.
Accessed January 2020
21
CARDIOLOGY
Brain Injury and Critical Congenital Heart Disease
Source: Claessens NHP, Chau V, de Vries LS, et al. Brain injury in infants
with critical congenital heart disease: insights from two clinical cohorts
with different practice approaches. J Pediatr. 2019;215:75–82.e2; doi:
10.1016/j.jpeds.2019.07.017
Investigators from Wilhelmina Children’s Hospital, Utrecht,
Netherlands, and The Hospital for Sick Children, Toronto, Canada,
conducted a prospective observational cohort study of infants
with critical congenital heart disease (CHD) to assess prevalence
of and risk factors for acquired brain injury after cardiac surgery.
Children with critical CHD who underwent open heart surgery
with cardiopulmonary bypass (CPB) at ≤60 days after birth at the
2 study hospitals from 2016 to 2017 were included. Demographic
characteristics were collected at baseline.
The primary predictor variables included pre- and postoperative
clinical characteristics, including CHD lesion, Apgar score, deliv-
ery mode, gestational age, balloon atrioseptostomy, postoper-
ative low cardiac output syndrome (LCOS; defined as lactate >4
and pH <7.30), duration of CPB, surgery duration, selective cere-
bral perfusion (SCP), and delayed sternal closure. The primary
outcomes were preoperative and new or extended postoperative
brain injury, as determined by means of brain MRI performed
according to clinical protocol. Brain injury was classified as hem-
orrhagic, cerebral sinovenous thrombosis, or ischemic. Ischemic
brain injury was further classified as focal, defined as a single
white matter lesion or stroke, or multifocal. Investigators deter-
mined the prevalence of preoperative and postoperative brain
injury and used multivariable logistic regression models to
determine the independent association of predictors with out-
comes after adjusting for potential confounders.
There were 124 infants included. The most common CHD lesion
was transposition of the great arteries with an intact ventricular
septum (n=45); the second most common was single-ventricle
physiology with aortic arch obstruction. Among the 100 infants
who had undergone preoperative MRI, 30% had ischemic injury,
57% had parenchymal injury, and 4% had sinovenous thrombosis.
Among the 120 infants who had undergone postoperative MRI,
51% had new ischemic injury, 21% had new or extended hemor-
rhagic injury, and 12% had new or extended sinovenous throm-
bosis. In multivariable analyses, single-ventricle physiology with
aortic arch obstruction (adjusted OR [aOR], 3.5; 95% CI, 1.1–12.0)
and LCOS (aOR, 4.6; 95% CI, 1.4–15.4) were associated with pre-
operative multifocal ischemic injury; balloon atrioseptostomy
(aOR, 3.2; 95% CI, 1.1–9.7) was associated with preoperative focal
ischemic injury. LCOS and SCP were significantly associated with
postoperative multifocal and focal ischemic injury, respectively.
The investigators conclude that brain injury is common in infants
with critical CHD.
22
COMMENTARY BY
David Spar, MD, FAAP, Pediatric Cardiology, University of
Cincinnati, Cincinnati, OH
Dr Spar has disclosed no financial relationship relevant to this commentary. This commentary does
not contain a discussion of an unapproved/investigative use of a commercial product/device.
CHD occurs in 3 in 1,000 children, and in these children neuro-
developmental disabilities and psychosocial issues occur in at
least 50% of those requiring surgical correction.1 Cerebral isch-
emia before, during, and after surgical repair of CHD has been
proposed to be the primary mechanism of central nervous sys-
tem injury, though additional factors may contribute to neuro-
logical dysfunction.2 Injury can occur prenatally, perioperatively,
and post-discharge. Prenatal, fetal, and postnatal MRI have
identified a high incidence of white matter injury, stroke, and
hemorrhage.3 Microcephaly occurs in 25% of neonates with CHD.4
Fetuses with hypoplasia of the aortic arch have the most reduced
brain growth during the third trimester of gestation.2 After birth,
white matter injury has been demonstrated in infants with hypo-
plastic left heart syndrome and daily decreases in cerebral oxy-
gen saturations between birth and time of surgery.2 This has also
been demonstrated in infants with dextro-transposition of the
great arteries as the timing from birth to surgery increases.5
There are many factors that may contribute to central nervous
system injury during surgical repair. To date, besides having a
higher hematocrit during CPB, there are no clear interventions
that have been shown to improve neurodevelopmental out-
comes.2 The postoperative period is a time when decreased
cerebral oxygen delivery may occur secondary to low cardiac
output, hypoxemia, and anemia. Cerebral autoregulation may
also be impaired during this period.5,6 Postoperative hypoten-
sion has been shown to correlate with white matter injury,7 and
length of stay has also been shown to be an independent risk
factor for worse cognitive outcome.8
The current investigators reviewed data on 124 participants from
2 institutions over a 2-year period. They included infants under-
going CPB who underwent MRI before and after surgery. Ischemic
brain injury was most common. Preoperative injury did not
increase the risk of new postoperative injury. Both preoperative
and postoperative multifocal injury were associated with LCOS.
Bottom Line: Brain injury is common in neonates with critical
CHD undergoing surgical repair.
References
1. Wernovsky G. Cardiol Young. 2006;16(suppl 1):92–104; doi: 10.1017/S1047951105002398
2. Wernovsky G, et al. Neurodevelopmental and psychosocial outcomes in children and
young adults with complex congenital cardiac disease. In: Anderson RH, et al, eds.
Anderson’s Pediatric Cardiology. 4th ed. New York, NY: Elsevier; 2020
3. Mahle WT, et al. Circulation. 2002;106(12 suppl 1):109–114
4. Miller SP, et al. N Engl J Med. 2007;357(10):1928–1938
5. Petit CJ, et al. Circulation. 2009;119:709–716; doi: 10.1056/NEJMoa067393
6. Bassan H, et al. Pediatr Res. 2005;57(1):35–41; doi: 10.1203/01.PDR.0000147576.84092.F9
7. Galli KK, et al. J Thorac Cardiovasc Surg. 2004;127(3):692–704; doi: 10.1016/j.
jtcvs.2003.09.053
8. Newburger JW, et al. J Pediatr. 2003;143(1):67–73; doi: 10.1016/S0022-3476(03)00183-5
aapgrandrounds.org
CRITICAL CARE
Outcomes in Pediatric Respiratory
Distress Syndrome After Trauma
Source: Killien EY, Huijsmans RLN, Ticknor IL, et al. Acute respiratory dis-
tress syndrome following pediatric trauma: application of Pediatric Acute
Lung Injury Consensus Conference criteria. Crit Care Med. 2020;48(1):e26–
e33; doi: 10.1097/CCM.0000000000004075
Investigators at multiple institutions conducted a retrospective
cohort study to assess the incidence, severity, and outcomes
of pediatric acute respiratory distress syndrome (PARDS) after
trauma. Participants were eligible if they were ≤17 years old and
were admitted with traumatic injury to a level 1 pediatric trauma
center in Seattle, WA, between 2009 and 2017. Eligible partici-
pants were identified using the trauma center’s registry.
The primary exposure variable was PARDS, defined as those who
met complete Pediatric Acute Lung Injury Consensus Conference
criteria within 7 days after injury as determined through chart
reviews. PARDS was further categorized as mild, moderate, or
severe based on the oxygenation index or oxygenation satu-
ration index at the time of PARDS onset. The primary outcome
was in-hospital mortality as determined through chart review.
Secondary outcomes included duration of mechanical venti-
lation, ICU and hospital length of stay, and discharge disposi-
tion among survivors. Investigators assessed the association
between PARDS and outcomes by using linear regression after
adjusting for potential confounders.
Among 2,470 eligible participants, 4.2% (n=103) met complete
PARDS criteria. At the time of onset, PARDS severity was mild in
55%, moderate in 29%, and severe in 14%. Mortality among par-
ticipants with PARDS was 34%, with the primary cause of death
in the majority (60%) being neurological failure; mortality was
highest among participants with severe PARDS at onset (50%).
In regression analyses, the risk of mortality was 3.7 times higher
in participants with PARDS than in those without PARDS (95% CI,
2.0–6.9). Among survivors, PARDS was associated with an addi-
tional 8.9 days of mechanical ventilation, 11.4 ICU days, and 16.5
total hospital days. The risk of requiring ongoing care on dis-
charge home was 1.5 times higher in participants with PARDS
than in those without PARDS (95% CI, 1.1–2.1).
The investigators conclude that the incidence of and mortality
from PARDS associated with trauma is higher than previously
thought.
COMMENTARY BY
Susan L. Bratton, MD, FAAP, Pediatric Critical Care Medicine, Salt
Lake City, UT
Dr Bratton has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.
Traumatic brain injury (TBI) is by far the most common cause of
death among children after traumatic injury.1 PARDS from both
direct causes (eg, pulmonary contusion, aspiration) and indirect
causes (eg, sepsis, neurogenic pulmonary edema) is well known,
• February 2020
TM
but risk of PARDS differs by severity of TBI.2 The current investi-
gators report the occurrence of PARDS in 4% of all trauma victims
admitted to the PICU. However, a study of children with severe
TBI (Glasgow Coma Scale ≤8) found that 20% developed acute
lung injury (partial pressure of oxygen/fraction of inspired oxy-
gen <300).3 Both studies found elevated risk of mortality and dis-
ability at discharge among those with hypoxic respiratory failure
compared to that in those without.
The authors of the current study did not report Glasgow Coma
Scale scores, but severe TBI was common because one-half of
dying children (with or without PARDS) met neurological cri-
teria for death. Similar proportions of patients with and with-
out PARDS (49% and 42%, respectively) died after withdrawal
of life-sustaining therapy (WLST). However, among those with
PARDS, 34% died with multiorgan failure compared to 5% without
PARDS. Only one child died from intractable hypoxia.
Documentation of neurological criteria for death requires 2
examinations and an observation period that is greater in
younger children and infants.4 Therefore, some patients die prior
to documentation of neurological death. Additionally, use of high
sedation doses or administration of neuromuscular blocking
agents can obfuscate the examination and must be discontinued
prior to examination. It is very likely that the majority with WLST
had persistent coma and severe brain injury and either did not
meet full criteria for neurological death or the parents and care
providers chose WLST because of poor prognosis and agreed
that additional time for observation was not in the child’s best
medical interest. The median days to death were 3.9 (PARDS) and
2.6 (no PARDS) in those with WLST. PARDS and severity of PARDS
are primarily associated with severity of brain injury.
Bottom Line: Increased mortality with PARDS in the setting of
severe TBI likely reflects more severe brain injury rather than
substantially increased risk of death from acute respiratory fail-
ure and ventilator-associated lung injury.
References
1. Keenan HT, et al. Dev Neurosci. 2006;28(4-5):256–263; doi: 10.1159/000094152
2. Villar J, et al. Crit Care Med. 2018;46(6):892–899; doi: 10.1097/CCM.0000000000003022
3. Bratton SL, et al. Neurosurgery. 1997;40(4):707–712
4. Nakagawa TA, et al. Ann Neurol. 2012;71(4):573–585; doi: 10.1002/ana.23552
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February 2020 issue of AAP Grand Rounds. Please keep this issue.
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CME OBJECTIVES
1. Describe the long-term efficacy of statin use for familial
hypercholesterolemia.
2. Understand the association of exercise with sudden cardiac death in
patients with hypertrophic cardiomyopathy.
3. Understand the effect of urine specific gravity on the accu-
racy of other urinalysis components and its effect on clinical
decision-making.
1. Parents of a child with familial hypercholesterolemia present for a well-child
visit. The parents are concerned about long-term use of medications but
are also concerned about early cardiovascular events. Based on the study
of 20-year follow-up of statin use in children with hypercholesterolemia by
Luirink et al, which of the following is the most appropriate response?
a. Side effects from statin therapy resulted in 52% of those with familial
hypercholesterolemia to no longer be using lipid-lowering drugs.
b. Children with familial hypercholesterolemia treated with statins achieved
target cholesterol levels only 11% of the time and did not have a mortality
benefit compared to findings in their unaffected siblings.
c. P
 articipants with familial hypercholesterolemia who started statins as
children had reduced cardiovascular events and mortality compared to
findings in their parents for whom statins were available only later in life.
d. Mean progression of carotid intima-media thickness over the follow-up
was significantly greater in those with familial hypercholesterolemia than
in their unaffected siblings.
e. At follow-up, 19% of those with familial hypercholesterolemia had cardio-
vascular disease.
2. A 16-year-old male adolescent requests that you complete the state-man-
dated preparticipation physical examination form for him to play soccer. He
just learned that his 44-year-old uncle received a diagnosis of hypertrophic
cardiomyopathy (HCM). According to the study by Weissler-Snir et al, which
of the following statements is most accurate?
a. Nearly 80% of HCM-related sudden cardiac deaths (SCDs) among those ≤20
years were associated with exercise.
b. The annual incidence of HCM-SCD for those with definite HCM was esti-
mated to be 0.6 per 1,000 person years.
c. Overall, 84% of HCM-SCDs occurred at rest.
d. For individuals with a diagnosis of HCM, HCM-SCD was associated only with
moderate to vigorous, but not light, activity.
e. Among those with HCM-SCD confirmed at autopsy, 60% were male.
3. A 9-month-old girl is admitted for an extended-spectrum β-lactamase (ESBL)
Escherichia coli UTI. She was initially treated with cefdinir and was febrile for
48 hours, but her last fever was 12 hours ago. She is now being treated with
meropenem. Her last UTI was 2 months ago and grew non-ESBL E coli. She
was treated with cephalexin and clinically improved; she was afebrile after
2 days. Results of renal bladder ultrasonography at that time were normal.
According to the study by Hyun et al, which of the following is most strongly
associated with her developing an ESBL UTI?
a. Age
b. Prior antibiotic use
c. Normal renal bladder ultrasonography scans
d. Fever duration with initial UTI
e. Female sex
4. A 4-month-old female infant has a rectal temperature of 39.4°C. A cathe-
terized urine sample is obtained for urinalysis and culture. The urinalysis
demonstrates 3+ leukocyte esterase and 2+ nitrites. The urine specific gravity
(SG) is 1.020. Which of the following is the most accurate finding of the study
by Shaikh et al concerning urine SG and the accuracy of urinalysis for diag-
nosing febrile UTI in children <24 months?
a. Inclusion of SG in decision-making had a negligible effect on the clinical
care of children with UTI.
b. Dilute urine increased the positive likelihood ratio (LR) for nitrite.
c. The leukocyte esterase–positive LR was significantly greater with concen-
trated urine.
d. Bacteria at Gram stain had a higher positive LR with dilute urine.
e. Urine white blood cell count per high-power field had a lower positive LR
with dilute urine.
24
5. Which of the following is the most accurate finding or conclusion of the study
by Hirai et al on safe infant sleep practices?
a. Current breastfeeding mothers were more likely to use approved sleep
surfaces.
b. Back sleep position was lowest among non-Hispanic American Indian or
Alaska natives.
c. The weighted estimate of back sleeping, room sharing without bed sharing,
no soft or loose bedding, and always or often slept on approved surfaces
were all >80%.
d. Receipt of provider advice was associated with increased use of safe sleep
practices.
e. Current maternal smoking was associated with an increased use of sepa-
rate approved sleep surfaces.
6. An 18-year-old female adolescent presents to your clinic for a family plan-
ning visit. She received a single dose of the quadrivalent HPV vaccine at age
15 years and became sexually active when she was 14 years old. Based on the
study by Schlecht et al, which of the following is the most accurate?
a. She is more likely to have oral HPV detected than someone who first
became sexually active 1 year ago.
b. She is less likely to have oral HPV types in the vaccine (HPV-6, HPV-11, HPV-
16, or HPV-18) detected than would a sexually active female adolescent
who had received 2 bivalent HPV vaccine doses.
c. If HPV is detected on an oral rinse, the oral HPV is likely to clear within 12
months.
d. She is more likely to have oral HPV detected than would a 16-year-old
sexually active female adolescent.
e. Her risk of oral HPV infection is higher if she reports smoking marijuana
and cigarettes.
7. Based on the study by Pelland-Marcotte et al, which is the most accurate
statement about late infectious complications in survivors of childhood
leukemia compared to matched controls?
a. Blood and central nervous system infections were more common in
survivors.
b. Death due to infections was highest in survivors but only in those who
received hematopoietic stem cell transplantation.
c. Genitourinary infections were the most frequent type of infection in survi-
vors compared to that in controls.
d. Hospitalization rates were more frequent 5 or more years after therapy
completion.
e. Acute myeloid leukemia, but not acute lymphoblastic leukemia, was
associated with higher rates of infection in survivors compared to that in
controls.
8. A neonate with complex congenital heart disease undergoes cardiac surgery
and has brain injury at MRI prior to discharge. According to the study by
Claessens et al, which of the following is most accurate concerning brain
injury in infants with critical congenital heart disease?
a. Hemorrhagic brain injury was more common than ischemic injury.
b. Sinovenous thrombosis was the most common preoperative injury.
c. Single-ventricle physiology with aortic arch obstruction was not associated
with increased risk of preoperative or postoperative brain injury.
d. Preoperative brain injury increased the risk of new postoperative brain
injury.
e. Low cardiac output syndrome was associated with preoperative and post-
operative multifocal brain injury.
9. A 10-year-old is struck by a car when crossing the street. He is unconscious
at the scene and taken to the closest trauma hospital. Although his pupils
are reactive, he has decorticate posturing to pain. He coughs when suctioned
but does not gag, and corneal reflexes are absent bilaterally. Over the first
day after admission, his chest radiograph shows bilateral patchy infiltrates,
and he has required increasing oxygen to maintain saturations of 95%. His
intracranial pressure has spikes to 30, and a head CT shows diffuse edema
and no large hematomas. Based on the study by Killien et al regarding
pediatric acute respiratory distress syndrome (PARDS) after trauma, which
of the following statements regarding the patient’s lung dysfunction is most
appropriate?
a. Mortality was 10%–15% with PARDS (those who met complete Pediatric
Acute Lung Injury Consensus Conference criteria).
b. Development of PARDS is associated with increased mortality.
c. PARDS occurred in 38% of all trauma victims admitted to the PICU.
d. The primary cause of death with PARDS was respiratory failure.
e. Severity of PARDS was not associated with the severity of brain injury.
8. e 6. c 2. a 4. a
9. b 7. a 5. d 1. c 3. b
Answers:
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