PIR Nov 2014vol 35 No 11

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Vol. 35 No. 11
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Pediatric Hearing Loss

Grindle
Spirometry for the Primary

Care Pediatrician
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Kaslovsky, Sadof
Respiratory Failure
Vo, Kharasch
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aeruginosa, and other gram-negative organisms. Antibiotic treatment should again be directed at the most common pathogens
for 7 to 10 days, taking into account the possibility of
multidrug-resistant organisms. If feasible, serial surveillance
of endotracheal aspirate specimens can identify multidrugresistant pathogens and help tailor antibiotic therapy.
The risk of VAT peaks at approximately 4 days after intubation, with an estimated incidence of 2% to 11%. The onset of
bacterial tracheitis in children with long-standing tracheotomies
is less predictable, with a reported incidence of less than 1%.
In general, tracheotomy-associated tracheitis is not aggressive
and, if there is close follow-up, can be treated in the outpatient setting with oral antibiotics, topical ciprooxacin and
dexamethasone, or tobramycin and dexamethasone drops
directed into the tracheotomy for several days. Recurrence
of tracheitis is more common in children with a long-term
tracheotomy.
During the past several decades, the incidence, diagnosis, and management of bacterial tracheitis have been
inuenced by new vaccines and by the heightened awareness among physicians of the alarmingly high morbidity
associated with delayed recognition. Despite its low incidence, clinicians must consider the possibility of bacterial
tracheitis in any patient with acute respiratory decompensation
and be able to distinguish it from viral croup, epiglottitis, and

other causes of upper airway obstruction.
COMMENTS: As Drs Kuo and Parikh point out, bacterial
tracheitis is rare in children with normal airways. For a child
with a tracheotomy tube, however, it is an ever-present worry.
With the defense systems of the upper airway bypassed and
a direct opening to the environment, the trachea with a tube
becomes akin to the throatreadily colonized by a host of
bacteria. The problem for the clinician faced with a febrile
child with respiratory symptoms is how to distinguish colonization from infection. Periodic surveillance tracheal cultures while the child is well may help. They dene the usual
ora and through information on sensitivities provide at least
a starting point if empiric antimicrobial therapy seems advisable. Culture at the time of illness may then identify a new
potential pathogen, with its sensitivities to antibiotics. In
addition, the Gram stains performed with the surveillance
cultures can usually establish a baseline neutrophil presence. A
signicant increase in the tracheal neutrophil count on a Gram
stain performed when the child is ill suggests active inammation, likely in the context of fever and infectious symptoms.
Henry M. Adam, MD
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Vol. 35 No. 11
NOVEMBER 2014
499
contents
Pediatrics in Review
ARTICLES
456

Christopher R. Grindle
465
Spirometry for the Primary Care Pediatrician

Robert Kaslovsky, Matthew Sadof
476
Respiratory Failure
Vol. 35 No. 11 November 2014

Editor-in-Chief: Joseph A. Zenel, Sioux Falls, SD
Associate Editor: Hugh D. Allen, Houston, TX
Editor, In Brief: Henry M. Adam, Bronx, NY
Consulting Editor, In Brief: Janet Serwint, Baltimore, MD
Editor, Index of Suspicion: Deepak M. Kamat, Detroit, MI
Editor, CME: Paula Algranati, Longmeadow, MA
Editorial Fellow: Mark F. Weems, Memphis, TN
Editor Emeritus: Lawrence F. Nazarian, Rochester, NY
Founding Editor: Robert J. Haggerty, Canandaigua, NY
Managing Editor: Luann Zanzola
Editorial Associate: Sara Strand
Medical Copyediting: Laura King
Phuong Vo, Virginia S. Kharasch

INDEX OF SUSPICION
487
Case 1: Recurrent Epistaxis in a 4-Year-Old Boy

Emily Vander Schaaf, Nicholas M. Potisek
Case 2: Eosinophilia in a 5-Year-Old Boy

Kriti Puri, Elizabeth P. Schlaudecker, Nicholas C. Newman
Case 3: Feeding Intolerance in a 3-Month-Old Girl

With Trisomy 21
Patricia M. Notario, Rajeev Nagpal
IN BRIEFS
493
Nutritional Considerations in Pediatric

Liver Disease
Russell Cameron, Debora Kogan-Liberman
496
497
Correction
Bacterial Tracheitis
Connie Y. Kuo, Sanjay R. Parikh
ONLINE
e53
Visual Diagnosis: 8-Day-Old Hypotonic

Newborn With Sparse Hair
Jorge Sales Marques, Manuela Mateus, Teresa Torres,
Helena Santos, Marta Vila Real, Ftima Santos
e57
Visual Diagnosis: 6-Month-Old Boy With

Leg Pain
Sebastian K. Welsh, David F. Crudo, Jordan E. Pinsker
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Answer Key appears on page 496.

Christopher R. Grindle, MD*
*Division of Otolaryngology, University of Connecticut School of Medicine, and Division of OtolaryngologyHead and Neck
Surgery, Connecticut Childrens Medical Center, Hartford, CT
Educational Gap
Hearing loss is a common condition presenting in children. Speech and
language outcomes for children with hearing loss are related to
identication of the hearing loss and to the degree of hearing loss. Early
identication and appropriate, prompt intervention yield better
outcomes. An understanding of the relevant anatomy, common causes,
testing strategies, and management of hearing loss can help the primary
care physicians maximize communication development in children.
Objectives
After reading this article, the reader will be able to:
1. Provide a basic overview of the anatomy of the ear and discuss

implications for conductive and sensorineural hearing loss.
2. Discuss the importance of newborn hearing screening and provide
details on how this testing is accomplished.
3. Discuss some of the causes of hearing loss in children.
4. Detail interventions that may be appropriate in children with hearing
loss.
Hearing loss is a common condition in children, with 1 in 1000 live births affected
with severe to profound permanent hearing loss. The prevalence increases to 6 in
1000 when all degrees of hearing loss, mild to profound, are considered. As
children age, the prevalence increases, and by age 18 years, 17 in 1000 individuals
are affected by some degree of permanent hearing loss. This makes hearing loss
more prevalent that diabetes mellitus and all pediatric cancers. (1) These
numbers, however, do not take into account all the children who are affected
by long-standing chronic effusions, which, though temporary, can have a signicant effect on speech and language development if not identied and
appropriately treated.
Hearing loss in children can derive from many forms. It can be congenital
(present at birth), genetic, syndromic, nonsyndromic, acquired, and/or progressive. It may manifest as conductive, sensorineural, or mixed hearing loss. The
evaluation, diagnosis, and management of children with hearing loss will involve
a multidisciplinary effort by pediatricians, otolaryngologists, audiologists, deaf
educators, speech and language pathologists, early intervention specialists, and
456
AUTHOR DISCLOSURE Dr. Grindle has

disclosed that he has a family member who
works for Bristol-Myers Squibb. This
commentary does not contain a discussion of
an unapproved/investigative use of
a commercial product/device.
ABBREVIATIONS
ABR
auditory brainstem response
CHL
conductive hearing loss
CMV
cytomegalovirus
OAE
otoacoustic emission
SNHL
sensorineural hearing loss
UNHS
universal newborn hearing
screening
many others. The main focus of care should always be on

providing appropriate communication strategies to the
affected individual.
A basic knowledge of the auditory system is needed to
understand how to appropriately intervene in childhood hearing loss. In addition, one must understand how response to
sound is measured clinically. The intensity of sound is measured in decibels. In testing paradigms, the intensity of the
sound is varied, and the patients responses are recorded. By
denition, 0 dB is the threshold of human hearing, meaning
that someone with normal hearing will hear a tone burst at this
intensity 50% of the time. Normal hearing is dened as being
within 15 dB of this threshold. Minimal hearing loss is 16 to
25 dB, mild hearing loss is 26 to 40 dB, moderate hearing loss
is 41 to 55 dB, severe hearing loss is 71 to 90 dB, and profound
hearing loss is greater than 90 dB. However, for any sound at
any intensity to be registered by the brain, all the components
of the auditory system must be working.
Essentially, there are 4 components: the outer ear, the
middle ear, the inner ear, and the auditory nerve. The outer
ear is a sound wave collection funnel. Its shape and conguration provide some enhancement to incoming sound,
but the effect is minimal (approximately 5 dB). However, the
external auditory canal must be patent to allow for the
transmission of sound waves to the tympanic membrane.
Numerous factors can interfere with the sound waves at this
point. Cerumen impaction, foreign body, malformation of
the auricle, or canal stenosis or atresia can all compromise
the function of the outer ear.
The middle ear starts at the tympanic membrane and
continues to the stapes footplate. The function of the middle
ear is to serve as a pressure transducer and overcome the
impedance mismatch that exists between sound waves in an
air vs uid medium of the sensory organ, the cochlea. Sound
waves that are propagating through the air interact with the
tympanic membrane. They cause a vibration of the tympanic
membrane that moves through the ossicles (the malleus,
then the incus, and nally the stapes). Adherent to the stapes
is the stapes footplate and the oval window membrane.
Primarily because of the vastly greater surface of the tympanic
membrane compared with the oval window membrane, the
sound waves that interact with the tympanic membrane are
transduced and amplied though the middle ear. There is
a small contribution from the size and orientation of the
ossicles. Overall, the gain is approximately 20 dB.
For the tympanic membrane and ossicles to function
properly, they must be intact and in an air-lled space. Thus,
large tympanic membrane perforations, ossicular discontinuity, and stiffening of the ossicular chain or stapes footplate
(otosclerosis) can cause hearing loss. In addition, if the
middle ear becomes lled with something other than air

(effusion or cholesteatoma), this can disrupt its function and
lead to hearing loss. This is particularly common in young
children who have eustachian tube dysfunction and frequent
otitis media with effusion.
Anything that disrupts sound getting to the cochlea can
be considered conductive hearing loss (CHL). Loss at the
point of the cochlea or proximal to the cochlea is considered
sensorineural hearing loss (SNHL). A combination of the 2
is termed a mixed loss. The cochlea is the sensory organ of
hearing. The cochlea itself is spiral in shape with 2 to 2
turns. Inside the cochlea are 3 distinct spaces that run its
length. The scala tympani and the scala vestibuli are both
lled with perilymph and surround the scala media, which
contains endolymph. Perilymph and endolymph have different electrolyte components similar to extracellular and
intracellular uid, respectively. An electric potential exists
between the 2 uid compartments and is essential for
generating action potentials along the cochlear nerve. The
organ of Corti is within the scala media. Within the organ of
Corti are the inner and outer hair cells, as well as many other
supporting cells. Sound waves cause a vibration of the
tympanic membrane, which is transduced through the
middle ear and cause vibrations of the oval window membrane. This wave propagates through the perilymph of the
cochlea and causes displacement along the basilar membrane of the scala media, effectively opening ion gated
channels in the hair cells and causing an action potential.
The cochlea is tonotopically organized such that low frequencies are registered at the apex and high frequencies at
the base of the cochlea.
These action potentials are carried by the auditory nerve
though various centers in the brainstem and to the auditory
cortex for higher-level processing. Obviously, a defect anywhere along this path could cause a hearing loss. These
defects can be macroscopic defects (eg, brainstem lesions or
abnormally formed cochleas) but far more commonly are
microscopic defects (eg, abnormal membrane gating proteins, ion channel defects, and collagen defects).
DIAGNOSIS OF HEARING LOSS

The earlier the diagnosis of hearing loss can be made, the
sooner interventions can be initiated to help the child
develop. Currently, all states have a universal newborn hearing screening (UNHS) program and early hearing and detection and intervention programs. In 1993, only 11 hospitals in
the United States screened more than 90% of their newborns. Since this time, there has been incredible expansion of
the programs such that in 2011 a total of 97% of all children
Vol. 35 No. 11
NOVEMBER 2014
457
born in the United States had completed a newborn hearing

evaluation. (2) Current data relating to universal newborn
hearing programs and early hearing detection and intervention programs can be found at http://www.cdc.gov/ncbddd/
hearingloss/data.html.
It is because of these early identication efforts that
interventions are able to begin early in a childs life. The
goal of these programs is to:
identify all children with a permanent hearing loss by age
3 months;
initiate appropriate interventions by age 6 months;
help establish a medical home for infants with permanent
hearing loss; and
track data and quality metrics for public health initiatives.
Newborn hearing screening and early intervention programs rely on objective testing of hearing that can reliably be
performed on newborn infants. These tests are otoacoustic
emission (OAE) testing and auditory brainstem response
(ABR) testing (also called brainstem auditory evoked response testing). These 2 tests are used as the key components in UNHS.
OAE testing relies on the fact that in response to certain
stimuli there are responses thought to originate from the
outer hair cells of the inner ear. These sounds can be recorded.
To perform OAE testing, sound is presented to the cochlea
through an insert speaker placed in the ear canal. This sound
evokes the cochlea into making a specic response, which can
be picked up and recorded by a microphone and recorder
within the ear canal insert. These OAEs are reliably present in
normal hearing ears and serve as a surrogate marker for the
function of the cochlea. OAE testing is inexpensive, does not
require sedation of the infant, and can be performed quickly.
Because this testing relies on presenting sound to the cochlea
at an appropriate intensity, it can be affected by external and
middle ear conditions (eg, canal stenosis, cerumen, or other
debris in the external canal or middle ear effusion). Results are
reported as present or absent.
The other testing paradigm commonly used for UNHS is
the ABR test. Electrodes placed on the scalp record the
resulting electrographic activity of sound impulse as it propagates along the auditory nerve and brainstem. Presented
impulses can be either high-frequency clicks or frequencyspecic tones. In automated ABR testing used in UNHS, the
intensity and frequency of the stimuli are preset to screen for
mild hearing loss. If an infant does not pass an automated
ABR test, a full ABR test can be performed. In this test, both
the intensity and frequency of the stimuli can be adjusted. In
this way, objective information can be attained as to the
specic degree of hearing loss (mild to profound) and sound
frequency of hearing loss (low to high). The ABR can also be
458
affected by outer ear and middle ear disease, although to

a lesser extent than the OAE. However, ABR testing requires
a calm, resting infant. As the child grows, the ability to
perform ABR testing without sedation decreases. Usually,
after approximately age 4 months, sedation is required.
Both OAE and ABR tests are useful for testing newborns
because they are objective, reliable, and repeatable and
require limited cooperation. The tests, however, are surrogate markers for normal hearing. It is thought that if the
cochlea is structurally intact, as reected by present OAEs,
and if there is integrity of the auditory nerve, as measured by
a normal ABR test result, then hearing should be normal. It
is only when the child gets older that hearing can be fully
tested. Behavioral audiometry or visual reinforcement audiometry can be performed on children as young as ages 6 to 9
months. Play audiometry typically is used for children older
than 2 years. At ages 4 to 5 years, children can cooperate with
routine or conventional audiometry. In these tests, pure
tones are presented to the ears separately or simultaneously.
Behavioral responses can be observed as the intensity and
frequency of the stimuli are modulated. These responses
coupled with word discrimination scores in older children
can give an accurate reection of a patients ability to hear
and understand at a particular hearing level.
An adjunct to all these forms of testing is tympanometry,
which can be used to measure the function of the external auditory canals and the middle ear. Normal middle
ear pressures (type A) indicate normal tympanic membrane and ossicular mobility and compliance. Type B or at
tympanograms are present if there is no mobility of the
tympanic membrane (eg, otitis media with effusion) or if
there is complete xation of the ossicles. This will also be
present if there is a tympanic membrane perforation. Type C
tympanograms are typically caused by retraction of the
tympanic membrane secondary to eustachian tube dysfunction. Results of the tympanograms can be a useful adjunct
when interpreting all other audiometric testing. For example, someone who fails his/her newborn screen on OAE
testing and who presents with a moderate CHL on ABR
testing but who has at, type B tympanogram may have
transient middle ear effusion and not permanent hearing
loss. Conversely, tympanograms will appear completely normal in an individual with pure SNHL.
Newborn hearing screens have signicantly decreased
the age at which children are diagnosed as having hearing
loss from a mean age of 2.5 years to 2 to 3 months. (3)
Irrespective of newborn hearing programs, there are known
high-risk criteria for hearing loss (Table 1). These high-risk
criteria do not effectively delineate which children will
have hearing loss and should not replace newborn hearing
screens. However, they are a useful adjunct in identifying

children who have or may be at high risk for developing
hearing loss. For those children with any high-risk criteria,
formal audiometric evaluation with OAE and full ABR
testing should be pursued if there is any concern about
hearing loss. It must be remembered that children with
progressive onset hearing loss will typically pass their UNHS.
Also, children with auditory neuropathy spectrum disorder
can present a diagnostic and management challenge. These
children typically have present OAEs but absent or abnormal
ABRs. Thus, they may pass screening paradigms that use
only OAEs. These children can have variable audiologic
presentations with hearing loss or hearing ability that do
not match what would be expected from their audiometric
data. These patients should be closely monitored for speech
and language development and may benet from traditional
hearing aids or cochlear implantation. (4)
Children with severe to profound hearing loss will develop their prelingual language skills at a normal pace,
TABLE 1.
High-Risk Criteria for Children
Birth to Age 28 Days

Family history of congenital or early-onset hearing loss
Congenital infection known to be associated with hearing loss
(eg, cytomegalovirus, rubella, herpes, syphilis, toxoplasmosis,
varicella)
Craniofacial abnormality
Birth weight <1500 g
Hyperbilirubinemia requiring exchange transfusion
Exposure to ototoxic medications
Bacterial meningitis
Low Apgar scores at birth (<3 at 5 minutes and <6 at 10 minutes)
Prolonged mechanical ventilation (>10 days)
Findings consistent with a syndrome with known hearing loss
Ages 29 days to 2 years
Concern about hearing, speech, language, or other
developmental delay
Bacterial meningitis
Neonatal risk factors associated with hearing loss
Head trauma, especially temporal bone fracture
Findings of syndrome associated with sensorineural hearing loss
Exposure to ototoxic medications (eg, aminoglycosides, loop
diuretics, cisplatin)
Neurodegenerative disorders
Infectious diseases associated with hearing loss
cooing and babbling until ages 6 to 9 months. They will,

however, begin to loose these skills and will not progress.
Thus, they will present with concerns for speech delay. It
also may be reported that the children do not turn their
heads in response to sounds and that they do not make eye
contact when spoken to. Parents may also note that there
may be delays in sitting, crawling, and walking. Paradoxically, some parents and caregivers of children will report that
the child can hear, or they may dismiss their childs inattentive behavior as ignoring or just kids being kids. The
intensity of normal conversation is approximately 30 to
50 dB. Normal street noise is approximately 60 dB. Loud
conversations (shouting) are approximately 80 dB. Chainsaws are approximately 90 dB. Thus, a child with mild to
moderate hearing loss will hear and react to loud shouting
and machinery. However, he or she will not be able to hear
soft sounds and will often lose the high-frequency consonant sounds that give words meaning. Even children with
profound hearing loss may seem to react to loud shouts and
bangs because they can feel the vibrations.
Concern about hearing loss should prompt further evaluation, regardless of the age of the child. As detailed above,
there are many different types of testing, both objective and
subjective, that can accurately determine a childs hearing
thresholds, irrespective of age.
CAUSES OF HEARING LOSS

The causes of hearing loss can be broadly divided into
genetic and acquired and further divided into congenital
(present at birth) or progressive. Approximately 50% to 60%
of all prelingual hearing loss is genetic. Of this, 70% are
nonsyndromic forms of hearing loss. The most common
type of nonsyndromic hearing loss is autosomal recessive in
75% to 80%. Furthermore, the most common type of nonsyndromic hearing loss is caused by defects in connexin 26,
comprising approximately 50% of all nonsyndromic autosomal recessive hearing loss (Figure 1).
As discussed above, nonsyndromic hearing loss is the
most common. Defects have been found in all inheritance
patterns. To date, more than 60 different gene loci have been
identied that can cause hearing loss. By convention, they are
named DFNA for autosomal dominant, DFNB for autosomal
recessive, and DFNX for X-linked. The number following the
DFN (A, B, or X) identies the gene locus. DFNB1, which is
caused by a defect in GJB2 (also called connexin 26), is the
most common of nonsyndromic hearing loss, accounting for
approximately 50% of autosomal recessive, nonsyndromic
hearing loss. Defects in GJB2 are caused by a number of
different mutations, the most common of which is 35delG.
Vol. 35 No. 11
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459
Figure 1. Summary of causes of prelingual

hearing loss. Adapted from Smith RJH,
Shearer AE, Hildebrand MS, et al. Deafness
and hereditary hearing loss overview.
In: Pagon RA, Adam MP, Ardinger HH, et al,
eds. GeneReviews. Seattle: University of
Washington; 19932014. Available at: http://
www.ncbi.nlm.nih.gov/books/NBK1434/.
Accessed Jan. 5, 2014
Regardless of cause, they all lead to abnormal function of the

gap junction protein.
In contrast to nonsyndromic hearing loss where there are
typically no other associated physical ndings, syndromic
hearing losses have various other physical ndings that are
apparent. Again, syndromic hearing loss is present in all
modes of inheritance. More than 500 syndromes that
include hearing loss have been described. Most syndromes
are rare; Table 2 summarizes some of the more common
syndromic causes of hearing loss.
Of the remaining 50% of all cases of congenital hearing
loss, 25% are caused by nongenetic factors. The most
common acquired form of congenital hearing loss is cytomegalovirus (CMV) infection. Primary infection of the
mother and fetus can result in a wide array of outcomes,
ranging from no symptoms to multiple sensory decits. If
symptomatic from the CMV infection, there is 50% likelihood that the child will have SNHL to a variable degree.
However, even if the infant is asymptomatic from the CMV
infection, there is a 10% to 15% chance of developing SNHL.
This hearing loss is often progressive and uctuating. (5)
Diagnosis of congenital CMV infection can only reliably be
made during the rst 3 weeks of life from a urine sample or
a cheek swab. If a child does not pass his/her UNHS and
there are no other obvious causes, then CMV testing should
be considered. Other congenital infections, such as measles,
mumps, and rubella, may also lead to hearing loss.
Another infectious origin bears particular comment. Bacterial meningitis, particularly from Streptococcus pneumoniae,
460
may lead to hearing loss. Hearing loss typically occurs early in

the infection, can be mild to profound, and can often be
prevented or improved with early and prompt antibiotic
therapy. In addition, treatment with dexamethasone has been
found to signicantly reduce the incidence of hearing loss in
those with Haemophilus inuenzae type B bacterial meningitis
and to some degree for those with other nonH inuenzae
type B bacterial meningitis. (6) Hearing loss in meningitis occurs in more than 30% of patients. Infections with S
pneumoniae are associated with hearing loss with even higher
frequency, 35%. (7) Patients with a diagnosis of bacterial
meningitis should have hearing testing performed as part
of their initial workuponce they are stable for this testing.
Although hearing loss typically occurs early, it may present
later and may be progressive. Therefore, audiologic follow-up
is recommended. Patients should have follow-up hearing
testing 4 to 8 weeks after discharge and then at 6 and 12
months after infection. (8) If there is hearing loss associated
with bacterial meningitis, imaging studies should be promptly
performed because there is a high association with cochlear
ossicansan inammatory process that obliterates the
structures of the cochlea, particularly the scala tympani. Magnetic resonance imaging can be particularly helpful in early
identication of this progressive destruction of the cochlea.
If ossicans is identied, early cochlear implantation may
be advocated.
Other causes of acquired hearing loss include trauma,
particularly temporal bone trauma. Fractures through the
cochlea and vestibule can result in severe to profound
TABLE 2.
Common Syndromic Causes of Hearing Loss
CAUSE
DESCRIPTION
Autosomal dominant
Waardenburg syndrome
Most common type of autosomal dominant syndromic hearing loss

4 types, all with varying degrees of nonprogressive SNHL and pigmentary abnormalities
Type 1: dystopia canthorum (lateral displacement of inner canthi of eyes) present
Type 2: dystopia canthorum absent
Type 3: limb abnormalities
Type 4: Hirschsprung disease present
Stickler syndrome
Progressive SNHL
Cleft palate present and spondyloepiphyseal dysplasia also may be present
Often have severe myopia which increases risk for retinal detachment
Branchiootorenal syndrome
Second most common autosomal dominant hearing loss

Variable degree of SNHL, CHL, or mixed hearing loss.
Abnormalities in rst and second branchial structures, resulting in preauricular pits, malformations of
external ear, abnormalities of the ossicles, branchial cleft cysts or stulas, and renal abnormalities.
Renal involvement may be absent
Neurobromatosis types 2
Hallmark is bilateral vestibular schwannomas

Denitive diagnosis made with MRI
Extremely rare in children, hearing loss often begins in third decade
Autosomal recessive
Usher syndrome
Most common autosomal recessive syndromic hearing loss

Most common cause of blindness or deafness (multisensory impairment)
Blindness secondary to retinitis pigmentosa
Early specialized eye examinations (electroretinography) can pick up disease as early as ages
2-4 years
May also have vestibular dysfunction
Type 1: congenital severe to profound SNHL and abnormal vestibular function
Type 2: congenital mild to severe SNHL and normal vestibular function
Type 3: progressive hearing loss and progressive loss of vestibular function
Pendred syndrome
Variable SNHL and euthyroid goiter

Often have enlarged vestibular aqueduct and cochlear abnormalities on CT
Jervell and Lange-Nielsen syndrome
Congenital severe to profound SNHL

Prolonged QT interval that may lead to syncopal episodes or sudden death
Consider screening ECG
If positive family history, consider cardiac evaluation
X-linked
Alport syndrome
Progressive hearing loss

Progressive glomerulonephritis
Ophthalmologic abnormalities (anterior lenticonus)
Abbreviations: CHLconductive hearing loss; CTcomputed tomography; ECGelectrocardiography; MRImagnetic resonance imaging; SNHLsensorineural
hearing loss.
SNHL. Fractures through the ossicles can disarticulate these

bones, causing moderate CHL. Acoustic trauma (noiseinduced hearing loss) can also cause permanent hearing
loss. Audiograms of individuals affected by noise-induced
hearing loss typically display a distinct pattern with a highfrequency dip (notch) at 4000 Hz. Certain medications are
also known to be ototoxic. These medications, which include
aminoglycoside antibiotics, loop diuretics, and cisplatin,
should be avoided if possible, and hearing should be monitored if these medications are used.
Last, hearing loss may be caused by otitis media with

effusion. This is the most common cause of childhood
hearing loss, although it is often not included on lists because
of its potentially transient nature. Middle ear effusion is
exceedingly common in association with otitis media. In
fact, 40% of all ears with resolved otitis media will have
persistent uid at 1 month, 20% at 2 months, and 10% at
3 months. (9) It is important to ask about subjective hearing
when evaluating those with otitis media. If there is concern
regarding hearing, objective testing should be performed.
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461
For those individuals with persistent chronic otitis media with

effusion for greater than 3 months who have an associated
hearing loss, surgical management with myringotomy and
tympanostomy tubes is a recommended treatment. (10) If,
however, there is no hearing loss present, no surgical
intervention is recommended because persistent effusion
in otherwise healthy children does not cause developmental
impairment. (11)
MANAGEMENT OF HEARING LOSS IN CHILDREN

Once hearing loss is identied, steps should be taken to
minimize the duration of hearing loss and/or maximize the
function of the residual hearing or cochlear function. In
addition, efforts should be made to militate against decits
in other sensory systems. The overall goals, especially in
children, are to minimize the effect that the hearing loss will
have on speech and language development and to provide
appropriate strategies for communication. In general terms,
the more pronounced the hearing loss and the longer the
duration of hearing loss without intervention, the more
signicant the effect on speech and language development.
All the management strategies and considerations are tailored to the specic condition of the child. Children with
permanent hearing loss should undergo an ophthalmology
evaluation to rule out ocular disease. Children with moderate and greater bilateral SNHL should undergo screening
electrocardiography to look for prolonged QT associated
with hearing loss. (12) If there is a family history of sudden
death, full cardiologic evaluation should be performed.
Decisions regarding genetic testing and imaging should
be made with the patient and family.
Medical care for hearing loss in children can include
appropriately chosen antibiotic therapy for otitis media. In
cases of prolonged otitis media with effusion with associated
hearing loss, antibiotics are unlikely to resolve the problem.
Myringotomy and tympanostomy tubes may be required for
removal of the effusion and improved middle ear aeration.
For children with mild to severe hearing loss, amplication may be a suitable option. Modern hearing aids can be
t to children as early as age 3 months. The amplication on
modern digital aids is adjustable to t the patients hearing
loss curve. Early amplication, even for those with mild loss,
is benecial in that it gives them access to the full range of
speech and language sounds. This and the longer duration
of use that comes with early amplication lead to better
speech and language development. (13)
Beyond providing hearing impaired children with equipment, it is important to make sure that the children are
getting the appropriate services to help foster their growth
462
and development. Often, simple seating rearrangements,

such as preferential seating in the front of the class and
classroom FM systems, can make a signicant difference.
Certain conditions that cause CHL are amenable to
surgical management. As mentioned above, CHL from
chronic otitis media with effusion can be treated with
tympanostomy tubes. Certain ossicular abnormalities can
be repaired or replaced with prosthetic ossicles. Cholesteatoma can cause erosion of the ossicles, which must be
managed surgically. Bone-anchored hearing aids and middle ear implants are placed surgically.
If these options fail to provide adequate hearing for
speech and language development and for communication
then alternate options must be considered. Decisions need to
be made concerning the desired mode of communication
manual (eg, sign language) or auditory or verbal. In appropriately selected patients who desire auditory or verbal
communication, have signicant hearing loss, and do not get
adequate return from conventional amplication, cochlear
implantation may be an option. In this procedure, a small
electrode array is surgically implanted within the cochlea.
This array is able to stimulate the cochlear nerve directly.
Summary
On the basis of strong research, universal newborn screening
should be performed before age 1 month with repeat or followup testing for those who do not pass performed before age 3
months and intervention started before age 6 months.
On the basis of strong research and consensus statement,
tympanostomy tubes should be considered for individuals with
bilateral persistent middle ear effusion for 3 months or greater
and a documented conductive hearing loss.
On the basis of consensus statement, all children with suspected
hearing loss should have an age appropriate hearing test.
On the basis of strong research, the most common form of
congenital hearing loss is genetic. Most of this is nonsyndromic
hearing loss.
References
1. Morton NE. Genetic epidemiology of hearing impairment. Ann N Y
Acad Sci. 1991;630:1631
2. American Academy of Pediatrics, Joint Committee on Infant
Hearing. Year 2007 position statement: principles and guidelines
for early hearing detection and intervention programs. Pediatrics.
2007;120(4):898921
3. Harrison M, Roush J, Wallace J. Trends in age of identication and
intervention in infants with hearing loss. Ear Hear. 2003;24
(1):8995
4. Berlin CI, Morlet T, Hood LJ. Auditory neuropathy/dyssynchrony: its

diagnosis and management. Pediatr Clin North Am. 2003;50
(2):331340, viiviii
5. Fowler K. Congenital cytomegalovirus infection: audiologic
outcome. Clin Infect Dis. 2013;57(suppl 4):S182S184
6. Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids
for acute bacterial meningitis. Cochrane Database Syst Rev. 2013;6
(6):CD004405 10.1002/14651858.CD004405.pub4
9. Teele DW, Klein JO, Rosner BA. Epidemiology of otitis media

in children. Ann Otol Rhinol Laryngol Suppl. 1980;89
(3, pt 2):56
10. Rosenfeld RM, Schwartz SR, Pynnonen MA, et al. Clinical practice
guideline: tympanostomy tubes in children. Otolaryngol Head Neck
Surg. 2013;149(1 suppl):S1S35
11. Berman S. The end of an era in otitis research. N Engl J Med.
2007;356(3):300302
7. Kutz JW, Simon LM, Chennupati SK, Giannoni CM, Manolidis S.

Clinical predictors for hearing loss in children with bacterial
meningitis. Arch Otolaryngol Head Neck Surg. 2006;132(9):941945
10.1001/archotol.132.9.941
12. Tranebjaerg L, Samson RA, Green GE. Jervell and Lange-Nielsen

syndrome. In: Pagon RA, Adam MP, Bird TD, et al, eds. GeneReviews.
Seattle: University of Washington; 2002:1993-2013. http://www.ncbi.
nlm.nih.gov/books/NBK1405/. Accessed January 5, 2014
8. Merkus P, Free RH, Mylanus EA, et al; 4th Consensus in Auditory

Implants Meeting. Dutch Cochlear Implant Group (CI-ON)
consensus protocol on postmeningitis hearing evaluation and
treatment. Otol Neurotol. 2010;31(8):12811286
13. Tomblin JB, Oleson JJ, Ambrose SE, Walker E, Moeller MP. The
inuence of hearing aids on the speech and language development
of children with hearing loss. JAMA Otolaryngol Head Neck Surg.
2014;140(5):403409
Parent Resources from the AAP at HealthyChildren.org

http://www.healthychildren.org/English/health-issues/conditions/ear-nose-throat/Pages/Hearing-Loss.aspx
Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/ear-nose-throat/paginas/hearing-loss.aspx
http://www.healthychildren.org/English/health-issues/conditions/ear-nose-throat/Pages/Hearing-Loss-When-to-Call-the-Pediatrician.
aspx
Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/ear-nose-throat/paginas/hearing-loss-when-to-call-thepediatrician.aspx
http://www.healthychildren.org/English/health-issues/conditions/ear-nose-throat/Pages/Acoustic-Trauma-Hearing-Loss-in-Teenagers.
aspx
Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/ear-nose-throat/paginas/acoustic-trauma-hearing-loss-inteenagers.aspx
English only: http://www.healthychildren.org/English/health-issues/conditions/ear-nose-throat/Pages/Music-How-Loud-is-Too-Loud.aspx
Vol. 35 No. 11
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PIR Quiz
1. The goal of the universal newborn hearing screening (UNHS) program is which of the
following:
A. Identify all children with moderate hearing loss by age 2 months and initiate
intervention by age 4 months.
B. Identify all children with permanent hearing loss by age 3 months and initiate
C. Identify all children with moderate hearing loss by age 1 month and initiate
D. Identify all children with permanent hearing loss by age 3 months and initiate
E. Identify all children by age 1 month and initiate intervention by age 3 months.
2. A 3-year-old girl presents to your clinic with a 2-month history of otitis media, resistant to
amoxicillin and amoxicillin clavulanate. On otoscopic examination, she has
nonerythematous tympanic membranes, which are dull and do not move on insufation.
You perform a tympanogram in your ofce. Which of the following tympanograms would
be most consistent with an ear effusion?
A.
B.
C.
D.
E.
Type
Type
Type
Type
Type
A.
B.
C.
D.
E.
3. An infant with auditory neuropathy spectrum disorder presents to your clinic. You know
this disorder involves a defect in the signal transmission of sound from the inner ear to the
brain. Which of the following hearing screen results would you expect in this patient?
A.
B.
C.
D.
E.
Present otoacoustic emissions and absent auditory brainstem response.

Present otoacoustic emissions and present auditory brainstem response.
Absent otoacoustic emissions and absent auditory brainstem response.
Absent otoacoustic emissions and present auditory brainstem response.
Otoacoustic emissions and auditory brainstem response are not reliable in this
disorder.
4. A 38-week-old female infant weighs 2100 g. On physical examination, she has

microcephaly and a palpable liver and spleen. She exhibits petechiae on her face and
trunk. You strongly suspect congenital cytomegalovirus (CMV). In counseling the parents,
you inform them of the progressive sensorineural hearing loss associated with congenital
CMV. Furthermore, you inform them the likelihood of sensorineural hearing loss in their
infant is:
A.
B.
C.
D.
E.
10%.
25%.
50%.
75%.
100%.
5. A 7-year-old boy is admitted to the hospital with fever and rash and is treated for bacterial
meningitis. He passes a hearing screen in the hospital before discharge. As you prepare his
discharge consultations, you schedule him for follow-up audiology testing. Which of the
following schedule is most appropriate?
A.
B.
C.
D.
E.
464
Follow-up hearing tested at 3 months, 6 months, and 9 months after discharge.

Follow-up hearing tested at 6 months and 1 year after discharge.
Follow-up hearing tested at 1 month, 6 months, and 12 months after discharge.
Follow-up hearing tested at 1 month and 12 months after discharge.
No follow-up hearing tests indicated unless clinical symptoms of hearing loss.
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2014 Pediatrics in Review
articles for AMA PRA
Category 1 CreditTM,
learners must
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Spirometry for the Primary Care Pediatrician

Robert Kaslovsky, MD,* Matthew Sadof, MD
*Department of Pediatrics, Albany Medical College, Albany, NY
Department of Pediatrics, Tufts University School of Medicine, Baystate Medical Center, Springeld, MA
Practice Gap
The 2007 National Heart, Lung and Blood Institute expert panel asthma
guidelines recommend that spirometry be part of routine asthma
diagnosis and monitoring of therapy, yet only 35% of pediatric practices
use spirometry for patients with asthma. Pediatricians should be aware
that routine ofce spirometry is feasible, practical, and important for
optimizing care for children with respiratory symptoms or risk of lung
disease.
Objectives
After completing this article, readers should be able to:
1. Understand the use of spirometry to diagnose and monitor the

treatment of asthma.
2. Identify the details needed for the optimal performance and
interpretation of spirometry.
INTRODUCTION
AUTHOR DISCLOSURE Dr Sadof has

disclosed no nancial relationships relevant to
this article. Dr Kaslovsky has disclosed he is
a speaker for Teva Pharmaceutical Industries
Ltd. This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.
ABBREVIATIONS
FEF25%75%
forced expiratory volume
between 25% and 75% of vital
capacity
FET
forced expiratory time
forced expiratory volume in 1
FEV1
second
FVC
forced vital capacity
NHLBI
National Heart, Lung, and
Blood Institute
Spirometry is a useful tool to help the practitioner distinguish normal from

abnormal pulmonary function, delineate obstructive from restrictive defects, and
monitor the disease or treatment. Most hospitals and many specialty ofces
(eg, pulmonology and allergy) have ready access to and familiarity with spirometry. The pediatric primary care practice may not have a spirometer or may lack
experienced personnel to properly administer and/or interpret the test results.
A published survey with data from 360 primary care practices revealed that only
52% used spirometry for patients with a diagnosis of asthma, and of those, only
35% of pediatric practices (vs 75% of family medicine practices) used spirometry
in clinical practice. (1) Equipment for spirometry is readily available at a reasonable
cost, and the procedure and interpretation of results are billable services that can
be used by any primary care practice. The interpretation of results can be performed by the primary care physician, possibly with the help of a specialist.
Who?
Most children older than 5 years, who can cooperatively take deep breaths, can be
coached to perform a good spirometry test. Younger children or those with
developmental delays, certain disabling conditions, or poor behavior may not be
willing or able to perform the test. (For those too young to voluntarily exhale into
Vol. 35 No. 11
NOVEMBER 2014
465
the spirometer, impulse oscillometry is an alternate technique that requires nothing more than passively breathing
into a mouthpiece. Description of this tool is beyond the
scope of discussion for this paper.) (2) Any child with
respiratory symptoms or who is at risk for lung disease
should have spirometry performed routinely. The 2007
NHLBI expert panel asthma guidelines recommend that
spirometry be performed at diagnosis, rather than relying
on measures of peak expiratory ow rates. (3)
What?
Spirometers can be of 2 general types: volume displacement
or ow measurement. Those that measure volume have
a (usually 10-L) drum with a piston, such that the change in
volume over time is measured directly, and ow rates are
calculated (change of volume over time). These devices are
computer linked and usually not easily portable, tend to be
more costly, and most likely would not be useful to a primary
care practice.
Flow-sensing devices can be handheld and are easily
portable from room to room in the ofce. They use disposable sensors, referred to as pneumotachometers, which
sense the ow over time. This measurement of ow is used
to calculate the volumes. These devices may be selfcontained or connected to a laptop or desktop computer.
Any spirometer used in an ofce setting should meet the
American Thoracic Society/European Respiratory Society
recommendations for spirometry (available online at http://
www.thoracic.org/statements/resources/pft/pft2.pdf). (4)(5)
The rst chapter of this document is essential reading for
all clinical staff, with descriptions of standards for hygiene,
calibration, quality control, and other maintenance issues. (5)
Measurements made by the spirometer are as follows:
Forced vital capacity (FVC): the total volume of air exhaled
after maximal inhalation.
Forced expiratory volume in 1 second (FEV1): the volume
of air exhaled in the rst second. Reversibility after
inhaled bronchodilator is determined by an increase in
FEV1 of 12% or more or 200 mL from baseline.
Ratio of FEV1 to FVC.
Peak expiratory ow rate: the highest ow obtained
during the forced expiratory maneuver, expressed as liters
per second. This is different than the peak ow meter
readings, which are expressed in liters per minute.
Forced expiratory volume between 25% and 75% of vital
capacity (FEF25%-75%): the ow in the midportion of the
forced expiratory maneuver, which is a reection of the
ow from the smaller airways.
Forced expiratory time: the time that the patient sustains
the expiratory maneuver.
466
Why?
There are many reasons to perform spirometry in a pediatric
patient:
To establish whether pulmonary mechanics are normal in
a child with symptoms.
To dene the nature and severity of any pulmonary
dysfunction (obstructive vs restrictive defect).
To dene the site of airway obstructioncentral vs
peripheral or intrathoracic vs extrathoracic.
To follow the course of pulmonary disease or assess the
effect of therapy.
To establish the presence or absence of airway reactivity.
To assess the risks of diagnostic or therapeutic procedures.
To monitor for adverse effects of chemotherapy or radiation therapy.
To predict prognosis or assess disability and to assess the
effect of disease on lung growth.
You can do this in your ofce! It is important to identify
what barriers exist in your ofce to map out a plan for
sustainable change. Time, patient ow, and quality are often
cited as barriers to spirometry implementation. It is important to remember that each practice is different. Some
practices will group asthma visits that include spirometry
(each practitioner has several dedicated asthma sessions
a month); others will prereview patients before each session
to develop a better patient ow strategy to allow for spirometry. An individualized implementation that matches existing
practice culture appears to be the best strategy to successfully
change and sustain practice patterns. (6)
Although regional (7) and distance or Internet-based
training efforts (8) have been successful at improving the
spirometry capacity and guideline-based asthma care in
primary care pediatricians ofces, many busy practitioners
still struggle with implementing and sustaining routine
spirometry into their busy practice.
The planned asthma visit (Table 1) is a tool that can be
used to implement spirometry in the busy practice. (9) In
this model, patients with asthma can be proactively assessed
for control with an asthma control test and spirometry. This
is a time when trained ofce staff can help to identify asthma
triggers in the home, school, and work environment. Medications and administration technique can be reviewed with
the patient and family, and immunizations, such as inuenza, can be given. Spirometry can also be performed with
a bronchodilator for initial visits to help establish reversibility. Spirometry without a bronchodilator can be performed at follow-up visits to monitor control. All this can
be completed before the practitioner enters the room. The
practitioner will review all the results, examine the patient,
and create or update a written action plan. Follow-up can be
based on severity, asthma control, and seasonal pattern. We

recommend follow-up visits in 2 to 6 weeks for asthma
that is not well controlled and 3 to 6 months for asthma that
is well controlled. Key points for assessing asthma control
and severity and stepwise therapy have been condensed to
a very usable format at the National Center for Medical
Home implementation website (10) and are displayed in Appendix A (information adapted from Texas Childrens Health
Plans Key Points for Asthma Guideline Implementation).
Once the pediatricians ofce staff gains comfort in
spirometry, it can become a useful tool in a busy practice.
The information generated by spirometry will inform the
patient and the practitioner when to step up and when to
step down therapy.
Consider the asthma patient who is a poor perceiver of
symptoms. This type of patient tends to report regular
controller medication use, with good technique, rarely reports needing albuterol, and rarely notices dyspnea on
exertion. When sick, this patient becomes very ill very
quickly and may require intensive care. Often this patient
has been to the specialist and does not feel the need for
further visits because their asthma is just ne. Spirometry
results obtained in the primary care ofce can reveal unnoticed obstruction and provide immediate feedback to the
physician, patient, and family.
COMMON PITFALLS
Calibration is a common pitfall. Because atmospheric pressure and temperature are continuously changing, volumedisplacement spirometers may have to be calibrated daily.
This requires a xed-volume (usually 3-L) syringe with
which to pump air into and out of the spirometer. The
device then recognizes this exact volume as 3 L and is then
TABLE 1.
The Planned Asthma Visit
All patients >4 years old receive the Asthma Control Test
Spirometry is performed with bronchodilator at the initial visit to
establish diagnosis (or without bronchodilator for follow-up)
Practitioner reviews results
Asthma action plan is reviewed or created
Follow-up appointment 16 months based on severity and/or
control
Ofce visit code 99214
Simple spirometry code 94010
Spirometry with bronchodilator code 94060
ready to use for the day. For ow-based spirometers, the

disposable pneumotachometer is factory calibrated and
coded so that the software adjusts for each calibrated unit.
Another common pitfall is test performance. Ofce
personnel who perform the spirometry have to be patient,
nonthreatening, and able to get the best effort out of each
patient they test. Merely purchasing a spirometer and assigning an untrained person to administer the test will not
produce adequate results. The American Thoracic Society
criteria for acceptable spirometry call for a 3-second exhalation in children (6 seconds for adults and older children),
with a zero ow plateau at the end of the breath, and an
appropriately rapid start of exhalation (back-extrapolated volume <5%). Cough, premature termination of exhalation, and
lack of reproducibility between efforts may render the test
result uninterpretable. (11)(12) There may be useful information gathered from less than optimal studies. At least 3 trials
should be performed, in which the highest FEV1 and FVC
values should not differ by more than 5%. (11)(12)
PREDICTED NORMAL VALUES

Reference values for spirometry are derived from studies of
specic populations of healthy people. One example is that of
National Health and Nutrition Examination Survey III. (13)
Popular pediatric predicted sets are those of Hsu et al, (14)
Polgar and Promadhat, (15) and Wang et al. (16) The age of
the patient should be represented in the reference set used.
Other factors that are important are sex, height, weight,
and race/ethnicity. Because height plays a big role in
determining the predicted values, an accurate height measurement should be performed at the time of spirometry.
For nonambulatory patients, arm span can be used to
estimate height. (17)(18) Commercial spirometers usually
will include a choice of reference values, such that the user
can choose one to match the specic patient population
being tested.
NORMAL SPIROMETRY
In general, parameters above 80% of predicted (and an
FEV1/FVC ratio >80%) are considered normal results
(Figure 1). (19)
FLOW-VOLUME LOOPS
A plot of ow vs volume is generated during spirometry and
should be examined to determine the acceptability of the test
and to give a preliminary idea of the interpretative pattern. A
normal ow-volume loop will show the vital capacity on the
Vol. 35 No. 11
NOVEMBER 2014
467
Figure 1. Two examples of normal spirometry results. The upper has

a short exhalation time (horizontal arrows) such as would be seen in
a younger child. The lower has exhalation time longer than 6 seconds,
such as would be expected in an older child or adult. FEF25%75 indicates
expiratory volume between 25% and 75% of vital capacity; FEF50%
indicates forced expiratory ow at 50%; FET, forced expiratory time; FEV1,
forced expiratory volume in 1 second; FIF50%, forced inspiratory ow at
50%; FVC, forced vital capacity; and PEFR, peak expiratory ow rate.
horizontal axis and the peak ow on the vertical axis. The

slope of the curve is an indication of the expiratory ows
(Figure 2). (FEV1 is not calculated from the ow-volume loop
but can be determined from the volume-time curve.)
COACHING THE PATIENT

To improve reliability, the patient should take a few tidal
breaths, inhale deeply and completely, and then blow rapidly
and as long as possible, until there is zero ow, before
inhaling the next breath. Computer-operated systems often
have child-friendly incentives, such as a rocket ship, blowing
out candles on a cake, and other animations that encourage
continued exhalation efforts. The person doing the coaching
has to be child-friendly and patient, yet has to have the
technical expertise to operate the equipment while coaching
the child. It is essential that the child have a tight seal on the
mouthpiece, with the tongue under and not in the mouthpiece. Nose clips are used to prevent loss of air through the
nose. The instructions should be take in a deep breath and
blow, blow, blow. until the test is completed. Three
reproducible trials are recommended, and up to 8 can be
performed and stored on most software. The 2 largest FVC
468
Figure 2. Normal expiratory ow-volume loop (upper left) and volume

time curve (lower right). Note the vital capacity is the linear distance on
the x-axis. The volume-time curve shows an exhalation time of 6.24
seconds and an end-expiratory plateau, indicating complete exhalation.
FET indicates forced expiratory time; FEV1, forced expiratory volume in 1
second; FEV3, forced expiratory volume in 3 seconds; and FVC, forced
vital capacity.
results should be within 150 mL of each other (within 100 mL

for FVC <1 L). In some children, only 1 or 2 acceptable tests
may be performed. For younger children, a parent may be
needed during the test, but older patients should be able to
perform the testing without parental input.
The ow-volume loop must be examined to ensure the
validity of the test. It should rapidly rise to a sharp peak, have
a smooth expiratory curve, and not terminate until full
exhalation has been achieved. Cough, sudden termination
of exhalation, and uneven expiratory effort are common
errors seen in ow-volume loops. The Centers for Disease
Control and Prevention has a web-based poster that illustrates
normal ow-volume loops and those with common errors.
(21) This poster (available at http://cdc.gov/niosh/docs/2011135/pdfs/2011-135.pdf) can be printed and hung in the testing
room, if desired (see Appendix B).
OBSTRUCTIVE LUNG DISEASE

Obstructive lung disease is characterized by decreased airow, as measured by FEV1 and FEF25%75%. The FVC is
usually normal in mild disease, but with more severe disease,
air trapping causes the vital capacity to decrease as the
residual volume increases. It is possible for both FVC and
FEV1 to be normal, but if the ratio of FEV1/FVC ratio is less
than 80%, obstructive lung disease is present. (19) When the
FEV1 and FEF25%75% are diminished, the ow-volume loop
will have a scooped out appearance because of lower ow
rates (Figures 3 and 4). Obstructive lung conditions other

than asthma include chronic obstructive pulmonary disease,
bronchiolitis, bronchiectasis, cystic brosis, congestive heart
failure, sarcoidosis, or pulmonary embolism.
BRONCHODILATOR RESPONSE
In general, an increase in FEV1 of greater than 12% (for low
lung volumes, minimum change of 200 mL) and/or an
increase in FEF25%75% of greater than 20% is considered
a signicant positive response to a bronchodilator (Figure 3).
(19)
RESTRICTIVE LUNG DISEASE

The dening characteristic of restrictive lung disease is
decreased lung volume. The FVC decreases, whereas the
measures of airow, FEV1, and FEF25%75% are preserved.
The key to recognition may lie in the ratio of FEV1/FVC,
which increases as the denominator (the FVC) decreases. In
addition, severe restriction will make all parameters
decrease, except the FEV1/FVC ratio. The ow-volume loop
retains its normal shape but becomes smaller as the vital
capacity diminishes (Figures 5 and 6). Examples of restrictive lung diseases include muscular dystrophy, scoliosis,
pulmonary brosis, and other types of pneumoconiosis.
Figure 4. Flow-volume curve for the results seen in Figure 3. Obstructive

lung disease is present, as indicated by the scooped-out appearance of
the expiratory curve (arrow indicates decreased airow).
Postbronchodilator curve reveals improved airow with similar vital
capacity. FET indicates forced expiratory time; FEV1, forced expiratory
volume in 1 second; FEV3, forced expiratory volume in 3 seconds; and
FVC, forced vital capacity.
inspiration, which produces stridor, dyspnea, and noises that

are often misinterpreted as wheezing.
COMPARISON OF TEST RESULTS

VOCAL CORD DYSFUNCTION SYNDROME
Vocal cord dysfunction is a condition in which a patient
attempts to inhale against partially or totally closed vocal
cords, resulting in inspiratory obstruction. This results in
attening of the lower (inspiratory) limb of the ow-volume
loop (Figure 7). Vocal cord dysfunction is often misdiagnosed
as asthma, with which it is often comorbid. (22) It occurs as
the result of paradoxical closure of the vocal cords on
Figure 3. Obstructive lung disease, as indicated by low forced expiratory

volume in 1 second (FEV1)/forced vital capacity (FVC) ratio, despite
normal values for the FVC and FEV1, and low forced expiratory ow
between 25% and 75% of vital capacity (FEF25%75%). The improvement
in FEV1 and FEF25%75% after bronchodilator is signicant. FEF50%
indicates forced expiratory ow at 50%; FET, forced expiratory time;
FIF50%, forced inspiratory ow at 50%; and PEFR, peak expiratory ow
rate.
The usual convention for dening signicant change

between test results is to have measured volumes (FVC
and FEV1) change by more than 10% and FEF25%75% by
20% to 30% (Figure 8). (19)
EVIDENCE-BASED SUMMARY
On the basis of some research and consensus,_the 2007
NHLBI expert panel asthma guidelines recommend
Figure 5. Restrictive lung disease is present. The forced vital capacity

(FVC) and forced expiratory volume in 1 second (FEV1) are low, but the
FEV1/FVC ratio is relatively preserved (box), which is the key to
recognition for restrictive patterns. FEF25%75% indicates expiratory ow
between 25% and 75% of vital capacity; FEF50%, forced expiratory ow at
50%; FET, forced expiratory time; FIF50%, forced inspiratory ow at 50%; and
PEFR, peak expiratory ow rate.
Vol. 35 No. 11
NOVEMBER 2014
469
Figure 8. Comparison of testing over time. The forced vital capacity

(FVC) and forced expiratory volume in 1 second (FEV1) indicate
improvement from the rst test to the second. FEF25%75% indicates
expiratory ow between 25% and 75% of vital capacity.
Figure 6. Flow-volume curve in restrictive lung disease. The shape is

normal (ie, not scooped out), but the size of the curve is very small,
indicating decreased volume, which is the key to recognition for
restrictive ow-volume loops. FET indicates forced expiratory time; FEV1,
forced expiratory volume in 1 second; FEV3, forced expiratory volume in
3 seconds; and FVC, forced vital capacity.
spirometry be part of routine asthma diagnosis and monitoring of therapy. (3) Just as hypertension is managed by
measuring blood pressure regularly and diabetes is managed by checking blood glucose levels, so should lung
diseases should be managed by performing spirometry in

capable patients. Multiple research studies have provided
evidence indicating that with currently available equipment
and proper training, primary care ofces can and should be
able to offer spirometry to test patients with pulmonary
symptoms. (7)(8)
References
1. Dombkowski KJ, Hassan F, Wasilevich EA, Clark SJ. Spirometry use
among pediatric primary care physicians. Pediatrics. 2010;126
(4):682687
2. Galant SP, Nickerson B. Lung function measurement in the
assessment of childhood asthma: recent important developments.
Curr Opin Allergy Clin Immunol. 2010;10(2):149154
3. National Asthma Education and Prevention Program. Expert Panel
Report 3: Guidelines for the Diagnosis and Management of Asthma;
National Heart, Blood, and Lung Institute. 2007. http://www.nhlbi.nih.
gov/guidelines/asthma/asthgdln.htm. Accessed September 25, 2014
4. Miller MR, Hankinson J, Brusasco V, et al. ATS/ERS Task Force.
Standardization of spirometry. Eur Respir J. 2005;26(2):319338
5. Miller MR, Crapo R, Hankinson J, et al. General considerations for
lung function testing. Eur Respir J. 2005;26:153161.
6. Ragazzi H, Keller A, Ehrensberger R, Irani AM. Evaluation of a practice-based intervention to improve the
management of pediatric asthma. J Urban Health. 2011;88
(suppl 1):3848
7. Cloutier MM, Wakeeld DB. Translation of a pediatric asthmamanagement program into a community in Connecticut. Pediatrics.
2011;127(1):1118
8. Stout JW, Smith K, Zhou C, et al. Learning from a distance:
effectiveness of online spirometry training in improving asthma
care. Acad Pediatr. 2012;12(2):8895
Figure 7. Extrathoracic obstruction. The expiratory ow-volume curve

appears normal in shape, but the inspiratory loop is very at (arrow),
indicating upper airway obstruction, such as is seen with vocal cord
dysfunction. FET indicates forced expiratory time; FEV1, forced expiratory
volume in 1 second; FEV3, forced expiratory volume in 3 seconds; and
FVC, forced vital capacity.
470
9. Stout J, Sadof M. The Planned Asthma Visit. http://www.

medicalhomeinfo.org/downloads/MHCCPA_Conf/
Conf2013_ThePlannedAsthmaVisit_HANDOUT.pdf. Accessed
September 25, 2014
10. Key points for asthma guideline implementation. http://www.
medicalhomeinfo.org/downloads/pdfs/
KeyPointsForAsthmaGuidelineImplementation.pdf. Accessed
September 25, 2014
11. American Thoracic Society. Lung function testing: selection of

reference values and interpretative strategies. Am Rev Respir Dis.
1991;144(5):12021218
17. Aggarwal AN, Gupta D, Jindal SK. Interpreting spirometric data:

impact of substitution of arm span for standing height in adults
from North India. Chest. 1999;115(2):557562
12. Zanconato S, Meneghelli G, Braga R, Zacchello F, Baraldi E. Ofce

spirometry in primary care pediatrics: a pilot study. Pediatrics.
2005;116(6):e792e797
18. Parker JM, Dillard TA, Phillips YY. Arm span-height relationships
in patients referred for spirometry. Am J Respir Crit Care Med.
1996;154(2, pt 1):533536
13. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference

values from a sample of the general U.S. population. Am J Respir Crit
Care Med. 1999;159(1):179187
19. Ruppel GL. Manual of Pulmonary Function Testing. 9th ed. St Louis,
MO: Mosby/Elsievier; 2009.
14. Hsu KHK, Jenkins DE, Hsi BP, et al. Ventilatory functions of
normal children and young adultsMexican-American, white, and
black. I. Spirometry. J Pediatr. 1979;95(1):1423
15. Polgar G, Promadhat V. Pulmonary Function Testing in Children:
Techniques and Standards. Philadelphia, PA: WB Saunders; 1971
16. Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG Jr. Pulmonary
function between 6 and 18 years of age. Pediatr Pulmonol. 1993;15(2):7588
20. Parker MJ. Interpreting spirometry: the basics. Otolaryngol Clin

North Am. 2014;47(1):3953
21. Centers for Disease Control and Prevention. http://www.cdc.gov/
niosh/docs/2011-135/pdfs/2011-135.pdf. Accessed September 25,
2014
22. Vlahakis NE, Patel AM, Maragos NE, Beck KC. Diagnosis of vocal
cord dysfunction: the utility of spirometry and plethysmography.
Chest. 2002;122(6):22462249
Vol. 35 No. 11
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471
PIR Quiz
1. An 8-year-old presents to your ofce with a prolonged cough. You perform spirometry, and
his initial forced expiratory volume in 1 second (FEV1) is 1.30 L. After use of an inhaled
bronchodilator, which of the following FEV1 results represents the most signicant positive
response?
A.
B.
C.
D.
E.
1.15
1.25
1.35
1.40
1.55
L.
L.
L.
L.
L.
2. Which of the following spirometry measurements reects the ow from the smaller
airways?
A.
B.
C.
D.
E.
Forced expiratory ow between 25% and 75% of vital capacity (FEF25%75%).

Forced expiratory time (FET).
FEV1.
FEV1/forced vital capacity (FVC) ratio.
FVC.
3. To gather the most useful and accurate information from spirometry testing, the child
should perform the test at least 3 times and:
A.
B.
C.
D.
E.
The child should exhale slowly and steadily for a minimum of 10 seconds.
The child should exhale through the nose and mouth forcefully for 1 to 2 seconds.
The child should hyperventilate for 30 to 45 seconds before testing.
The FEV1 should increase by at least 12% each time.
The highest FEV1 and FVC values should not differ by more than 5%.
4. When interpreting spirometry results, the most likely condition causing diminished FEV1
and FEF25%75% and resulting in a ow-volume loop with a scooped-out appearance is:
A.
B.
C.
D.
E.
Asthma.
Pneumoconiosis.
Pulmonary brosis.
Scoliosis.
Vocal cord dysfunction.
5. Which of the following clinical conditions is most likely to cause the following ndings on
spirometry: a small but normal-shaped ow-volume loop and demonstration of increased
ratio of FEV1/FVC?
A.
B.
C.
D.
E.
472
Asthma.
Bronchiectasis.
Chronic obstructive pulmonary disease.
Muscular dystrophy.
Sarcoidosis.
learners must
or higher on this
assessment, which
than 60% on the
given additional
achieved.
Appendix A
Vol. 35 No. 11
NOVEMBER 2014
473
Appendix A Continued.
474
Appendix B
Vol. 35 No. 11
NOVEMBER 2014
475
Respiratory Failure
Phuong Vo, MD,* Virginia S. Kharasch, MD
*Division of Pediatric Pulmonary and Allergy, Boston Medical Center, Boston, MA
Division of Respiratory Diseases, Boston Childrens Hospital, Boston, MA
Practice Gap
The primary cause of cardiopulmonary arrest in children is unrecognized
respiratory failure. Clinicians must recognize respiratory failure in its
early stage of presentation and know the appropriate clinical
interventions.
Objectives
After completing this article, readers should be able to:
1. Recognize the clinical parameters of respiratory failure.

2. Describe the respiratory developmental differences between children
and adults.
3. List the clinical causes of respiratory failure.
4. Review the pathophysiologic mechanisms of respiratory failure.
5. Evaluate and diagnose respiratory failure.
6. Discuss the various clinical interventions for respiratory failure.
WHAT IS RESPIRATORY FAILURE?

Respiratory failure is a condition in which the respiratory system fails in oxygenation or carbon dioxide elimination or both. There are 2 types of impaired gas
exchange: (1) hypoxemic respiratory failure, which is a result of lung failure, and
(2) hypercapnic respiratory failure, which is a result of respiratory pump failure
(Figure 1). (1)(2)
_ mismatch
_ Q)
In hypoxemic respiratory failure, ventilation-perfusion (V=
results in the decrease of PaO2) to below 60 mm Hg with normal or low PaCO2.
_ mismatch results in the increase of
_ Q
(1) In hypercapnic respiratory failure, V=
PaCO2 to above 50 mm Hg. Either hypoxemic or hypercapnic respiratory failure
can be acute or chronic. Acute respiratory failure develops in minutes to hours,
whereas chronic respiratory failure develops in several days or longer. In acute
hypercapnic respiratory failure, the pH decreases below 7.35, and, for patients
with underlying chronic respiratory failure, the PaCO2 increases by 20 mm Hg
from baseline. (2) Acute and chronic hypoxemic respiratory failure cannot be
readily distinguished from arterial blood gases. Clinical markers, such as
polycythemia, pulmonary hypertension, or cor pulmonale, indicate chronic
hypoxemia.
476
AUTHOR DISCLOSURE Drs Vo and Kharasch

have disclosed no nancial relationships
relevant to this article. This commentary does
not contain a discussion of an unapproved/
investigative use of a commercial product/
device.
ABBREVIATIONS
ECMO
extracorporeal membrane
oxygenation
VAP
ventilator-associated pneumonia
_ Q_
V=
ventilation perfusion
Figure 1. Types of respiratory failure.
EPIDEMIOLOGY
Infants and young children have a higher frequency of
respiratory failure. (3)(4) Approximately half of respiratory
failure cases are seen in the neonatal period, resulting from
complications of prematurity and transitioning to extrauterine life. In addition, developmental differences between
children and adults also explain the higher incidence. (1)
(3)(4) First, infants and young children have a smaller upper
airway, with the subglottic area being the narrowest. Any
inammatory process can result in airway narrowing and
subsequently in increased work of breathing. Second,
immature stages of lung growth and development present
with fewer numbers of alveoli, smaller intrathoracic airway
caliber with little cartilaginous support, and underdeveloped
collateral ventilation, predisposing infants to atelectasis.
Third, infant respiratory muscles have reduced type 1 muscle bers, specically the diaphragm, resulting in lower
respiratory tract muscle bulk and reserve. Fourth, the chest
wall is more compliant than in adults because of a less bony
thorax, compromising thoracic expansion, and may result in
accessory muscle use and paradoxical patterns of respiration.
Fifth, bradypnea, apnea, or tachypnea commonly results from
the immaturity of the respiratory center. All these factors
result in a higher metabolic demand per kilogram of body
weight, resulting in increased work of breathing and early
fatigue.
PATHOPHYSIOLOGY
Respiration involves the nervous, cardiovascular, musculoskeletal, and respiratory systems. The causes of respiratory
failure can come from any of these systems and are expansive. Common causes can be grouped based on underlying
conditions, such as lung and airway disorders, respiratory

pump failure, respiratory center failure, and failure to meet
increased metabolic needs (Table 1).
The pathophysiologic mechanisms that lead to respira_ mismatch or im_ Q
tory failure involve primarily either V=
pairment of oxygen transfer at the alveolar-capillary
_ mismatch most commonly con_ Q
membrane. (1)(2)(5) V=
tributes to respiratory failure. During gas exchange, per_
_ Q1).
fusion and ventilation try to match each other (V=
(6)
However, both do not perfectly match, even in healthy
lungs. During alveolar ventilation, some capillary units are
underperfused, whereas others are overperfused. Similarly, during perfusion, some alveolar units are under_
_ Q
ventilated, whereas others are overventilated. A high V=
ratio is when the alveoli are well ventilated but are not well
_ ratios act like dead space. A low V=
_
_ Q
_ Q
perfused. High V=
ratio is when the alveoli units are well perfused but are not
_ ratios act like shunts.
_ Q
well ventilated. Low V=
Diffusion limitation is the impairment of transfer of oxygen
at the alveolar-capillary membrane. (1)(2)(6) This can result
from alveolar or interstitial inammation and brosis. Diffu_ mismatch.
_ Q
sion limitation usually coexists with V=
These 2 common pathophysiologic mechanisms of respiratory failure are observed in a variety of diseases. Pulmonary
conditions that involve the bronchi (eg, status asthmaticus
and bronchiolitis) or inammation or infection of the parenchyma (eg, pneumonia, aspiration, cystic brosis, and ciliary
dysmotility) result in airway obstruction and/or parenchymal
_ mismatch and impaired gas exchange.
_ Q
loss, leading to V=
Specically, status asthmaticus occurs because of progression
of airway inammation, bronchospasm, and mucous plugging during days to weeks or sudden onset of asphyxia from
_
_ Q
bronchospasm. In either case, airway obstruction causes V=
mismatch, incomplete alveolar gas exchange, and lung
Vol. 35 No. 11
NOVEMBER 2014
477
TABLE 1.
Causes of Respiratory Failure
Lung and airway disorders

Lung parenchyma
Bronchiolitis
Severe asthma
Aspiration
Pneumonia
Pulmonary edema
Cystic brosis
Airway
Laryngotracheobronchomalacia
Croup
Tracheitis
Vascular malformations (ring, sling, right-sided aortic arch)
Subglottic stenosis, complete tracheal ring
Respiratory pump failure
Restrictive lung disorders (kyphoscoliosis)
Chest wall abnormalities: congenital or traumatic (ail chest)
Neuromuscular disorders (phrenic nerve paralysis, myopathies,
muscular dystrophies)
Diaphragmatic disorders (paralysis, congenital diaphragmatic
hernia)
Respiratory center failure
Brain injuries (traumatic)
Central nervous system infection (controlled mechanical
ventilation) or hypoxic encephalopathies
Drug overdose or adverse effects
Congenital (leukomalacia) or genetic disorders (congenital
hypoventilation syndrome)
Failure to meet increased metabolic needs
Septic shock
hyperination. End-expiratory alveolar pressure increases as

a result, creating an autopositive end-expiratory pressure
state. Work of breathing is increased to overcome the autopositive end-expiratory pressure for inspiratory ow to occur,
eventually leading to inspiratory muscle fatigue and respiratory failure. (7) In cystic brosis, similarly, an acute pulmonary exacerbation can result in airway obstruction and
_ mismatch and reduced
_ Q
mucous plugging, leading to V=
functional residual capacity. Increased work of breathing
results in respiratory muscle fatigue, leading to hypoventila_
_ Q
tion, hypercarbia, and respiratory failure. In addition to V=
478
mismatch, impairment of gas exchange at the alveolarcapillary membrane is observed in progressive cystic brosis
disease with pulmonary brosis and destruction. (8) Obstruction from infectious causes, foreign-body aspiration, burn
injuries, anaphylaxis, or decreased muscle tone from depressed consciousness or neuromuscular disorders can
result in complete or partial airway obstruction. Complete
obstruction causes asphyxia, where the lungs are not ventilated but well perfused. Adequate airow is usually initially
observed in partial obstruction. As airow obstruction increases from either a valvelike effect in foreign-body aspiration or airway inammation and mucous secretions,
respiratory failure can occur. (9) Central nervous system
disorders include congenital malformations, such as absent
corpus callosum; abnormal central control of respiration,
such as periodic breathing; apnea of prematurity; central
apnea; Ondine curse; acquired injuries, such as head trauma;
intracranial bleeding; hypoxic ischemic encephalopathy; and
cerebral palsy. In these conditions, respiratory efforts are
inadequate and hypoventilation or apnea ensues, resulting in
carbon dioxide retention and respiratory failure. (10)
CLINICAL PRESENTATIONS
The clinical presentations of respiratory failure depend on
the underlying cause and the level of hypoxemia and hypercapnia. Infants and children most commonly present with
increased work of breathing: tachypnea, grunting, nasal
aring, and retractions. (3)(11) These signs of increased
work of breathing are blunted in those with neuromuscular
disorders. These patients instead present with tachypnea
and shallow breathing without retractions.
Additional signs and symptoms of respiratory failure
may be observed, depending on the level of hypoxemia
and hypercapnia (Table 2). (4) Impending respiratory failure
can present as dyspnea, mood changes, disorientation,
pallor, or fatigue. With acute hypercapnia, ushing, agitation, restlessness, headache, and tachycardia can occur.
Children with chronic respiratory failure often present with
worsening hypercapnia and hypoxemia. Reduced consciousness or coma and depressed tendon reexes occur
with severe chronic carbon dioxide retention. Cyanosis,
polycythemia, cor pulmonale, and pulmonary hypertension
are complications of chronic hypoxemia.
HISTORY AND PHYSICAL EXAMINATION

Determining whether there is any need for emergency
intervention is the rst step in assessing a patient with
respiratory failure. Vital signs, work of breathing, and level
TABLE 2.
Signs and Symptoms of Hypoxia and

Hypercapnia
HYPOXIA
HYPERCAPNIAa
Mild
Mild
None or depressed
efciency
Moderate
Flushed skin
Headaches
Moderate
Dyspnea
Tachypnea
Headaches, dizziness
Tachycardia
Fatigue
Dyspnea
Pallor
Muscle twitches,
depressed tendon
reexes
Tachycardia, cardiac
arrhythmias
Drowsiness, confusion
Hypertension
Mood changes: euphoria,
disorientation, or depression
Ataxia, tingling
Hypertension
Severe
Severe
Cyanosis
Papilledema
Coma
Hypotension
Bradycardia
Visual impairment
Loss of consciousness,
seizures, coma
a
In chronic hypercapnia, signs and symptoms of hypercapnia are
observed when PCO2 increases above baseline level.
of consciousness indicate which patients require immediate

respiratory support. Respiratory support should be urgently
provided for a patient with signicant tachypnea, retractions, grunting, nasal aring, and head bobbing. (11) Delay
in respiratory support may lead to the patient becoming
increasingly fatigued, resulting in shallow breathing, reduced
consciousness, and cyanosis. Emergency intubation and
mechanical ventilation should be initiated when such impending signs of respiratory failure are assessed. Airway
control and ventilatory support should also be initiated in
patients with impending cardiac arrest or central nervous
system disorders with decreased responsiveness. (3)(11)
After determining whether emergency respiratory intervention is necessary, the next step is to obtain a comprehensive history to evaluate for likely causes of the respiratory
failure. Risk factors, such as prematurity, immunodeciency,
anatomical abnormalities, and chronic pulmonary, cardiac, or
neuromuscular disorders (eg, cystic brosis, asthma, unrepaired congenital heart disease, myasthenia gravis, or spinal
muscular dystrophy) must be identied. (4) Additional factors, such as history of fevers, symptoms of respiratory
infection (cough, rhinorrhea, or nasal congestion), history
of seizures, head trauma, or possible exposures to sedatives,
must be noted. (3)(4)
For the physical examination, vital signs are very helpful
to indicate the severity of the respiratory failure. (3)(11)
Tachypnea is a sensitive indicator of respiratory disease.
Increased respiratory rate is one of the earliest compensatory mechanisms of respiratory failure. However, respiratory rates can be elevated during infancy, sleeping, eating,
and increased activity in healthy children. Heart rate also
increases to maintain adequate oxygen delivery. Blood pressure can be initially normal or high. When respiratory
failure is in the decompensated phase, low blood pressure
occurs. Pulse oximetry saturation estimates the oxygen
saturation of hemoglobin. A 90% oxygen saturation on
pulse oximetry correlates with a PaO2 of 60 mm Hg based
on the sigmoid shape of the oxyhemoglobin dissociation
curve (Figure 2). (6) Pulse oximetry measures only saturation. It does not measure oxygen content or delivery. Thus,
pulse oximetry has several limitations. The oxygen saturation can be falsely high with an elevated carboxyhemoglobin
level in a patient with carbon monoxide or methylene
chloride poisoning. (12) Carbon monoxide binds to hemoglobin with much greater afnity than oxygen, leading to
tissue hypoxia. It also causes a left shift of the oxyhemoglobin dissociation curve, thereby decreasing the release of the
oxygen and causing further tissue hypoxia. In a patient with
an elevated methemoglobin level, the pulse oximetry saturation tends to be overestimated. In patients with poor tissue
perfusion due to shock, hypovolemia, or hypothermia, the
pulse oximetry is unable to detect the oxygen saturation accurately; these patients may have falsely low oxygen saturation.
The initial step of the physical examination of respiratory
failure is assessing the work of breathing. (3)(11) One should
assess the respiratory rate and quality, keeping in mind agespecic norms. When tachypnea is accompanied by retractions, nasal aring, or grunting, respiratory support with
either noninvasive or invasive positive pressure is needed.
Bradypnea is often observed in respiratory center failure,
indicating the need for emergency respiratory intervention.
Bradypnea or hypoventilation is also observed in patients
with neuromuscular disorders. These patients have shallow
and ineffective breathing and usually do not present with
retractions. In these patients, spirometric measurements
with forced vital capacity less than 40% correlate with
carbon dioxide retention and nocturnal hypoventilation.
When assessing the respiratory rate, the chest wall should
also be inspected. Asymmetric chest expansion indicates
Vol. 35 No. 11
NOVEMBER 2014
479
Figure 2. Oxygen dissociation curve.
possible pneumothorax, moderate to severe empyema or

pleural effusion, or chest trauma. Paradoxical movement of
the chest and abdomen during inspiration and expiration
signals respiratory distress.
Auscultation of the chest provides information about the
symmetry and quality of air movement and the presence of
abnormal breath sounds. (3)(11) Wheezing can be heard on
inspiration or expiration. Typically, expiratory wheeze reects disease of the lower airways, such as asthma. In acute
moderate to severe asthma, inspiratory wheeze may accompany expiratory wheeze. A local or asymmetric wheeze can
indicate possible airway obstruction due to a foreign body or
a mass. Stridor is a high-pitched inspiratory wheeze usually
caused by upper airway narrowing or obstruction in such
conditions as laryngomalacia, croup, tracheitis, subglottic
stenosis, or vascular rings. Crackles or rales are heard when
alveoli open and imply small airway diseases, such as
pneumonia, congestive heart failure, pulmonary brosis,
or other interstitial pulmonary processes.
In addition to the respiratory examination, examination
of the heart for any abnormal heart sounds is important for
assessing heart conditions that can lead to respiratory
failure. (3)(11) Furthermore, a neurologic examination is
also pertinent by assessing for mental status changes with
the Glasgow Coma Scale. (4) Neurologic impairment is
observed when the Glasgow Coma Scale score is low. A
score of 8 or below indicates severe neurologic compromise.
At this level of altered mental status, the patient is not able
to control his or her airway and secretions. Intubation and
480
mechanical ventilation are required. Aside from assessing

for mental status changes, the neurologic examination should
also include examination of muscle strength. Conditions
in which muscle strength are decreased, such as mitochondrial diseases, Guillain-Barre syndrome, spinal muscular
atrophy, or Duchenne muscular dystrophy, lead to respiratory
failure. (3)(4)
DIAGNOSIS
Laboratory and radiographic studies are helpful in the assessment of respiratory failure and the monitoring of the
response to therapeutic management. However, emergency
respiratory support should be initiated when indicated and
not be delayed while awaiting results of diagnostic studies.
Laboratory studies, such as an arterial blood gas, endtidal carbon dioxide, oxygen saturation, a complete blood
cell count with differential, and renal and liver functions,
should be performed. The arterial blood gas accurately measures the extent of the gas exchange abnormality and conrms the type and chronicity of respiratory failure. (4)
Normal arterial blood gas values are as follows: pH 7.4
(reference range, 7.387.42); PO2, 80 to 100 mm Hg; PCO2, 35
to 45 mm Hg; oxygen saturation, 95% on room air; bicarbonate, 22 to 26 mEq/L; and base excess, 2 to 2 mEq/L. In
acute respiratory failure, PaO2 is less than 60 mm Hg, pH is
below 7.35, PaCO2 is greater than 50 mm Hg, and serum
bicarbonate concentration is low or normal. In chronic
carbon dioxide retention, carbon dioxide is increased, pH
is normal, and serum bicarbonate concentration and base

excess are increased. The arterial blood gas of the patient
with an opiate overdose differs based on the severity of the
overdose. In mild to moderate opiate overdose, respiratory
acidosis is observed with a pH below 7.35, PaCO2 greater
than 50 mm Hg, and a low or normal serum bicarbonate
concentration. In severe opiate overdose, a mixed respiratory
and metabolic acidosis is observed. End-tidal carbon dioxide
is measured from expired air from the nose by a capnometer
and is a common and reliable tool used in the emergency
department and critical care setting.
The complete blood cell count helps to assess such
causes as infection, anemia, or polycythemia. In addition,
respiratory, blood, urine, and pleural cultures and polymerase
chain reaction can be performed when indicated to identify
the specic bacterial cause. Renal and liver function tests
provide clues to the cause of or identify complications associated with respiratory failure. Electrolyte abnormalities, such
as hypernatremia or hyponatremia, cause seizures, and hyperkalemia causes cardiac arrhythmia.
Chest radiography should be performed in patients who
present with respiratory failure to help identify or conrm
the cause of the respiratory failure. If a cardiac cause of acute
respiratory failure is suspected, electrocardiography and
echocardiography should be performed.
Pulmonary function testing evaluates the functional status of the respiratory system by measuring the volume and
ow of air movement, gas exchange, and strength of the
respiratory muscles. Pulmonary function testing includes
a group of tests, such as spirometry, lung volumes, diffusion
capacity, and maximal respiratory pressures, among others.
It helps to determine the characteristics of the respiratory
disease and to guide management. Pulmonary function
testing is not typically performed when the patient is critically ill. Flexible bronchoscopy can also be performed to aid
in diagnosis and therapeutic management.
TABLE 3.
Biopsies and bronchoalveolar lavage for microbiologic,

cytologic, and histologic testing can be obtained with bronchoscopy. When a patient is critically ill, it may not be safe to
perform the bronchoscopy because manipulation of the
airway may induce bronchospasm or atelectasis.
MANAGEMENT
Early diagnosis, close monitoring, and timely intervention
are of utmost importance in a patient presenting with
respiratory distress. (3)(4) The primary cause of cardiopulmonary arrest in children is unrecognized respiratory failure. Interventions in a patient with respiratory failure range
from close monitoring and supplemental oxygen to full
respiratory support with mechanical ventilation. The initial
step in the treatment of a patient with respiratory failure is
rapid assessment of airway, breathing, and circulation to
determine whether the patient needs urgent intervention.
Indications for intubation and mechanical ventilation
include the patients inability to maintain an adequate
airway and protect the airway from aspiration, failure of
oxygenation and ventilation, and deteriorating status that
will lead to inability to maintain airway patency and normal
gas exchange.
The initial step and most basic airway management for
a patient in respiratory failure is bag-mask ventilation,
which allows for oxygenation and ventilation until a more
denitive airway can be established. Although the patient is
receiving bag-mask ventilation, necessary equipment (endotracheal tube, large-bore suction, beroptic scope, laryngoscope, carbon dioxide detector, and intubation drugs) can be
prepared for intubation. (4) When possible, intubation
should be performed by the most experienced medical
professional (emergency care personnel, critical care physicians, and anesthesiologists) to ensure successful intubation and to avoid multiple unsuccessful attempts. Failure to
Interpretation of Blood Gas Resultsa
CONDITION
pH
Paco2
BASE EXCESS
Acute respiratory acidosis or acute hypoventilation
Acute respiratory alkalosis or acute hyperventilation
Acute or chronic respiratory acidosis
/[
Acute metabolic acidosis with respiratory compensation
Chronic respiratory acidosis with metabolic compensation
Normal/slightly Y
Ydecrease; [increase; 4no change.
Vol. 35 No. 11
NOVEMBER 2014
481
quickly secure an adequate airway can lead to morbidity or

death.
Sedative agents alone or in conjunction with paralytic
agents are used for intubation. When a difcult airway is
anticipated (eg, Pierre Robin syndrome or anterior mediastinal mass), paralytic agents are avoided, and the patient is
intubated in a more awake state or with a berscope. If
successful intubation is unlikely, the airway can be secured
with a laryngeal mask airway. (3) The laryngeal mask airway is
a supraglottic airway device used as an important alternative airway device in the emergency setting when a very
difcult airway is encountered. Placement of the laryngeal
mask airway does not require laryngoscopy or paralytic
agents. Although it is an easier device to secure an adequate airway, the laryngeal mask airway does not protect
against aspiration.
Once patients are evaluated and emergency intervention
with intubation and mechanical ventilation is not indicated,
mild cases of respiratory failure may require only close
monitoring and supplemental oxygen as needed by lowor high-ow nasal canula or a nonrebreather mask.
A nonrebreather mask can deliver a higher amount of
oxygen (1015 L/min) than a nasal cannula. (4) Respiratory
drive in patients with chronic respiratory failure is stimulated primarily by hypoxia. Improving oxygenation in
these patients can lead to blunting of the hypoxic drive
of the respiratory center, resulting in decreased alveolar
ventilation and increased carbon dioxide retention and
leading to acute respiratory failure on top of chronic
respiratory failure.
Noninvasive ventilation is used to manage both acute and
chronic respiratory failure. (10)(13) It is now commonly used
not only in the emergency department and critical care
setting but also in the patients homes. It is indicated in
patients who are cooperative and have increased work of
breathing or respiratory muscle fatigue. It is contraindicated
in patients with altered mental status, cardiac instability, and
inability to protect the airway because of a weak cough or
swallowing. Its use in the pediatric intensive care unit is
associated with decreased intubation rates. (14) Modes of
noninvasive ventilation include continuous positive airway
pressure or bilevel positive airway pressure. The positive
pressure can be delivered through a variety of interfaces
(mouthpiece, oronasal face mask, nasal pillow, or helmet
mask). Continuous positive airway pressure provides a continuous level of positive airway pressure during the entire
respiratory cycle to keep the airways open. Bilevel positive
airway pressure provides an inspiratory positive airway
pressure and an expiratory positive airway pressure. The
inspiratory positive airway pressure is generated as the
482
patient breathes in, providing effective inspiratory volume

expansion, whereas the expiratory positive airway pressure
is generated as the patient breathes out, maintaining positive end-expiratory pressure to prevent airway collapse and
to keep the lungs expanded. Common complications of
noninvasive ventilation include facial pressure skin injury
from prolonged use, dry mucous membranes, and thickened secretions.
Positive pressure ventilation or mechanical ventilation is
most commonly used to manage acute respiratory failure.
(5) The goal of mechanical ventilation is to relieve respiratory distress by decreasing the inspiratory work of breathing,
improving pulmonary gas exchange, allowing the lungs to
heal, reversing respiratory muscle fatigue, and preventing
further complications due to abnormal gas exchange. There
are several types of mechanical ventilators that offer different modes and features. Mechanical ventilators provide
positive pressure ventilation by pressure-limited ventilation
or volume-limited ventilation. In pressure-limited ventilation, the gas is allowed to ow into the lungs until a preset
airway pressure limit is reached, at which time a valve
opens, allowing exhalation to ensue. In volume-limited
ventilation, gas ows to the patient until a preset volume
is delivered to the ventilator circuit, even if this entails a very
high airway pressure. One of the factors to consider when
deciding which ventilator to use is the mode of mechanical
ventilation or the method of inspiratory support. There is
limited evidence-based research to demonstrate that the
mode affects clinical outcomes; therefore, the decision on
which mode to use is based on the capability of available
ventilators to manage small infant volumes and clinicians
experience with the mechanical ventilators. Common modes
of mechanical ventilation include controlled mechanical ventilation, assist control, synchronized intermittent mandatory
ventilation, and pressure support ventilation. In the controlled mechanical ventilation mode, the ventilator delivers
a preset minute ventilation (preset tidal volume and respiratory rate), and the patient cannot trigger additional breaths
above what is set. This mode is usually used for patients who
are paralyzed, heavily sedated, or comatose. In the assist
control mode, minimum minute ventilation is set, and the
patient can trigger additional breaths. If the patient fails to
trigger a breath within a selected time, the ventilator delivers
the breaths. The assist control mode is not appropriate when
the patient is ready to wean off the ventilator because it gives
a full breath each time. The synchronized intermittent mandatory ventilation mode allows the patient to increase minute
ventilation by preset breath rate synchronized with spontaneous breathing, rather than patient-initiated ventilator
breathing as in the assist control mode. In the pressure
support ventilation mode, the ventilator delivers a preset

pressure support level while the patient triggers each breath
because there is no preset minute ventilation. In addition to
these conventional modes of ventilation, high-frequency
ventilation is commonly used, especially in premature neonates. The high-frequency oscillatory ventilator delivers small
tidal volumes by oscillating air movements at an extremely
rapid rate (3001500 breaths per minute). A Cochrane review
concludes no difference in benet between high-frequency
oscillatory ventilation compared with conventional ventilation in preterm infants. (15) A previous study found that
length of mechanical ventilation, intensive care unit length
of stay, and mortality were signicantly higher in highfrequency oscillatory ventilation patients compared with
the controlled mechanical ventilation patients ages 1 to 18
years who were hospitalized in the pediatric intensive care
unit of a diverse group of hospitals that care for children in
the United States. (16)
Newer modalities include neurally adjusted ventilatory
assist and proportional assist ventilation. These modalities
of assisted ventilation require that the patient spontaneously breathes and the delivered airway pressure changes,
depending on the patients breathing effort; thus, varying
degrees of unloading of work by the respiratory muscles on
inspiration on a breath by breath basis are delivered. In the
neurally adjusted ventilatory assist, an esophageal sensor
represents neural output from the respiratory center, controlling the timing and magnitude of the delivered pressure.
(17)
Ventilator complications include infection and lung
injury. Ventilator-associated pneumonia (VAP) has been
described more in adult than children. The estimated incidence of VAP in pediatrics is 3 per 1000 ventilator-days. (18)
Objective diagnosis of VAP is not well dened, even in
adults. In a prospective study of a sample of children in the
pediatric intensive care unit, Srinivasan et al (18) found that
VAP was more likely in patients who were female, had
undergone surgery, were taking narcotics, and were fed
enterally. In 2011, the Centers for Disease Control and
Prevention formed a VAP Surveillance Denition Working
Group. Guidelines outline the identication of patients with
respiratory status deterioration (eg, increased need of
inspired oxygen or positive end-expiratory pressure) after
having been stable while receiving ventilatory support;
evidence of respiratory infection with abnormal white blood
cell count, culture, or temperature; and initiation of antibiotic therapy. (19)
Ventilator-induced lung injury is another potential complication of mechanical ventilation. Ventilator-induced lung
injury is a result of alveolar overdistension and cyclic
atelectasis from high pulmonary pressure and oxygenation.

The most common risk factor for ventilator-induced lung
injury is acute respiratory distress syndrome. Strategies to
prevent ventilator-induced lung injury include using small
tidal volumes that range from 6 to 8 mL/kg, applying
positive-end expiratory pressure, and maintaining a low
plateau airway pressure of 30 cm H2O or less. (20)(21)
(22) These strategies are based on adult studies.
In premature infants particularly, prolonged mechanical ventilation not only leads to acute complications, such
as infection and lung injury, but also results in long-term
sequelae, such as chronic lung disease and neurodevelopmental delays. Strategies to minimize these complications
include preservation of spontaneous breathing by applying patient-triggered and volume target ventilation,
administering respiratory stimulants (eg, caffeine), and
using nasal continuous positive airway pressure or nasal
intermittent positive pressure ventilation after extubation.
(23)
Extracorporeal membrane oxygenation (ECMO) can be
considered when all other options have failed and the
respiratory failure is a result of a reversible underlying
illness. (24)(25) ECMO provides cardiopulmonary support
extracorporeally to prevent further lung injury from highpressure ventilation and allow the lungs to heal. ECMO was
initially used almost exclusively in neonates. Its use to
support older pediatric patients has increased throughout
the years. In the past 5 years, there have been approximately
300 to 500 cases annually. (25) Relative contraindications for
ECMO include patients who have irreversible respiratory or
cardiac failure, who cannot undergo anticoagulation, and
who undergo ventricular assist device implantation. Complications include bleeding, thromboembolism, and heparininduced thrombocytopenia. (26) Prognosis depends primarily
on the underlying illness. Mortality remains approximately
43%. Risk factors associated with death include older patient
age, other nonpulmonary organ dysfunction, prolonged
use of mechanical ventilation (>2 weeks) before ECMO,
prolonged ECMO support, and complications during
ECMO. (25)(26)
A small group of severely compromised children may
require prolonged mechanical ventilation. Overall, their
prognosis is good compared with adults. Outcomes data
reveal that 65% of children who require a postacute
rehabilitation facility for prolonged weaning are eventually
discharged to home and that 45% of children discharged to
pulmonary rehabilitation were weaned on discharge. (27)
(28) Weaning protocols have been established for the
management of chronic respiratory failure in children.
(29)
Vol. 35 No. 11
NOVEMBER 2014
483
Summary
On the basis of research evidence, (1)(2) numerous diseases and
conditions can impair gas exchange, resulting in failure to meet
the bodys metabolic demands and leading to respiratory failure.
On the basis of consensus, (1)(2)(7)(8)(9)(10) the clinical
presentations of respiratory failure depend on the underlying
cause and the level of hypoxemia and hypercapnia. Early
diagnosis, close monitoring, and timely intervention are of
utmost importance.
On the basis of research evidence, (5)(14)(25) interventions range
from noninvasive methods, such as close monitoring and
supplemental oxygen, to full respiratory support with mechanical
ventilation and in extreme cases even the use of extracorporeal
membrane oxygenation.
13. Hess DR. The growing role of noninvasive ventilation in patients

requiring prolonged mechanical ventilation. Respir Care. 2012;57
(6):900920
14. Marohn K, Panisello JM. Noninvasive ventilation in pediatric
intensive care. Curr Opin Pediatr. 2013;25(3):290296
15. Soll RF. Elective high-frequency oscillatory ventilation versus
conventional ventilation for acute pulmonary dysfunction in
preterm infants. Neonatology. 2013;103(1):78, discussion 89
16. Gupta P, Green JW, Tan X, Gall C, et al. Comparison of highfrequency oscillatory ventilation and conventional mechanical
ventilation in pediatric respiratory failure. JAMA Pediatr. 2014;163
(3):243249
17. Sinderby C, Beck J. Proportional assist ventilation and neurally
adjusted ventilatory assistbetter approaches to patient ventilator
synchrony? Clin Chest Med. 2008;29(2):329342, vii
ACKNOWLEDGMENT
18. Srinivasan R, Asselin J, Gildengorin G, Wiener-Kronish J, Flori HR.

A prospective study of ventilator-associated pneumonia in children.
Pediatrics. 2009;123(4):11081115
The authors thank Karen Contador, a student at Boston

University, for assistance with editing.
19. Magill SS, Klompas M, Balk R, et al. Developing a new, national

approach to surveillance for ventilator-associated events. Crit Care
Med. 2013;41(11):24672475
References
1. Gutierrez JA, Duke T, Henning R, South M. Respiratory failure and
acute respiratory distress syndrome. In: Taussig LMLL, ed. Pediatric
Respiratory Medicine. Vol 2. Philadelphia, PA: Mosby Elsevier;
2008:253274
2. Roussos C, Koutsoukou A. Respiratory failure. Eur Respir J Suppl.
2003;47(suppl 47):3s14s
3. Hammer J. Acute respiratory failure in children. Paediatr Respir Rev.
2013;14(2):6469
4. Nitu ME, Eigen H. Respiratory failure. Pediatr Rev. 2009;30
(12):470478.
5. Tobin MJ, Laghi F, Jubran A. Ventilatory Failure, Ventilator Support,
and Ventilator Weaning. Comprehensive Physiology. Hoboken, NJ:
John Wiley & Sons Inc.; 2012
6. Leff AR, Schumacker PT. Respiratory Physiology. Philadelphia, PA:
WB Saunders Company; 1993
20. The Acute Respiratory Distress Syndrome Network. Ventilation

with lower tidal volumes as compared with traditional tidal volumes
for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med. 2000;342(18):13011308
21. Futier E, Constantin J-M, Paugam-Burtz C, et al; IMPROVE Study
Group. A trial of intraoperative low-tidal-volume ventilation in
abdominal surgery. N Engl J Med. 2013;369(5):428437
22. Caironi P, Cressoni M, Chiumello D, et al. Lung opening and
closing during ventilation of acute respiratory distress syndrome.
Am J Respir Crit Care Med. 2010;181(6):578586
23. Bancalari E, Claure N. Strategies to accelerate weaning from
respiratory support. Early Hum Dev. 2013;89(suppl 1):S4S6.
24. Rehder KJ, Turner DA, Bonadonna D, Walczak RJ Jr, Cheifetz IM.
State of the art: strategies for extracorporeal membrane
oxygenation in respiratory failure. Expert Rev Respir Med. 2012;6
(5):513521
7. Gluckman TJ, Corbridge T. Management of respiratory failure in

patients with asthma. Curr Opin Pulm Med. 2000;6(1):7985.
25. Maslach-Hubbard A, Bratton SL. Extracorporeal membrane

oxygenation for pediatric respiratory failure: history,
development and current status. World J Crit Care Med. 2013;2
(4):2939
8. Sprague K, Graff G, Tobias DJ. Noninvasive ventilation in

respiratory failure due to cystic brosis. South Med J. 2000;93
(10):954961
26. Zangrillo A, Landoni G, Biondi-Zoccai G, et al. A meta-analysis of

complications and mortality of extracorporeal membrane
oxygenation. Crit Care Resusc. 2013;15(3):172178
9. Peger A, Eber E. Management of acute severe upper airway

obstruction in children. Paediatr Respir Rev. 2013;14(2):7077
27. OBrien JE, Haley SM, Dumas HM, et al. Outcomes of post-acute
hospital episodes for young children requiring airway support. Dev
Neurorehabil. 2007;10(3):241247
10. Falsaperla R, Elli M, Pavone P, Isotta G, Lubrano R. Noninvasive

ventilation for acute respiratory distress in children with central
nervous system disorders. Respir Med. 2013;107(9):13701375
11. Brown MAME, Morgan WJ. Clinical assessment and diagnostic
approach to common problems. In: Taussig LMLL, ed. Pediatric
Respiratory Medicine. Vol 2. Philadelphia, PA: Mosby Elsevier;
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12. Rehberg S, Maybauer MO, Enkhbaatar P, Maybauer DM, Yamamoto

Y, Traber DL. Pathophysiology, management and treatment of
smoke inhalation injury. Expert Rev Respir Med. 2009;3
(3):283297
28. OBrien JE, Dumas HM, Haley SM, et al. Ventilator weaning
outcomes in chronic respiratory failure in children. Int J Rehabil Res.
2007;30(2):171174
29. OBrien JE, Birnkrant DJ, Dumas HM, et al. Weaning children from
mechanical ventilation in a post-acute care setting. Pediatr Rehabil.
2006;9(4):365372
PIR Quiz
1. You are seeing 2 brothers ages 2 months and 6 years, respectively, for upper respiratory
tract infection. Rapid antigen testing suggests infection with respiratory syncytial virus.
Which of the following factors is most important in placing the younger sibling at greater
risk of developing respiratory decompensation compared with his older brother?
A.
B.
C.
D.
E.
Decreased accessory muscle use.

Decreased airway size.
Decreased chest wall compliance.
Decreased lung compliance.
Greater reliance on mouth breathing.
2. Which of the following is a clinical marker of chronic hypoxemia?

A.
B.
C.
D.
E.
Depressed tendon reexes.

Flushed skin.
Papilledema.
Polycythemia.
Tachypnea.
3. A 10-month-old girl presents with poor feeding, fever, cough, and respiratory difculty for
the last 2 days. Physical examination reveals axillary temperature of 38.9C, respiratory rate
of 65 breaths per minute, and heart rate of 170 beats per minute. Respirations are labored
with nasal aring and intercostal retractions. Auscultation of chest reveals diffuse crackles
(rales) and wheezing throughout the chest. There are alternating periods of drowsiness
and agitation. Use of 100% oxygen at 15 L/min via a nonrebreather face mask is initiated.
Pulse oximetry recording reveals 93% oxygen saturation. Which of the following will
prompt you to proceed with tracheal intubation and mechanical support of respiration?
A. Arterial blood gas revealing PaO2 less than 60 mm Hg on currently administered
oxygen.
B. Arterial blood gas revealing pH less than 7.25 and PCO2 less than 60 mm Hg.
C. Chest radiograph revealing diffuse alveolar interstitial inltrates.
D. Lack of improvement after a trial of nebulized albuterol inhalation.
E. No new information is necessary, so the patient should undergo tracheal intubation and mechanical support of respiration now.
learners must
or higher on this
assessment, which
than 60% on the
given additional
achieved.
4. A 12-year-old boy presents with tingling, numbness, and weakness of his lower extremities
for 1 day. The weakness has gradually progressed, and now he is unable to walk. Physical
examination reveals a comfortable-appearing child with normal sensorium. He is afebrile,
with a respiratory rate of 18 breaths per minute and a heart rate of 74 beats per minute.
Respiratory pattern appears normal. He has sensory loss to pinprick up to the
midabdomen. He has decreased muscle strength: grade II/V in the lower extremities and
IV/V in the muscles of the hand. He appears to have normal strength in his shoulders and
arms. He has good gag and cough reexes. Deep tendon reexes are absent in the lower
extremities and diminished in the upper extremities. The rest of his physical examination
ndings are normal. Which of the following is the best method of determining need for
assisted ventilation?
A.
B.
C.
D.
E.
Assessment of respiratory distress by frequent physical examinations.

Capnography to measure end-tidal PCO2 in exhaled gas at the nose.
Frequent assessment for mental status changes using the Glasgow Coma Scale.
Pulse oximetry recording to measure oxygen-hemoglobin saturation.
Serial arterial blood gas measurements.
5. A 16-year-old girl with cystic brosis is admitted for low-grade fever, productive cough,
and shortness of breath. She is being followed up in the clinic for advancing lung disease.
Her baseline vital capacity is 40% of normal. Vital signs on presentation are as follows:
axillary temperature, 38.5C; pulse, 100 beats per minute; and respirations, 24 breaths per
minute. She has nasal aring, intercostal retractions, and diffuse bilateral wheezes and
crackles (rales) on chest auscultation. She is appropriately interactive. Her pulse oximetry
oxygen hemoglobin saturation on 30% oxygen, which she receives at home, is 85%. Her
Vol. 35 No. 11
NOVEMBER 2014
485
arterial blood gas reveals the following: pH, 7.28; PCO2, 62 mm Hg; and PO2, 55 mm Hg. Highow nasal cannula (15 L/min) with 100% oxygen is initiated. Fifteen minutes later, the
patient becomes unresponsive with shallow respirations at rate of 10 breaths per minute;
lung examination ndings are unchanged. A subsequent arterial blood gas determination
reveals the following: pH, 7.08; PCO2, 110 mm Hg; and PO2, 102 mm Hg. Which of the
following is the most likely explanation of the change in this childs worsened clinical state?
A.
B.
C.
D.
E.
486
Bilateral pneumothoraces.
Cerebral edema.
Exacerbation of cor pulmonale.
Respiratory muscle fatigue.
Suppression of peripheral chemoreceptors.
THE CASE
1
2
3
Recurrent Epistaxis in a 4-Year-Old Boy

Eosinophilia in a 5-Year-Old Boy
Feeding Intolerance in a 3-Month-Old Girl
With Trisomy 21
CASE 1 PRESENTATION
EDITORS NOTE
We invite readers to contribute case
presentations and discussions. Please use
the Submit and Track My Manuscript link
on the Pediatrics in Review homepage:
http://pedsinreview.aappublications.org.
AUTHOR DISCLOSURE Drs Vander Schaaf,
Potisek, Puri, Schlaudecker, Newman, Notario,
and Nagpal have disclosed no nancial
relationships relevant to this article. This
A previously healthy 4-year-old boy presents for evaluation of a unilateral nose

bleed refractory to compression lasting for 1.5 hours. He has had episodes of
epistaxis in the past secondary to nasal manipulation but none this severe. Three
weeks ago he had a runny nose and congestion, which are now resolved. His family
denies vision changes, headaches, nausea, hematuria, dysuria, any known ingestions, or any skin ushing. There is no history of bleeding disorders in his family.
On physical examination he is afebrile, with a heart rate of 121 beats per
minute, a respiratory rate of 24 breaths per minute, a right arm blood pressure of
200/130 mm Hg, and an oxygen saturation of 99% on room air. His weight is 17
kg (50th percentile) and height is 112 cm (95th percentile). He appears well and
has normal physical examination ndings, with the exception of an abdominal
bruit and barely palpable femoral pulses.
Initial laboratory results are as follows: white blood cell count, 21,900/mL
(21.9 109/L); absolute neutrophil count, 18,400/mL (18.4 109/L); absolute
lymphocyte count, 2100/mL (2.1 109/L); hemoglobin, 9.9 g/dL (99 g/L); platelet
count, 324 103/mL (324 109/L); mean corpuscular volume, 85 fL; red blood
cell distribution width, 13.5%; an unremarkable peripheral blood smear; urea
nitrogen, 45 mg/dL (16.1 mmol/L); creatinine, 1.39 mg/dL (123 mmol/L); and
normal serum electrolyte levels. The results of thyroid function studies, coagulation prole, and urinalysis are normal. Renal ultrasonography with Doppler and
head computed tomography results are interpreted as normal. Electrocardiography suggests left ventricular hypertrophy, and echocardiography reveals left
ventricular hypertrophy. An additional imaging study helps establish the suspected diagnosis.
CASE 1 DISCUSSION
Abdominal ultrasonography revealed a long segment of abdominal aortic narrowing,
involving the mesenteric and renal arteries (initial renal ultrasonography result was
interpreted as normal), consistent with a diagnosis of midaortic syndrome (MAS).
Abdominal magnetic resonance angiography (MRA) conrms this diagnosis.
Pediatric hypertension affects roughly 5% of all children. Typical symptoms
include epistaxis, headaches, blurred vision, and vomiting; however, hypertension
Vol. 35 No. 11
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487
may be asymptomatic in chronic processes. For this reason,

blood pressure monitoring should begin on all children 3
years and older at every physician visit. Most pediatric hypertension cases are secondary to underlying renal, cardiac,
urologic, endocrine, and neoplastic conditions. Approximately 10% of cases are secondary to renovascular anomalies,
with renal artery stenosis accounting for most of these cases.
Differential Diagnosis
Epistaxis is commonly encountered by the pediatrician and is
typically anterior or posterior in origin. Anterior nosebleeds
account for most nosebleeds because of the highly vascular
Kiesselbach plexus in this region. Anterior nosebleeds are
typically caused by direct trauma, foreign bodies, mucosal
dryness, infection, or irritants. Posterior nosebleeds are less
common and may be the result of signicant nasal trauma or
potentially a tumor. Systemic causes include bleeding disorders, vasculitis, or hypertension as was found in our patient.
Worrisome ndings concerning nosebleeds are recurrent
episodes and episodes refractory to routine management.
The Condition
MAS is an uncommon cause of renovascular hypertension
in children. It results from narrowing of the abdominal
aorta, typically involving the renal arteries and other visceral
branches. Most cases of MAS are primarily idiopathic.
However, it may be associated with underlying conditions,
such as neurobromatosis type I, mucopolysaccharidosis,
William syndrome, Alagille syndrome, giant cell arteritis, or
congenital rubella. Hypertension is present in most MAS
cases. Claudication, oliguric renal failure, and intestinal
ischemia occur infrequently. The classic diagnostic triad
consists of an abdominal bruit, diminished or absent femoral pulses, and a discrepancy between blood pressures of
the upper and lower extremities. The physical examination
ndings of diminished femoral pulses and blood pressure
discrepancy between the upper and lower extremities can be
seen in coarctation of the aorta; however, echocardiography
typically detects this condition and is isolated to the aorta.
Once the diagnosis of MAS is suspected, MRA can conrm the diagnosis, with angiography remaining the gold
standard. Aortic narrowing may also be seen on computed
tomography angiography, abdominal ultrasonography, or
echocardiography during the evaluation of hypertension. If
MAS is suspected to be secondary, then a genetic evaluation
should be considered to evaluate the patient for the potential
underlying conditions mentioned above. In addition, evaluating for an inammatory state by obtaining an erythrocyte
sedimentation rate and C-reactive protein may help suggest
giant cell arteritis as a cause of MAS.
488
Management
Hypertension secondary to MAS is typically severe and often
requires numerous antihypertensive medications and/or
surgical correction. Although hypertension can be controlled with several antihypertensive medications, surgery
is the denitive treatment. Surgery is often indicated for
unresponsive hypertension to medical therapy, claudication,
intestinal ischemia, or when the survival of the kidney is in
jeopardy. The decision for timing of surgical intervention is
often case dependent. Most cases are managed by a singlestaged aorto-aortic bypass of the diseased segment of the aorta
along with a surgical revascularization procedure of the renal
and splanchnic arteries as required.
Patient Course
On arrival, antihypertensive therapy was initiated for our patient. He was initially administered a nicardipine drip and
clonidine patch with the goal of maintaining a higher systemic
blood pressure to ensure adequate perfusion of his kidneys in
the setting of acute kidney injury. Unfortunately, the patient
became oliguric and developed progressively worsening renal
failure, ultimately requiring hemodialysis. He subsequently
developed respiratory failure and was intubated. After identifying MAS as the underlying cause of his hypertension, he was
transferred to a facility experienced in surgical correction of
this condition and underwent bilateral renal revascularization.
Two months after surgical repair, he is normotensive and not
taking any antihypertensive medications.
Lessons for the Clinician

Epistaxis may be a presenting sign of hypertension.
Routine blood pressure screening for children should
begin at 3 years of age, which may identify asymptomatic
hypertension.
Midaortic syndrome is an uncommon cause of hypertension and can present with the triad of abdominal bruit,
diminished lower extremity pulses, and a discrepancy in
blood pressures between upper and lower extremities.
(Emily Vander Schaaf, MD,* University of North Carolina,
Chapel Hill, NC, Nicholas M. Potisek, MD, Wake Forest School
of Medicine, Winston-Salem, NC)
*Dr Vander Schaafs current afliation is Wake Forest School of
Medicine, Winston-Salem, NC.
CASE 2 PRESENTATION
A 5-year-old boy is referred for a signicantly elevated white
blood cell count of 40,000/mL (40.0 109/L), with 76%
eosinophils (absolute eosinophil count of 30,400 /mL [30.4
109/L]), 16% neutrophils, and 7% lymphocytes, and normal

hemoglobin and platelet levels. The environmental health
clinic has been monitoring his persistently elevated blood
lead levels for the previous 6 months, with levels ranging from
10.4 mg/dL to 12.8 mg/dL (0.500.62 mmol/L). The environmental health clinic had ordered the complete blood cell count
to evaluate for anemia.
There is no history of weight loss, loss of appetite, cough,
loose stools, photophobia, rash, focal respiratory symptoms,
or cardiovascular symptoms. The patients mother reports
that the child has occasional abdominal pain and intermittent low-grade fevers. He was born prematurely (28 weeks)
and had a brief stay in the neonatal intensive care unit for
feeding difculties. The mother also reports that the child
has behavioral issues, notably head-banging, hand-to-mouth
behaviors, and pica. There is no signicant family or travel
history. His twin has an elevated blood lead level but
a normal complete blood cell count. They have a pet dog
and cat; he frequently plays in the dirt and in a sandbox at
his daycare.
On physical examination, the patient has nonfocal examination ndings, pertinently negative for any lymphadenopathy, rash, abnormal pigmentation, masses or lumps, or
evidence of malnutrition. Laboratory ndings include a normal serum electrolyte level and a uric acid level of 2.9 mg/dL
(170.6 mmol/L), mildly elevated lactate dehydrogenase
(1090 IU/L), normal IgE (97 IU/mL), and a stool specimen
negative for ova and parasites. A T-cell receptor test result for
Vb (variable segments of the b chain of T-cell receptor)
expression is negative for monoclonality and, hence, for
hematologic malignant neoplasms. His chest radiographic
ndings are normal. The results of computed tomography
of the chest, abdomen, and pelvis are normal; echocardiography reveals no evidence of eosinophilic myocarditis. Additional evaluation reveals the cause of his eosinophilia.
CASE 2 DISCUSSION
An infectious diseases consultant recommended serologic
testing for Toxocara and ophthalmologic examination by
slitlamp to rule out ophthalmologic larva migrans (OLM).
The Toxocara serologic test (IgG by enzyme-linked immunosorbent assay) result was positive, with titers of 0.304
optical density (OD) at presentation (reference range,
00.299 OD). Ophthalmologic examination did not reveal
evidence of OLM.
Differential Diagnosis
The initial differential diagnoses in a child presenting with
severe hypereosinophilia includes neoplasm (including acute
myeloid leukemia, acute lymphoblastic leukemia, and Hodgkin

lymphoma); allergic disorders, such as atopic dermatitis,
asthma, and various forms of rhinitis; Addison disease;
collagen vascular diseases (including vasculitides and
eosinophilia-myalgia syndrome); hypereosinophilic disorders (including mastocytosis); parasitic infections (including Trichinella, schistosomiasis in travelers, and, rarely,
fungal infections, such as aspergillosis and coccidiomycosis);
and medication effects. The mnemonic NAACP (Neoplasms,
Allergic disorders, Addison disease, Collagen vascular diseases, Parasitic infestations) is often used as a memory aid.
In our patient, initial evaluation was not concerning for
malignant neoplasms, increased cell lysis, myocarditis, or
intestinal parasites. However, the patient had a history of pet
exposure and pica, further raising red ags for parasite
exposure.
The Condition
Eosinophilia is dened as eosinophil percentage greater
than 3% to 5% in the peripheral blood, with severity corresponding to absolute eosinophil count: mild, eosinophil
count of 600 to 1500/mL (1.5 109/L); moderate, eosinophil
count of 1500 to 5000/mL (1.55.0 109/L); and severe,
eosinophil count greater than 5000/mL (>5.0 109/L).
Primary eosinophilia may be due to various myeloid and
lymphoid neoplasms. However, secondary eosinophilia, due
to infections and other systemic diseases, such as collagen
vascular disorders, pulmonary eosinophilic diseases, allergic
disorders, and metabolic diseases, must be excluded rst.
Toxocariasis is a syndrome caused by the nematode
Toxocara canis or Toxocara cati. The dog and the cat are
the denitive hosts for T canis and T cati, respectively. Eggs
are shed in stool by the animal, become infective after
approximately 3 weeks (after embryonation), and remain
infective for several years in the environment. After ingestion by dogs or cats, the eggs hatch and the larvae penetrate
the gut wall; migrate through the lungs, the bronchial tree,
and the esophagus; and develop into adults in the small
intestine, from where they are shed in stool. Humans are
the unintentional hosts. Transmission is fecal-oral, by ingestion of the eggs or larvae, through contaminated hands or
other objects, or by ingestion of contaminated soil.
Toxocariasis is classically characterized by eosinophilia,
hepatomegaly, fever, and hyperglobulinemia due to the
systemic penetration of the worm larvae. Toxocariasis is
now formally classied into the classic systemic form, compartmentalized (neurologic larva migrans), or OLM, covert
and asymptomatic forms. Several authors have reported
signicant prevalence rates of asymptomatic infection, ranging from 5% in the white pediatric population to 25% in the
Vol. 35 No. 11
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489
African American pediatric population. Further seropositivity

for Toxocara in various developed countries varies from 0.7%
in New Zealand to 7.5% in Australia and up to 14% in the
United States. Seroprevalence is higher in tropical countries
(30% in Nigeria, 36% in Brazil, and up to 81% in Nepal). The
high rate of seroprevalence in the United States, compared
with other industrialized nations in Europe, may be due to
asymptomatic toxocariasis, requiring a heightened awareness
of the potential for OLM and need for treatment.
Management and Prevention

Treatment of clinical features and to prevent complications,
such as OLM and neurologic larva migrans, is recommended in all forms except the asymptomatic, in which only
preventive treatment may be considered in the case of
positive serologic test results and signicant eosinophilia.
Treatment is typically with anthelminthics: albendazole,
mebendazole, or thiabendazole. Albendazole, 15 mg/kg
daily, divided into 2 doses, for a 5-day course, is considered
rst-line therapy. Treatment may also include corticosteroids and anti-inammatory agents to counter the inammatory reaction produced when the organism is killed. OLM
treatment includes anti-inammatory agents, and the patient may also require procedural intervention to remove or
dissolve the eosinophilic granulomatous lesion.
Good hygiene practices, such as hand washing (especially
after contact with pets or high-risk areas, such as playgrounds
and sandboxes), timely disposal of pet feces, and routine
deworming of pets, are critical for prevention of toxocariasis.
Patient Course
Our patients condition may be classied into either an
asymptomatic or covert form based on his symptoms of
abdominal pain. The signicant eosinophilia and the high
titers of anti-Toxocara antibodies prompted treatment to
prevent complications. He was prescribed mebendazole
therapy, 100 mg twice daily for 5 days, because albendazole
was not available at his pharmacy. A follow-up white blood
cell count 4 weeks later was signicantly improved at
10,000/mL (10.0 109/L), with 22% eosinophils and an
absolute eosinophil count of 2230//mL (22.3 109/L).
Follow-up Toxocara antibody levels were elevated at 0.585
OD; however, his complete blood cell count continued to
normalize. Most recently, his lead level was 9.3 mg/dL (0.45
mmol/L), and the complete blood cell count was signicant
for a white blood cell count of 9100//mL (9.1 109/L), with
13% eosinophils (absolute erythrocyte count of 1180//mL
[11.8 109/L]), 28% lymphocytes, and 58% neutrophils.
We never positively identied the source of the infection
but strongly suspected the sandbox at the daycare. The cats
490
getting into it were strays, and the family and the health
department tried to convince the owner to cover the sandbox
when not in use, but without effect. Ultimately, the children
stopped going to that daycare. The pets were never tested or
treated. Unfortunately, the health department jurisdiction
where the case occurred has a limited budget for enforcement activities related to environmental health.

Toxocariasis is an important cause of asymptomatic
eosinophilia in children, especially in a situation with risk
factors such as pica, pet exposure, and poor hand hygiene.
Preventive measures should be included in the anticipatory guidance and counseling of parents to prevent
toxocariasis in such settings, such as hand washing and
timely disposal of cat and dog feces.
(Kriti Puri, MD, Elizabeth P. Schlaudecker, MD, MPH, Nicholas
C. Newman, DO, MS, Cincinnati Childrens Hospital Medical
Center, Cincinnati, OH)
CASE 3 PRESENTATION
A 3-month-old full-term girl with trisomy 21 presents to the
gastroenterology clinic with progressive feeding intolerance. For the past 3 weeks, she has had large nonbloody
spit-ups after every feed, either formula colored or light
brown in appearance. She has a normal appetite and does
not appear to be distressed after spit-ups. Her parents report
that she previously tolerated 3 oz of formula every 3 hours.
She has been stooling regularly without diarrhea and has
no other signs of illness. Birth weight was 3.85 kg (80th
percentile). She has a history of a small ventricular septal
defect and congenital bilateral clubfoot.
Physical examination reveals a well-appearing girl with
typical Down syndrome dysmorphic features. Her temperature is 37.2C, pulse is 89 beats per minute, respiratory rate
is 22 breaths per minute, blood pressure is 97/56 mm Hg,
and oxygen saturation is 97% on room air. Her perfusion is
normal. She currently weighs 3.93 kg (less than the third
percentile), her length is 57.5 cm (25th percentile), and her
head circumference is 39 cm (25th percentile). She has
normal heart sounds with a 2/6 systolic murmur over the
left sternal border. Her abdomen is soft, nondistended, and
nontender with normal bowel sounds. There are no abdominal masses or hepatomegaly. She has normal female external genitalia without lesions or hernias.
The result of a basic electrolyte panel is normal. A pyloric
ultrasonography result is normal. An upper gastrointestinal
(GI) tract series reveals distension of the stomach and

duodenal bulb with a transition point at the level of the
proximal duodenum and gastric stasis with reux of residual gastric contents. Surgical exploration reveals the ultimate diagnosis.
CASE 3 DISCUSSION
Exploratory laparotomy revealed an annular pancreas, causing extrinsic duodenal compression. The patient underwent
duodenal duodenostomy from which she recovered well and
subsequently tolerated oral feeds.
include congenital heart disease with congestive heart failure,

milk protein intolerance, metabolic disorders, renal disorders, and signicant elevations in intracranial pressure.
The clinician must have a higher suspicion for anatomical
anomalies in patients with underlying genetic syndromes,
such as trisomy 21 as in this patient. The GI symptoms that
may be common in infancy, such as gastroesophageal reux
and constipation, may in fact represent symptoms related to
underlying anatomical defects, such as duodenal malformations or Hirschsprung disease. Approximately 15% of patients
who have trisomy 21 have a congenital obstructive GI tract
abnormality. Five percent of patients with trisomy 21 will have
duodenal atresia or annular pancreas.
Diagnosis of Feeding Intolerance

The most common cause of recurrent spit-ups after feeds is
gastroesophageal reux. However, this is typically seen in
otherwise healthy infants as a result of intermittent lower
esophageal sphincter relaxation, leading to retrograde ow
of gastric uid. The clinician must recognize red ags in the
history and physical examination to determine whether
further workup is necessary; these signs include poor weight
gain, bilious emesis, repeated large volume emesis, respiratory distress, and abdominal distension.
In the face of persistent spit-ups after feeds associated
with poor weight gain, the clinician must consider the
possibility of proximal GI obstruction. This can occur at
any point from the esophagus to the duodenum, keeping in
mind that obstructions past the ampulla of Vater at the
junction between the rst and second portions of the
duodenum typically result in bilious emesis. The most
common cause of proximal GI obstruction in early infancy
is pyloric stenosis, which can be excluded by sonography.
The most serious cause of intestinal obstruction to consider
in infancy is malrotation because an associated volvulus can
lead to bowel ischemia due to compression of the superior
mesenteric artery. Additional causes to consider are antral
webs, duodenal stenosis, and annular pancreas. Flat and
upright abdominal radiographs may be helpful if obstruction is suspected. The absence of a gastric bubble may
suggest a left upper quadrant mass, displacing the stomach
to the right. A distended stomach bubble would be more
consistent with a gastric outlet or duodenal obstruction. In
the absence of an acute surgical abdomen, an upper GI tract
radiocontrast study is helpful to dene the anatomical
structures of the patient. An upper GI tract study should
be performed when the infants predominant symptom is
bilious vomiting because midgut volvulus may be catastrophic and early surgical intervention is essential.
NonGI tract causes of emesis in an infant should also be
considered, depending on the clinical situation. These causes
The Condition
Annular pancreas is a relatively rare congenital condition,
with an incidence of 1 in 2000 live births. In 70% of cases,
annular pancreas is associated with other anomalies, such as
esophageal atresia, imperforate anus, congenital heart disease, and malrotation. Exact embryonal origins are unclear,
but the leading theory is that it results from aberrant rotation
of the ventral portion of the pancreas, preventing its fusion
with the dorsal portion. This causes wrapping of the pancreas 270 around the duodenum, typically at the second
portion as the duodenum descends in the abdomen.
Most patients with annular pancreas remain asymptomatic through their lifetime. However, of those children who
are symptomatic, more than two-thirds present as infants
with signs of obstruction, including bilious emesis, feeding
intolerance, and abdominal distension. When presenting in
later childhood and adulthood, patients experience symptoms
of peptic ulcer disease, duodenal obstruction, or pancreatitis.
Imaging studies of symptomatic infants, such as abdominal radiography, may reveal the classic double bubble sign
consistent with duodenal obstruction. An upper GI tract
series can reveal associated ndings, such as a transition
point between the rst and second parts of the duodenum.
Endoscopic retrograde cholangiopancreatography, magnetic
resonance cholangiopancreatography, and endoscopic ultrasonography are more recent additional modalities that can
be used to diagnose annular pancreas. The gold standard of
diagnosis is exploratory laparoscopy or laparotomy.
Management
The rst step in treating a patient with an apparent upper
GI tract obstruction is to provide gastric decompression
through the placement of a nasogastric tube. Intravenous
rehydration and correction of any electrolyte abnormalities
should be performed. Surgical repair is the ultimate treatment for patients with annular pancreas to relieve the
Vol. 35 No. 11
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491
external compression it imposes on the duodenum. This

involves bypass procedures, such as duodenoduodenostomy,
gastrojejunostomy, or duodenojejunostomy, which are favored
over pancreatic resection due to its associated complications,
including pancreatitis and pancreatic stula formation.
In patients with existing genetic syndromes, such as

trisomy 21, rare anatomical anomalies, such as annular
pancreas, should be considered.
(Patricia M. Notario, MD, Rajeev Nagpal, MD, Advocate
Childrens Hospital, Oak Lawn, IL)

Clinicians must have a high suspicion for intestinal obstruction in patients with persistent feeding intolerance when their
emesis is nonbilious and associated with poor weight gain.
492
To view Suggested Reading lists for these cases, visit https://

pedsinreview.aappublications.org and click on the Index of
Suspicion link.
Brief
in
Nutritional Considerations in Pediatric Liver Disease

Russell Cameron, MD,* Debora Kogan-Liberman, MD
*Pediatric Gastroenterology, Bronson Healthcare Group, Kalamazoo, MI
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Childrens Hospital at Monteore, Albert Einstein College of Medicine,
Bronx, NY
AUTHOR DISCLOSURE Drs Cameron and

Kogan-Liberman have disclosed no nancial
Growth and Developmental

Considerations in Pediatric Liver
Transplantation. Alonso EM. Liver Transpl.
2008;14(5):585591
Guidelines for Nutritional Care for Infants
With Cholestatic Liver Disease Before Liver
Transplantation. Baker A, Stevenson R,
Dhawan A, Goncalves I, Socha P, Sokal E.
Pediatr Transpl. 2007;11(8):825834
The Role of Basic Nutritional Research in
Pediatric Liver Disease: An Historical
Perspective. Cleghorn G. J Gastroenterol
Hepatol. 2009;24(suppl 3):S93S96
Pediatric Hepatology: A Half-Century of
Progress. Balistreri WF. Clin Liver Dis. 2000;4
(1):191210
Optimizing Nutritional Management in
Children with Chronic Liver Disease.
Nightingale S, Ng VL. Pediatr Clin N Am.
2009;56(5):11611183
Within the last 60 years, pediatric hepatology has seen many advances in improvement in timely diagnosis and management of chronic liver disease and also
in liver transplantation. Growth failure and malnutrition have always been important factors in the treatment of children with liver disease, specically cholestatic liver diseases. The liver has a central function in nutrient metabolism, and
the abnormalities seen in chronic liver disease result in nutritional and metabolic
deciencies. Nutritional needs are dependent on the type of liver disease, age of the
patient, and whether the disease is acute or chronic. In the setting of acute liver
disease, such as acute viral hepatitis, malnutrition is unusual; however, in fulminant liver failure, nutritional modications are needed to manage hepatic encephalopathy. Chronic liver disease may be cholestatic or noncholestatic and in most
instances is associated with malnutrition.
Cholestatic injury to the liver reects a diverse group of diseases, resulting
from biliary obstruction, disorders of bile synthesis or transport, metabolic and
endocrine disorders, infections, and toxic effects. The most common is biliary
atresia, occurring in approximately 1 of 10,000 live births; it is the most common
indication for liver transplantation in children. Patients have relatively progressive
hepatic disease and, often, poor nutritional status, making preoperative management of malnutrition a challenge.
Malnutrition is a negative prognostic indicator of overall survival, and the inability
to improve nutritional status before surgery increases the risk of postoperative complications and mortality. Adequate nutrition allows for growth, improved immunologic status, and improved transplantation outcomes.
Nutritional status in the setting of liver disease can be difcult to assess. Weight
alone is not a sufcient marker for nutritional status, especially if the patient has
ascites or organomegaly: uid retention and a disproportionately large organ may
result in substantial weight gain, whereas the overall nutritional status is actually
poor. The ascites and organomegaly, as well as portal hypertension, can also
contribute to poor oral tolerance, furthering the failure to gain appropriate weight
for age and preventing the often needed catch-up weight gain. Although serial
abdominal circumference measurement may aid in determining whether weight
gain is secondary to ascites, it is an imprecise way of differentiating true weight
gain from uid gain. More accurate measures include triceps skinfolds and
middle upper arm circumference measurements, with standards for age available
from the World Health Organization. These measurements, however, require
calipers and training in proper technique. Peripheral edema is a potential cause of
overestimation of both measures and if present needs to be considered.
Both the childs age and the specic disease affecting the liver contribute to the
issues of nutrition and growth facing each patient. Assessment and support are
key components of effective care, which is best performed by a team of physicians
Vol. 35 No. 11
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493
and nutritionists with knowledge and expertise in treating

children with chronic liver disease.
The characteristic physical ndings in infants and children with cholestatic liver disease suggest why weight for
age alone is not sufcient in the assessment of nutritional
status. Body habitus typically is marked by thin limbs and
a protuberant abdomen. A decrease in middle upper arm
circumference is often the earliest change in progressive
disease, with triceps skinfold thickness the next measure to
decrease. As abdominal girth increases, it may equal and
eventually exceed thoracic girth. Unless rickets develops
early in the disease from vitamin D deciency, height for age
is the last anthropometric measure to decrease. Even with
adequate nutritional support, further delay in linear growth
can continue despite improvement in body weight.
The factors that affect nutrition are 4-fold:
hypermetabolism and increased energy needs,
malabsorption and poor use of calories,
anorexia, and
disordered use of nutrients absorbed.
Growth impairment in cholestatic liver disease is related to
the lack of intraluminal bile acid, leading to fat malabsorption.
Hepatocellular dysfunction and portal hypertension also play
a role, but fat malabsorption is primary. Also contributing to
poor linear growth is the decreased liver production of insulinlike growth factor seen with hepatocyte loss.
To counteract malabsorption, poor use of nutrients, and
a resting energy expenditure 30% to 40% greater than
normal, total caloric intake must be increased. The estimated
energy requirement in affected infants may be as much as
150% of what healthy infants need, and for older children,
the gure ranges from 120% to 170%. Beyond total energy,
nutritional requirements are broken down into carbohydrate,
specic fat, and protein requirements, as well as specic
vitamin and micronutrient needs. Carbohydrates provide
most calories and are important in helping to maintain
normoglycemia: children with chronic liver disease are prone
to hypoglycemia during fasting states because of reduced
gluconeogenesis and glycogen storage capacity. Glucose is
preferred to galactose and other sugars to avoid potential
intolerances. Short-chain polymers are preferred to both high
monomer-containing diets with increased osmotic loads and
to starches, which may be malabsorbed and lead to colonic
fermentation, bloating, and diarrhea.
Fat is calorically dense and also provides essential polyunsaturated fatty acids. With the fat malabsorption and
steatorrhea that are characteristic of cholestatic liver diseases,
494
although increasing total fat intake increases overall fat absorption, it will also lead to increases in diarrhea and steatorrhea. Medium chain triglycerides (MCTs) are a readily
available source of energy and are absorbed directly from
the venous blood without the need for bile and emulsication. Supplying 30% to 70% of total fat as MCTs provides
adequate fat calories, reduces malabsorption of fat and steatorrhea, and improves weight gain. However, providing all
fat calories as MCTs can lead to essential fatty acid (EFA)
deciency. The EFAs are linoleic acid and a-linolenic acid,
which are not produced by the body but are necessary for
production of long-chain polyunsaturated fatty acids and are
important in brain and eye development. To prevent deciency, approximately 10% of energy should be provided as
supplemental EFAs, with a ratio of linoleic to a-linolenic acid
of 1:5 to 1:15. Certain dietary oils (walnut, canola, sunower,
and soybean), as well as sh oils and egg yolks, can be used in
oral and enteral tube feeding to provide additional fat calories.
Formulas with adequate amounts of MCTs as a proportion of
total fat calories are recommended for infants with cholestatic
liver disease. Older children may benet from MCT oil supplementation to their meals.
Amino acid metabolism is altered in chronic liver disease, with branched-chain amino acid levels decreased and
aromatic amino acid levels increased. Branched-chain amino
acid supplementation may reduce protein catabolism, improve nitrogen retention, and improve protein synthesis.
Children with chronic liver disease typically require 2 to
3 g/kg daily as the protein intake sufcient for growth. With
hepatocyte loss, liver insufciency, and portosystemic shunting, protein intake can lead to hyperammonia. Nonetheless,
protein restriction should not be used to reduce ammonia
levels; rather, hyperammonemia should be treated with
lactulose or sodium benzoate.
Fat malabsorption can lead to deciency of the fat soluble
vitamins (A, D, E, and K). Other vitamins and minerals can
be decient as well, and proper monitoring is important.
Supplementation, available in an oral water soluble form,
with vitamins A, D, E, and K is recommended for all children
with cholestatic liver disease (Table). Water soluble vitamins
should be supplemented at twice the recommended daily
allowance because of the risk of altered metabolism by the
diseased liver. Trace elements (calcium, zinc, magnesium, and
selenium) should be supplemented based on the patients
plasma levels. Careful attention should be paid to the potential
for copper toxicity in the setting of cholestasis, and serum
levels should be drawn during nutritional assessments. Iron
supplementation is not routinely recommended because iron

deciency is not common in the absence of chronic blood loss.
Total daily uid requirements are the same as for
a healthy child unless there is a concern about uid retention and ascites. Although careful attention should be paid
to electrolytes, correction of hyponatremia should generally
be avoided because raising the sodium level can exacerbate
uid retention.
Oral feeding should be encouraged as long as nutritional
needs can be met as evidenced by adequate growth and
development. Oral tolerance is often affected in chronic liver
TABLE.
disease by ascites, organomegaly, gastroesophageal reux,

and dyspepsia, which can lead to anorexia, early satiety, nausea,
and vomiting. With cholestatic disease, MCT-containing formula should be the milk for bottle-fed infants and should be
used to supplement breastfed infants. Fortication of the
formula is another option to increase energy intake. Developmentally appropriate foods (rst purees and later solids)
should be encouraged to promote oral feeding and prevent
oral feeding aversion.
When energy needs cannot be met orally, enteral feeding
via nasogastric tubes is an effective alternative. Nasogastric
Fat Vitamin Deciencies
VITAMIN SOURCE
DEFICIENCY
TOXIC EFFECTS
Vitamin A Retinyl palmitate (animal

sources)sh oils,
liver, dairy
Carotenoids (plant
sources)green
vegetables, orangecolored fruit, and
vegetables)
Night blindness,
xerophthalmia
Liver brosis,
Serum retinol,
hypercalcemia,
serum retinol/RBP
pseudotumor cerebri,
ratio, retinal dose
painful bone lesions
response test,
liver retinol level
5000-25,000 U/d,
coadministered
with TPGS for
improved
absorption
Hypocalcemia,
hypophosphatemia,
muscle hypotonia,
and rickets
Hypercalcemia and
pseudotumor
cerebri
25-Hydroxyvitamin
D serum levels
(measure serum
ionized calcium
and phosphorus)
400 IU/d,
25-hydroxyvitamin
D3 preferred
Supplementation
should be given
with adequate
calcium and
phosphorus
25-Hydroxyvitamin
D serum levels
>20 ng/mL
Poor nerve
conduction,
leading to hypo- or
areexia, ataxia,
peripheral
neuropathy,
and myopathy
Vision loss
Hemolytic anemia
Impaired neutrophil
chemotaxis
Vitamin E (serum
Oral TPGS-E
tocopherol)/total
supplementation
lipid ratio
(>0.8 mg/g normal)
Vitamin D Synthesized in skin

with exposure to
UV-B light
Dry skin
Possible immune
dysfunction
MEASUREMENT
Food sources: fortied

dairy products
and sh oil
Vitamin E a-Tocopherol highest

bioavailability
Nuts, green leafy

vegetables, and
vegetable oil
Hemorrhagic disease
Vitamin K Dietary source: vitamin
K1 (phylloquinone)
green leafy vegetables,
dairy products, and liver
Synthesis of uncarboxylated
Enteric bacteria derived:
proteins (coagulation
vitamin K2
(menaquinones)
factors: II, VII, IX, X,
and protein C and S)
SUPPLEMENTATION
15-25 IU/kg daily

preferably as TPGS
Prothrombin
time or INR
Orally 2.5-5 mg/d
PIVKA II assay
(proteins induced
in vitamin
K absence)
Intravenous,
intramuscular,
or subcutaneous
administration
may be necessary
Abbreviations: INR=international normalized ratio; PIVKA=Proteins Induced by Vitamin K Absence; RBP=retinal-binding protein; TPGS=D-a-tocopheryl
polyethylene glycol succinate; TPGS-E=vitamin E D-a-tocopheryl polyethylene glycol succinate.
Vol. 35 No. 11
NOVEMBER 2014
495
feeding can be performed at home overnight as supplementation to daytime oral feeds, which should be encouraged to
maintain feeding skills. Gastrostomy feeding is not a route
of choice because placement of the gastrostomy tube can be
complicated by organomegaly, ascites, and bleeding risks.
Used only when enteral feeding cannot meet a childs
nutritional needs, parenteral nutrition is a last resort that
comes with its own sets of concerns: the risk of sepsis
from central catheter infections and additional parenteral
nutritionrelated toxic effects to the liver.
Malnutrition and growth failure in children with liver
disease are multifactorial. Despite advances in management, malnutrition has remained a challenge, and nutritional support is a central goal in the care of these children.
Malnutrition has been associated with poor outcomes.
Assessment of nutritional status is complicated by changes
in body habitus and uid retention. Children with chronic
cholestatic liver disease have increased overall caloric needs,
as well as specic needs in the composition of their intake of
macromolecules. Attention must also be paid to micronutrient and vitamin deciencies. Care is best provided within
a multidisciplinary team, including primary care physicians,

hepatologists, transplant surgeons, nutritionists, or dieticians
with expertise in liver disease, social workers, and feeding
therapists.
COMMENTS: Pediatric hepatology has indeed seen great
advances during the past several decades. One of the rst
patients I had the privilege of caring for at the start of my
career in the 1980s was a girl born with biliary atresia. For
the rst 6 years of her life, this girl invested nearly all her
energy in scratching, never able to relieve the intense itching
from her jaundice. She barely spoke and did not play. She
scratched. She scratched until the xanthomas that covered
her body bled. So small for her age, she actually looked younger
than her sister, who was born a year or two after her. However,
when she was 6, this girl had her life transformed. She went
to Pittsburgh to receive one of the earliest pediatric liver
transplantations. She did not need to scratch any more.
Henry M. Adam, MD
Editor, In Brief
CME Quiz Correction

In the December 2013 article Managing Feeding Problems and Feeding Disorders (Phalen JA. Pediatrics in Review.
2013;34:549, doi: 10.1542/pir.34-12-549), the correct answer to Question 4 should be: A. Drools constantly and dribbles
food from mouth. In the online version of the journal, a correction has been posted with the article, and the online quiz
has been updated to reect the correct answer. The journal regrets the error.
ANSWER KEY FOR NOVEMBER 2014 PEDIATRICS IN REVIEW:

Pediatric Hearing Loss: 1. D; 2. B; 3. A; 4. C; 5. C.
Spirometry for the Primary Care Pediatrician: 1. E; 2. A; 3. E; 4. A; 5. D.
Respiratory Failure: 1. B; 2. D; 3. E; 4. B; 5. E.
496
Brief
in
Bacterial Tracheitis
Connie Y. Kuo, MD, Sanjay R. Parikh, MD
Department of Otolaryngology, Seattle Childrens Hospital, Seattle, WA
AUTHOR DISCLOSURE Drs Kuo and Parikh

device.
Tracheitis in Pediatric Patients. Graf J,

Stein F. Semin Pediatr Infect Dis. 2006;17
(1):1113
Bacterial Tracheitis: A Therapeutic
Approach. Shargorodsky J, Whittemore KR,
Lee GS. Laryngoscope. 2010;120(suppl 4):
24982501
An Update on Inammatory Disorders of
the Pediatric Airway: Epiglottitis, Croup,
and Tracheitis. Stroud RH, Friedman NR.
Am J Otolaryngol. 2001;22(4):268275
Bacterial Biolm Presence in Pediatric
Tracheotomy Tubes. Perkins J, Mouzakes J,
Periera R, Manning S. Arch Otolaryngol Head
Neck Surg. 2004;130(3):339343
Tracheal Infections Associated With
Tracheostomy Tubes and Endotracheal
Intubation in Children. Woods CR. UpToDate.
http://www.uptodate.com/contents/
tracheal-infections-associated-withtracheostomy-tubes-and-endotrachealintubation-in-children. Accessed May 17,
2014.
A Multi-Institutional Analysis of
Tracheotomy Complications. Halum SL, Ting
JY, Plowman EK, et al. Laryngoscope. 2012;122
(1):3845
Occurring almost exclusively in children, bacterial tracheitis is a rare but rapidly

life-threatening upper airway disease with reported mortality rates as high as
20%. Clinicians must recognize this disease promptly to prevent impending
airway obstruction and its associated complications, which include acute respiratory distress syndrome and septic shock. Approximately 80% of patients with
bacterial tracheitis require intubation, and 94% are admitted to the intensive care
unit. Bacterial tracheitis affects 2 groups of pediatric patients: those with a native,
intact airway and those with an articial airway established with an endotracheal
tube or tracheotomy tube.
Bacterial tracheitis without tracheotomy is also known as membranous
laryngotracheobronchitis, bacterial laryngotracheobronchitis, and pseudomembranous
croup. As implied by these alternative names, the hallmark ndings of bacterial
tracheitis are ulceration and pseudo membrane formation in the trachea,
mucopurulent exudate, and sloughing of the mucosa, which obstruct the tracheal
lumen and can lead to signicant airway obstruction. Historically, the leading
causative organisms include Staphylococcus aureus, Haemophilus inuenzae,
a-hemolytic Streptococcus, and Streptococcus pyogenes. Moraxella catarrhalis has
been implicated with increasing frequency and is associated with a more severe
course. Gram-negative organisms are rare, yet Pseudomonas and Klebsiella species
have been responsible in a few cases. It is also widely believed that tracheitis may
represent a bacterial superinfection of viral tracheobronchitis most commonly
caused by inuenza, parainuenza, or respiratory syncytial virus.
A thorough history and physical examination can often lead to the diagnosis of
bacterial tracheitis. Its occurrence peaks in the fall and winter months, with an
incidence of 4 to 8 per 1,000,000 children. The mean age at diagnosis is 5 years.
Frequently, the child presents with a several-day prodrome of an upper respiratory
tract viral infection (cough, coryza, and sore throat) and then develops rapid onset
of high temperatures (>101.3F [38.5C]), stridor, hoarseness, and a toxic appearance. Clinical deterioration typically occurs within 2 to 10 hours. Odynophagia,
dysphagia, drooling, and snifng posturing are usually absent. Some children
may have concurrent pneumonia, sinusitis, otitis media, or pharyngitis. Leukocytosis or leukopenia is often present.
The differential diagnoses include croup, viral laryngotracheobronchitis, epiglottitis,
bronchiolitis, angioedema, and diphtheria in nonvaccinated patients. However,
suspicion of bacterial tracheitis should increase when a patient with respiratory
distress fails to respond to racemic epinephrine and/or systemic corticosteroids,
which typically improve croup and viral laryngotracheobronchitis.
When the history and physical examination lead to suspicion of bacterial
tracheitis, the next step in the workup depends on the status of the patients airway.
In patients with a stable airway, clinicians should perform anteroposterior and
lateral neck radiography followed by examination with exible laryngoscopy, if
Vol. 35 No. 11
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497
tolerated. Radiographs classically reveal irregular borders of

the tracheal margins and haziness of the tracheal column,
indicative of pseudomembrane detachment. A steeple sign
(superior tapering of the trachea manifested as an inverted Von
anteroposterior neck radiograph) may also be present, as seen
in viral laryngotracheobronchitis. Flexible laryngoscopy reveals
mucopurulent secretions in the glottic or subglottic regions.
Patients with minimal airway symptoms and normal exible
laryngoscopy examination ndings can be treated medically. If
symptoms worsen, rigid bronchoscopy with the patient under
general anesthesia is warranted.
On the contrary, the priority for patients in severe respiratory distress with airway compromise is to secure the
airway. Endotracheal intubation may be necessary, and to
account for airway inammation and thick secretions, the
inner diameter of the endotracheal tube should be 1-mm
smaller than what is normally indicated. Urgent diagnosis
and treatment should then proceed in the operating room
with direct rigid bronchoscopy, preferably performed by a
pediatric otolaryngologist. Endoscopic ndings include edema
and erythema of the subglottis, mucopurulent tracheal secretions, and thick pseudomembranes along the tracheal wall
mucosa. Denitive treatment entails aggressive debridement
of the mucopurulent debris with suction and foreign-body
forceps. Gram stain, bacterial culture, and sensitivities of
tracheal secretions and viral cultures are performed to help
direct medical therapy.
Postoperatively, patients are admitted to the intensive
care unit for further monitoring and aggressive supportive
care. Children who are not intubated still need close observation by medical personnel skilled in airway management.
In some cases, transfer to a tertiary care center may be
indicated. For all patients, treatment with intravenous
broad-spectrum antibiotics should be initiated and eventually tailored based on culture results. Reasonable empiric
antibiotic options include vancomycin or clindamycin plus
ampicillin-sulbactam, a third-generation cephalosporin (ceftriaxone or cefotaxime), or a uoroquinolone in patients
with penicillin allergy. Inhaled or systemic steroids and
racemic epinephrine have no proven efcacy in relieving
airway obstruction from bacterial tracheitis.
For children who do not improve clinically with antibiotics, a subsequent endoscopy may be indicated to remove
reaccumulated debris. The decision to intubate and when to
extubate is individualized, with a plan formulated by the
pediatric intensivist in conjunction with the endoscopist.
Extubation is performed when fever, toxic appearance, and
498
tracheal secretions have decreased and a positive air leak is

present. Intubation usually lasts 2 to 7 days, and length of
hospital stay varies from 5 to 12 days. Patients who continue
to improve after extubation should be transitioned to oral
antibiotic therapy for 10 to 14 days after discharge. Most
patients make a full recovery.
Patients with preexisting intubation or a tracheotomy
who develop bacterial tracheitis comprise a unique entity
that warrants special clinical assessment and consideration.
These patients have an increased risk of tracheitis because
an articial airway provides an easy portal of entry for
bacteria and also disrupts innate mucosal immunity. Furthermore, the tube may cause ulceration and tracheal denudation, increasing the risk of infection. Bacterial biolms
that contain live bacteria have also been demonstrated to
colonize the internal surface of tracheotomy tubes.
No specic risk factors have been identied for ventilatorassociated tracheitis (VAT) or tracheotomy-associated tracheitis. In patients with an articial airway, symptoms of
tracheitis typically have an onset more indolent and subacute than in patients with an intact airway. Clinical suspicion should heighten when a patient exhibits increasing
purulent tracheal secretions that require more frequent
airway suctioning; with changes in the color, viscosity, or
odor of secretions; with a decrease in oxygen saturations;
and, if applicable, when changes in mechanical ventilation
settings are needed to maintain gas exchange. Bacterial
tracheitis in these patients may be challenging to distinguish from an associated lower respiratory tract infection,
such as pneumonia, but the absence of pulmonary inltrates on chest radiograph can support the diagnosis. Nonetheless, isolated tracheitis is uncommon in patients with an
articial airway; a concurrent bronchial and/or pulmonary
infection is frequently present. If untreated, VAT is also
considered a precursor to ventilator-associated pneumonia.
Similar to bacterial tracheitis of the intact airway, the
diagnosis of bacterial tracheitis in children with an articial
airway is based on clinical, microbiologic, and endoscopic
ndings. Patients may have fever without an obvious source,
and an increase in neutrophils and the presence of new
microbes on tracheal aspirates can help distinguish new
bacterial infection from normal ora colonization. However,
tracheal aspirates do not differentiate tracheal from pulmonary
infection. Tracheoscopy performed with a exible beroptic
scope can conrm the diagnosis with evidence of tracheal
inammation. The most common colonizing microbes are
S aureus, H inuenzae, Streptococcus pneumoniae, Pseudomonas
tracheotomy.

Henry M. Adam, MD
Editor, In Brief
Vol. 35 No. 11
NOVEMBER 2014
499
8-Day-Old Hypotonic Newborn With

Sparse Hair
Jorge Sales Marques, MD, Manuela Mateus, MD, Teresa Torres, MD,
Helena Santos, MD, Marta Vila Real, MD, Ftima Santos, MD
PRESENTATION
On a routine postdelivery checkup, an 8-day-old boy is found to have new onset of
pallor and hypotonia. Physical examination reveals pudgy cheeks, micrognathia
and retrognathia, and white, sparse hair (Figure 1).
The pregnancy was unremarkable, with all ultrasonographic ndings
described as normal. He was the rst and only child of a young and unrelated
couple. The father has rheumatoid arthritis and ankylosing spondylitis. The
patient was born at 39 weeks of gestation, weighing 2990 g and having Apgar
scores of 9/10 (1 and 5 minutes, respectively). Delivery was by caesarian section
because of pelvic-fetal incompatibility.
AUTHOR DISCLOSURE Drs Sales Marques,

Mateus, Torres, Santos, Vila Real, and Santos
device.
Figure 1. Newborn male infant with white, sparse hair.

Servio Pediatria, Centro Hospitalar Vila Nova de Gaia, Portugal.
Vol. 35 No. 11
NOVEMBER 2014
e53
Laboratory investigation reveals a white blood cell count of

9570/mL (9.6 109/L), with 24% neutrophils and 50.1%
lymphocytes; a hemoglobin level of 20.6 g/dL (206 g/L); and
a platelet count of 160 103/mL (160 109/L). The C-reactive
protein level is in the reference range. Levels of glucose, blood
urea nitrogen, and creatinine are all normal, as are the results
of tests of liver function and calcium-phosphorus metabolism. Ceruloplasmin (3.0 mg/dL [30 mg/L]; reference range,
20-60 mg/dL [200600 mg/L]) and copper levels (21.5 mg/dL
[3.4 mmol/L]; reference range, 70155 mg/dL [1124 mmol/L])
are very low.
Magnetic resonance angiography (MRA) of the brain reveals elongated and tortuous vessels (Figure 2). Skeletal
radiography reveals irregularity of the occipital region and
proximal region of the right tibia consistent with sequelae
of fractures. There is a recent fracture of the left clavicle
(Figure 3).
DIAGNOSIS
The clinical diagnosis of Menkes disease was based on the
typical hair changes associated with hypotonia, pale skin,
and signs of spontaneous fractures in the neonatal period.
The diagnosis was conrmed by the MRA results (elongated
and tortuous brain vessels), by pili torti (attened hair shafts
with clusters of narrow twists at irregular intervals) revealed
by electronic microscopy (Figure 4), and by the detection of
a new mutation of the ATP7A gene in the molecular study
from exons 18 to 23.
DISCUSSION
Menkes kinky hair disease is an X-linked recessive trait
condition that affects males. Female carriers generally do
not manifest symptoms unless unusual genetic circumstances are present. Menkes kinky hair disease is rare, with
an estimated incidence of 1 case in 250,000 live births
(1 case in 50,000100,000 in Australia).
Figure 2. Brain magnetic resonance angiography reveals elongated and

tortuous vessels.
e54
Figure 3. Recent fracture of the left clavicle.
The disorder is caused by a defect in the ATP7A gene,

identied in 95% to 98% of all the cases by standard
screening techniques. To date, approximately 200 different
mutations have been reported. Most ATP7A gene defects are
intragenic mutations or partial gene deletions. The defect
alters copper metabolism, resulting in low plasma copper
levels that affect bone, skin, hair, and blood vessel structure
and nerve function.
Pregnancy and delivery usually are unremarkable, but
delivery may be premature. Newborns usually do not manifest any signs or symptoms that lead to this diagnosis.
Cephalohematomas and spontaneous fractures are occasionally observed at birth. In the early neonatal period,
patients may present with prolonged jaundice, hypothermia, hypoglycemia, and feeding difculties. Pectus excavatum, umbilical hernias, and inguinal hernias also
have been described. The rst sign may be apparent only
at ages 1 to 2 months, consisting of characteristically
hypopigmented or depigmented and unusually sparse
and dull scalp hair that resembles steel wool in appearance and feel. The hair is dull and friable, especially in
those areas of the scalp that are subjected to friction.
By ages 2 to 2.5 months, loss of motor skills and muscle
tone, seizures, and feeding difculties often manifest. Pale
skin, frontal or occipital bossing, micrognathia, and pudgy
cheeks may be observed.
Laboratory ndings in Menkes kinky hair disease include low plasma copper and ceruloplasmin levels, although these may also be found in healthy infants during
the rst 6 weeks of life. Thus, they are not pathognomonic for this condition. Placental copper levels may be
measured and are reliable for diagnosis during the prenatal period, but this concentration is checked only when
the disease is suspected. Brain MRA can reveal gross
structural lesions and vascular tortuosity and helps determine the degree of myelination. Radiography often reveals abnormalities of bone formation in the skull
(wormian bones), long bones (metaphyseal spurring),
and ribs (anterior aring and multiple fractures). Pili
torti apparent on electronic microscopy are typical of this
disease.
Figure 4. Electronic microscopy

demonstrating pili torti hair: attened hair
shafts with clusters of narrow twists at
irregular intervals.
TREATMENT
If given in the rst months of life, copper histidinate in
a dose of 50 to 150 mg/kg per day, injected subcutaneously,
can increase life expectancy from the expected life span of 3
to 13 years, at least in some patients. In addition, this
treatment has an effect on neurologic manifestations and
neurodevelopmental outcome, which are improved in
approximately 30% of the patients. Nevertheless, in approximately 50% of the patients, this therapeutic approach has
not proven to be of any signicant benet, even when started
early in life. Oral administration is not an option because of
low intestinal copper absorption.
DISEASE COURSE
Menkes disease is a very severe disease with a high mortality
rate. Low body copper and ceruloplasmin levels have a signicant effect on several organs, and patients usually die of
pneumonia, although some patients die suddenly in the
absence of any apparent acute medical condition. Whereas
most patients exhibit a severe classic form, approximately
9% may have a milder form of Menkes disease called
occipital horn syndrome. Parents of children who have this
disorder are advised to have prenatal genetic counseling
because the risk of the condition being present in future
pregnancies is 50% and the disease may be diagnosed by

identifying the mutation.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of Menkes disease includes
Ehlers-Danlos syndrome, Marfan syndrome, cutis laxa, mitochondrial disorders, osteogenesis imperfecta, and child
abuse.
PATIENT COURSE
The patient started treatment with subcutaneous copper
histidinate in a dose of 50 mg/kg per day at age 2 months.
After 10 days of this treatment, copper levels (100 mg/dL [15.7
mmol/L]) and ceruloplasmin levels (17 mg/dL [170 mg/L])
were near normal. He developed seizures characterized by
masticatory movements, hypersalivation, eye deviation,
and limb muscle contractions. Electroencephalography
revealed persistent paroxysmal activity, particularly during
sleep. His seizures continued despite being given sodium
valproate, phenobarbital, and clonazepam. Seizures were
nally controlled with intravenous methylprednisolone.
His prognosis is poor because symptoms started in the
neonatal period and his ATP7A deletion is very long (from
exon 18 to 23).
Vol. 35 No. 11
NOVEMBER 2014
e55
Summary
A hypotonic newborn or infant with pale skin and sparse, friable,
hypopigmented, or depigmented hair should have his copper and
ceruloplasmin plasma levels evaluated because this is the usual clinical
presentation of Menkes disease. Menkes disease is an X-linked
recessive disease caused by a defect in the ATP7A gene, identied in
95% to 98% of the cases. Identifying the mutation conrms the
diagnosis and allows for prenatal counseling and diagnosis in a future
pregnancy. When administered within the rst few months of life,
copper histidinate, given subcutaneously in a dose of 50 to 150 mg/kg
per day, appears to be effective not only by increasing life expectancy
from 3 to 13 years but also by improving neurologic symptoms and
neurodevelopmental outcomes in approximately 30% of the patients.
e56
Suggested Reading
Bindu PS, Taly AB, Kothari S, et al. Electro-clinical features and
magnetic resonance imaging correlates in Menkes disease. Brain
Dev. 2013;35(5):398405
Kaler SG. ATP7A-related copper transport diseases-emerging
concepts and future trends. Nat Rev Neurol. 2011;7(1):
1529
Kodama H, Fujisawa C, Bhadhprasit W. Inherited copper transport
disorders: biochemical mechanisms, diagnosis, and treatment.
Curr Drug Metab. 2012;13(3):237250
Tang J, Donsante A, Desai V, Patronas N, Kaler SG. Clinical outcomes in
Menkes disease patients with a copper-responsive ATP7A
mutation, G727R. Mol Genet Metab. 2008;95(3):174181
Tmer Z. An overview and update of ATP7A mutations leading to
Menkes disease and occipital horn syndrome. Hum Mutat.
2013;34(3):417429
6-Month-Old Boy With Leg Pain

Sebastian K. Welsh, MD,* David F. Crudo, MD, Jordan E. Pinsker, MD
PRESENTATION
A 6-month-old white boy presents to the emergency department for pain on
manipulation of his right lower extremity. His father reports lifting him off the
couch the day before when the boys right leg had become stuck in a space
between the cushions. After his father pulled his leg free, the child appeared to be
uncomfortable, but his symptoms rapidly resolved. No other history of trauma is
reported. However, today the patient was seen crying when his older sister was
pulling on his right leg.
The patients perinatal history is unremarkable. The medical history is
signicant only for strabismus, which was recently noted by his pediatrician.
He is being formula fed and takes rice cereals and early-stage baby foods. He takes
no medications. Both height and weight are tracking at the 90th percentile. He is
meeting all developmental milestones.
On physical examination, the child is alert and interactive. His examination
ndings are notable for a blue hue to his sclerae that has been present since birth
(Figure 1). He has pain to palpation over the right anterior tibia and refuses to bear
weight on that leg. Skin examination reveals no ecchymoses, lacerations, marks,
or abrasions. He has no other areas of tenderness, and the remainder of his
physical examination ndings are normal. Intentional trauma is a concern given
the minimal force of the reported mechanism of injury that led to this childs
fracture. Radiographs in the emergency department reveal an oblique, nondisplaced, middiaphyseal right tibial fracture (Figure 2).
Genetics testing reveals the underlying diagnosis.
AUTHOR DISCLOSURE Drs Welsh, Crudo,

and Pinsker have disclosed no nancial
commentary does contain a discussion of
Figure 1. Recent photograph of the child at age 2 years. The blue hue to his sclerae has been
present since birth.
*Department of Pediatrics, Tripler Army Medical Center, Honolulu, HI.
Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC.
William Sansum Diabetes Center, Santa Barbara, CA.
Vol. 35 No. 11
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e57
The mechanism that causes type II OI (lethal in the

perinatal period), type III OI (severely deforming with short
stature), or type IV OI (moderate bone deformities and
variable short stature) is different. In these conditions, a
glycine substitution in the procollagen helix leads to a mixture of normal and abnormal procollagen production.
Modern bone histologic techniques have allowed further
subtypes to be dened in children who do not have COL1A1
or COL1A2 mutations (types V-IX).
Determining which type of OI a child has can be done by
genetic testing of the COL1A1 and COL1A2 genes or by showing
decreased or abnormal production of type 1 collagen from
cultured skin broblasts. Regardless of which method is used,
it is important to recognize the clinical heterogeneity seen in
OI. Some patients with the more mild forms (type I and type
IV) have few fractures and do not need any treatment. However,
for those with fractures early in life and repeated fractures, early
referral for multidisciplinary management is essential.
Figure 2. Oblique, nondisplaced, middiaphyseal right tibial fracture.
DIAGNOSIS
Because of this patients blue sclerae and presentation with
a fracture, genetic testing is performed. COL1A1 and
COL1A2 sequencing analysis conrms a mutation
(c.3162delT) in COL1A1, the gene that encodes the a1-chain
of type 1 collagen. This child is diagnosed as having osteogenesis imperfecta (OI) type 1.
DISCUSSION
Nine subtypes of OI have been described. In type I OI, an
autosomal dominant mutation in the COL1A1 gene causes
premature termination of pro-a1-collagen messenger RNA
(mRNA). This abnormal mRNA is rapidly degraded by
nonsense mediated decay, and as a result, patients with
type I OI have only 50% of the normal procollagen mRNA,
generated from the unaffected allele. As a result of this
decreased production of type 1 collagen, patients with type I
OI have increased bone fragility and an increased rate of
fractures. Patients with type I OI can have slightly short
stature and blue sclerae. They commonly have vertebral
fractures but usually have an absence of major bone deformities. Hearing loss can develop, usually after age 10
years. Dentogenesis imperfecta is typically absent in type I
OI, but kyphosis and scoliosis may develop over time.
e58
When an infant presents with an unexplained fracture, the

differential diagnosis can be difcult. Intentional trauma is
a frequent cause of fractures in infancy, and bone diseases
associated with increased bone fragility can be subtle or
difcult to diagnose. Bone diseases include OI, osteopenia
of prematurity, rickets, copper deciency, disuse demineralization, Menkes syndrome (kinky hair syndrome), scurvy,
osteopetrosis, hypophosphatasia, congenital syphilitic periostitis, osteomyelitis, leukemia, vitamin A toxicity, and
metabolic and kidney diseases that cause calcium wasting
and demineralization.
OI needs to be distinguished from intentional trauma.
Both intentional trauma and OI can present with multiple or
recurrent fractures, fractures that do not match the history
of trauma, and the nding of fractures of varying ages and at
different stages of healing. Metaphyseal and rib fractures
once thought pathognomonic for child abuse can occur in OI.
The presence or absence of blue sclerae is unreliable because
they may be seen in unaffected infants until age 18 months
and may not be seen in OI type IV. Testing for OI should be
performed when there is a reasonable clinical suspicion for
the presence of OI or a similar bone fragility disorder.
MANAGEMENT
Treatment of OI involves a coordinated multidisciplinary
approach that consists of physical and occupational therapy,
orthopedic surgical interventions, and medications to reduce
fracture rates, prevent long-bone deformities and scoliosis,
minimize pain, and maximize mobility and other functional

capabilities. Physical and occupational therapists can design
programs to assist in mobility and reduce fracture risk.
Orthopedic specialists are needed to manage fractures and
may need to place telescoping intramedullary rods in the
femurs and tibiae to prevent or correct malformations.
Service of an otolaryngologist may be needed to address
hearing loss. Genetic counseling should be provided to the
family regarding risk for subsequent children.
In many centers worldwide, bisphosphonate administration to children with moderate and severe forms of OI has
been adopted as part of routine clinical care. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast
function. Although bisphosphonates are not currently
approved by the US Food and Drug Administration for this
indication because of a lack of long-term safety data, this
therapy has arisen from more than 15 years of experience
with these agents in this condition.
Various bisphosphonates have been found to prevent
skeletal deformities, preserve mobility, decrease fracture
rate and bone pain, and improve bone strength and quality
of life of OI patients. Although there is no consensus on the
optimal agent, dosage, or duration of therapy, pamidronate
administered intravenously has the most published evidence of benecial effects. The greatest gains from intravenous pamidronate treatment take place in the rst 2 to 4
years of therapy. However, continued skeletal growth in
children places them at risk for being unable to maintain
the positive gains in mineralization made during the initial
therapy. Despite there being no completed randomized
trials to help guide the clinician, at-risk children may indeed benet from longer-term bisphosphonate therapy to
preserve the gains realized in the initial therapy phase
and lessen the chance of fractures occurring at adjoining
bisphosphonate-treated and bisphosphonate-naive bone.
There are important short-term and long-term safety
concerns with the use of bisphosphonates. In the short term,
transient hypocalcemia, inuenza-like symptoms, and esophageal irritation are common. Nephrotoxicity, anterior uveitis,
and atrial brillation can occur uncommonly. The risk of
hypocalcemia can be mitigated by maintenance of a normal
vitamin D status and ongoing provision of adequate calcium
and vitamin D supplementation during therapy.
Bisphosphonates have an extremely long half-life. Children continue to release pamidronate from their skeleton 4
to 10 years after therapy. Potential long-term adverse effects
include radiographic metaphyseal bands, iatrogenic osteopetrosis, fractures after discontinuation of bisphosphonate
therapy in growing children, delayed healing at osteotomy
sites, esophageal cancer, and osteonecrosis of the jaw. No
cases of some of these adverse effects (eg, esophageal cancer

and osteonecrosis of the jaw) secondary to bisphosphonate
use have been seen in children with OI to date.
Because of the adverse effects, bisphosphonate therapy is
not justied in children with very mild forms of OI. However,
bisphosphonate therapy should be offered to patients who
have long-bone deformities, vertebral compression fractures,
or frequent fractures. Because the effect of bisphosphonates
on the skeleton is clearly growth dependent, referral to
a pediatric endocrinologist to begin bisphosphonate therapy
as early as possible in severely affected patients is warranted.
PROGNOSIS
The prognosis for an individual with OI varies greatly,
depending on the number and severity of symptoms. Patients with type I (mild type) typically experience most of
their fractures before puberty. It is uncommon to have bone
deformities, and they are usually of normal or near-normal
stature. Hearing loss is a major concern.
PATIENT COURSE
This child had 4 additional fractures in his feet and legs
during the next 2 years. He was then referred to the pediatric
endocrinology department at age 2 years. A bone density
scan revealed reduced bone mineral density of the lumbar
spine (z score 2.0) (Figure 3). His 25-hydroxyvitamin D
level was 20 ng/mL (50 nmol/L) (borderline for vitamin
D deciency), and treatment was initiated with vitamin D
(ergocalciferol) at 2000 IU/d. His 25-hydroxyvitamin D
level normalized to 35 ng/mL (87 nmol/L) within 2 months.
In addition, intravenous pamidronate treatment was initiated for 3 days every 3 months, and consideration is currently being given to placing intramedullary telescoping
rods in both lower extremities.
Figure 3. Bone mineral density of the lumbar spine was 0.361 g/cm2 at
age 2 years, demonstrating moderate osteopenia (z score 2.0).
Vol. 35 No. 11
NOVEMBER 2014
e59
Summary
Pediatricians play an important role in diagnosing OI as a cause of
fracture and may be asked to differentiate this uncommon
genetic diagnosis from intentional trauma and other causes of
fracture.
Early referral to a pediatric endocrinologist, physical therapist,
and orthopedic surgeon for the evaluation and treatment of low
bone mass and recurrent fractures is important because early
medical and surgical intervention may help to minimize the rate
of future fractures, even within the rst year of life.
Continued follow-up with physical and occupational therapy,
audiology testing, and regular evaluations of dental health are all
essential for children with OI.
e60
Note: The views expressed in this article are those of the

authors and do not reect the ofcial policy or position of the
US Department of the Army, US Department of Defense, or the
US government.
Suggested Reading
Rauch F, Glorieux FH. Osteogenesis imperfecta, current and future
medical treatment. Am J Med Genet C Semin Med Genet. 2005;139C
(1):3137
Ruck J, Dahan-Oliel N, Montpetit K, Rauch F, Fassier F. Fassier-Duval
femoral rodding in children with osteogenesis imperfecta receiving
bisphosphonates: functional outcomes at one year. J Child Orthop.
2011;5(3):217224
van Dijk FS, Cobben JM, Kariminejad A, et al. Osteogenesis
imperfecta: a review with clinical examples. Mol Syndromol.
2011;2(1):120
2015
AAP CME Schedule
JANUARY
FEBRUARY
Clinical Pediatric
MARCH
APRIL
Workshop on
CME Course
San Francisco, CA
May 22-24
Perinatal Practice
Strategies
Scottsdale, AZ
March 27-29
CME Course
Lake Tahoe, CA
Neonatal/Perinatal
CME Course
Santa Fe, NM
April 24-26
Coding Seminar
Scottsdale, AZ
March 27
Register Online
www.aap.org/
livecme
Pediatric Academic
San Antonio, TX
February 21-25
AUGUST
SEPTEMBER
PREP:ID
and Toxic Stress

in Pediatrics
San Francisco, CA
July 30-August 2
OCTOBER
NOVEMBER
National Conference
& Exhibition
Washington, DC
October 24-27
Infectious Diseases
Chicago, IL
August 17-22
Violence, Abuse
Call Toll-Free
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April 25-28
PREP The Course
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May 22-24
CME Course
Orlando, FL
March 13-15
Hospital Medicine:
Caring for Newborns
and Children in the
Hospital Setting
San Diego, CA
January 16-18
MAY
DECEMBER
tracheotomy.

Henry M. Adam, MD
Editor, In Brief
CME Course
Nashville, TN
December 11-13
October 23
CME Course
Chicago, IL
September 4-6
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Phoenix, AZ
November 13-15
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Atlanta, GA
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in the topic.

Vol. 35 No. 11
NOVEMBER 2014
499
8-Day-Old Hypotonic Newborn With

Sparse Hair
Jorge Sales Marques, MD, Manuela Mateus, MD, Teresa Torres, MD,
Helena Santos, MD, Marta Vila Real, MD, Ftima Santos, MD
PRESENTATION
On a routine postdelivery checkup, an 8-day-old boy is found to have new onset of
pallor and hypotonia. Physical examination reveals pudgy cheeks, micrognathia
and retrognathia, and white, sparse hair (Figure 1).
The pregnancy was unremarkable, with all ultrasonographic ndings
described as normal. He was the rst and only child of a young and unrelated
couple. The father has rheumatoid arthritis and ankylosing spondylitis. The
patient was born at 39 weeks of gestation, weighing 2990 g and having Apgar
scores of 9/10 (1 and 5 minutes, respectively). Delivery was by caesarian section
because of pelvic-fetal incompatibility.
AUTHOR DISCLOSURE Drs Sales Marques,

Mateus, Torres, Santos, Vila Real, and Santos
device.
Figure 1. Newborn male infant with white, sparse hair.

Servio Pediatria, Centro Hospitalar Vila Nova de Gaia, Portugal.
Vol. 35 No. 11
NOVEMBER 2014
e53
Laboratory investigation reveals a white blood cell count of

9570/mL (9.6 109/L), with 24% neutrophils and 50.1%
lymphocytes; a hemoglobin level of 20.6 g/dL (206 g/L); and
a platelet count of 160 103/mL (160 109/L). The C-reactive
protein level is in the reference range. Levels of glucose, blood
urea nitrogen, and creatinine are all normal, as are the results
of tests of liver function and calcium-phosphorus metabolism. Ceruloplasmin (3.0 mg/dL [30 mg/L]; reference range,
20-60 mg/dL [200600 mg/L]) and copper levels (21.5 mg/dL
[3.4 mmol/L]; reference range, 70155 mg/dL [1124 mmol/L])
are very low.
Magnetic resonance angiography (MRA) of the brain reveals elongated and tortuous vessels (Figure 2). Skeletal
radiography reveals irregularity of the occipital region and
proximal region of the right tibia consistent with sequelae
of fractures. There is a recent fracture of the left clavicle
(Figure 3).
DIAGNOSIS
The clinical diagnosis of Menkes disease was based on the
typical hair changes associated with hypotonia, pale skin,
and signs of spontaneous fractures in the neonatal period.
The diagnosis was conrmed by the MRA results (elongated
and tortuous brain vessels), by pili torti (attened hair shafts
with clusters of narrow twists at irregular intervals) revealed
by electronic microscopy (Figure 4), and by the detection of
a new mutation of the ATP7A gene in the molecular study
from exons 18 to 23.
DISCUSSION
Menkes kinky hair disease is an X-linked recessive trait
condition that affects males. Female carriers generally do
not manifest symptoms unless unusual genetic circumstances are present. Menkes kinky hair disease is rare, with
an estimated incidence of 1 case in 250,000 live births
(1 case in 50,000100,000 in Australia).
Figure 2. Brain magnetic resonance angiography reveals elongated and

tortuous vessels.
e54
Figure 3. Recent fracture of the left clavicle.
The disorder is caused by a defect in the ATP7A gene,

identied in 95% to 98% of all the cases by standard
screening techniques. To date, approximately 200 different
mutations have been reported. Most ATP7A gene defects are
intragenic mutations or partial gene deletions. The defect
alters copper metabolism, resulting in low plasma copper
levels that affect bone, skin, hair, and blood vessel structure
and nerve function.
Pregnancy and delivery usually are unremarkable, but
delivery may be premature. Newborns usually do not manifest any signs or symptoms that lead to this diagnosis.
Cephalohematomas and spontaneous fractures are occasionally observed at birth. In the early neonatal period,
patients may present with prolonged jaundice, hypothermia, hypoglycemia, and feeding difculties. Pectus excavatum, umbilical hernias, and inguinal hernias also
have been described. The rst sign may be apparent only
at ages 1 to 2 months, consisting of characteristically
hypopigmented or depigmented and unusually sparse
and dull scalp hair that resembles steel wool in appearance and feel. The hair is dull and friable, especially in
those areas of the scalp that are subjected to friction.
By ages 2 to 2.5 months, loss of motor skills and muscle
tone, seizures, and feeding difculties often manifest. Pale
skin, frontal or occipital bossing, micrognathia, and pudgy
cheeks may be observed.
Laboratory ndings in Menkes kinky hair disease include low plasma copper and ceruloplasmin levels, although these may also be found in healthy infants during
the rst 6 weeks of life. Thus, they are not pathognomonic for this condition. Placental copper levels may be
measured and are reliable for diagnosis during the prenatal period, but this concentration is checked only when
the disease is suspected. Brain MRA can reveal gross
structural lesions and vascular tortuosity and helps determine the degree of myelination. Radiography often reveals abnormalities of bone formation in the skull
(wormian bones), long bones (metaphyseal spurring),
and ribs (anterior aring and multiple fractures). Pili
torti apparent on electronic microscopy are typical of this
disease.
Figure 4. Electronic microscopy

demonstrating pili torti hair: attened hair
shafts with clusters of narrow twists at
irregular intervals.
TREATMENT
If given in the rst months of life, copper histidinate in
a dose of 50 to 150 mg/kg per day, injected subcutaneously,
can increase life expectancy from the expected life span of 3
to 13 years, at least in some patients. In addition, this
treatment has an effect on neurologic manifestations and
neurodevelopmental outcome, which are improved in
approximately 30% of the patients. Nevertheless, in approximately 50% of the patients, this therapeutic approach has
not proven to be of any signicant benet, even when started
early in life. Oral administration is not an option because of
low intestinal copper absorption.
DISEASE COURSE
Menkes disease is a very severe disease with a high mortality
rate. Low body copper and ceruloplasmin levels have a signicant effect on several organs, and patients usually die of
pneumonia, although some patients die suddenly in the
absence of any apparent acute medical condition. Whereas
most patients exhibit a severe classic form, approximately
9% may have a milder form of Menkes disease called
occipital horn syndrome. Parents of children who have this
disorder are advised to have prenatal genetic counseling
because the risk of the condition being present in future
pregnancies is 50% and the disease may be diagnosed by

identifying the mutation.
The differential diagnosis of Menkes disease includes
Ehlers-Danlos syndrome, Marfan syndrome, cutis laxa, mitochondrial disorders, osteogenesis imperfecta, and child
abuse.
PATIENT COURSE
The patient started treatment with subcutaneous copper
histidinate in a dose of 50 mg/kg per day at age 2 months.
After 10 days of this treatment, copper levels (100 mg/dL [15.7
mmol/L]) and ceruloplasmin levels (17 mg/dL [170 mg/L])
were near normal. He developed seizures characterized by
masticatory movements, hypersalivation, eye deviation,
and limb muscle contractions. Electroencephalography
revealed persistent paroxysmal activity, particularly during
sleep. His seizures continued despite being given sodium
valproate, phenobarbital, and clonazepam. Seizures were
nally controlled with intravenous methylprednisolone.
His prognosis is poor because symptoms started in the
neonatal period and his ATP7A deletion is very long (from
exon 18 to 23).
Vol. 35 No. 11
NOVEMBER 2014
e55
Summary
A hypotonic newborn or infant with pale skin and sparse, friable,
hypopigmented, or depigmented hair should have his copper and
ceruloplasmin plasma levels evaluated because this is the usual clinical
presentation of Menkes disease. Menkes disease is an X-linked
recessive disease caused by a defect in the ATP7A gene, identied in
95% to 98% of the cases. Identifying the mutation conrms the
diagnosis and allows for prenatal counseling and diagnosis in a future
pregnancy. When administered within the rst few months of life,
copper histidinate, given subcutaneously in a dose of 50 to 150 mg/kg
per day, appears to be effective not only by increasing life expectancy
from 3 to 13 years but also by improving neurologic symptoms and
neurodevelopmental outcomes in approximately 30% of the patients.
e56
Suggested Reading
Bindu PS, Taly AB, Kothari S, et al. Electro-clinical features and
magnetic resonance imaging correlates in Menkes disease. Brain
Dev. 2013;35(5):398405
Kaler SG. ATP7A-related copper transport diseases-emerging
concepts and future trends. Nat Rev Neurol. 2011;7(1):
1529
Kodama H, Fujisawa C, Bhadhprasit W. Inherited copper transport
disorders: biochemical mechanisms, diagnosis, and treatment.
Curr Drug Metab. 2012;13(3):237250
Tang J, Donsante A, Desai V, Patronas N, Kaler SG. Clinical outcomes in
Menkes disease patients with a copper-responsive ATP7A
mutation, G727R. Mol Genet Metab. 2008;95(3):174181
Tmer Z. An overview and update of ATP7A mutations leading to
Menkes disease and occipital horn syndrome. Hum Mutat.
2013;34(3):417429
6-Month-Old Boy With Leg Pain

Sebastian K. Welsh, MD,* David F. Crudo, MD, Jordan E. Pinsker, MD
PRESENTATION
A 6-month-old white boy presents to the emergency department for pain on
manipulation of his right lower extremity. His father reports lifting him off the
couch the day before when the boys right leg had become stuck in a space
between the cushions. After his father pulled his leg free, the child appeared to be
uncomfortable, but his symptoms rapidly resolved. No other history of trauma is
reported. However, today the patient was seen crying when his older sister was
pulling on his right leg.
The patients perinatal history is unremarkable. The medical history is
signicant only for strabismus, which was recently noted by his pediatrician.
He is being formula fed and takes rice cereals and early-stage baby foods. He takes
no medications. Both height and weight are tracking at the 90th percentile. He is
meeting all developmental milestones.
On physical examination, the child is alert and interactive. His examination
ndings are notable for a blue hue to his sclerae that has been present since birth
(Figure 1). He has pain to palpation over the right anterior tibia and refuses to bear
weight on that leg. Skin examination reveals no ecchymoses, lacerations, marks,
or abrasions. He has no other areas of tenderness, and the remainder of his
physical examination ndings are normal. Intentional trauma is a concern given
the minimal force of the reported mechanism of injury that led to this childs
fracture. Radiographs in the emergency department reveal an oblique, nondisplaced, middiaphyseal right tibial fracture (Figure 2).
Genetics testing reveals the underlying diagnosis.
AUTHOR DISCLOSURE Drs Welsh, Crudo,

and Pinsker have disclosed no nancial
commentary does contain a discussion of
Figure 1. Recent photograph of the child at age 2 years. The blue hue to his sclerae has been
present since birth.
*Department of Pediatrics, Tripler Army Medical Center, Honolulu, HI.
Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC.
William Sansum Diabetes Center, Santa Barbara, CA.
Vol. 35 No. 11
NOVEMBER 2014
e57
The mechanism that causes type II OI (lethal in the

perinatal period), type III OI (severely deforming with short
stature), or type IV OI (moderate bone deformities and
variable short stature) is different. In these conditions, a
glycine substitution in the procollagen helix leads to a mixture of normal and abnormal procollagen production.
Modern bone histologic techniques have allowed further
subtypes to be dened in children who do not have COL1A1
or COL1A2 mutations (types V-IX).
Determining which type of OI a child has can be done by
genetic testing of the COL1A1 and COL1A2 genes or by showing
decreased or abnormal production of type 1 collagen from
cultured skin broblasts. Regardless of which method is used,
it is important to recognize the clinical heterogeneity seen in
OI. Some patients with the more mild forms (type I and type
IV) have few fractures and do not need any treatment. However,
for those with fractures early in life and repeated fractures, early
referral for multidisciplinary management is essential.
Figure 2. Oblique, nondisplaced, middiaphyseal right tibial fracture.
DIAGNOSIS
Because of this patients blue sclerae and presentation with
a fracture, genetic testing is performed. COL1A1 and
COL1A2 sequencing analysis conrms a mutation
(c.3162delT) in COL1A1, the gene that encodes the a1-chain
of type 1 collagen. This child is diagnosed as having osteogenesis imperfecta (OI) type 1.
DISCUSSION
Nine subtypes of OI have been described. In type I OI, an
autosomal dominant mutation in the COL1A1 gene causes
premature termination of pro-a1-collagen messenger RNA
(mRNA). This abnormal mRNA is rapidly degraded by
nonsense mediated decay, and as a result, patients with
type I OI have only 50% of the normal procollagen mRNA,
generated from the unaffected allele. As a result of this
decreased production of type 1 collagen, patients with type I
OI have increased bone fragility and an increased rate of
fractures. Patients with type I OI can have slightly short
stature and blue sclerae. They commonly have vertebral
fractures but usually have an absence of major bone deformities. Hearing loss can develop, usually after age 10
years. Dentogenesis imperfecta is typically absent in type I
OI, but kyphosis and scoliosis may develop over time.
e58
When an infant presents with an unexplained fracture, the

differential diagnosis can be difcult. Intentional trauma is
a frequent cause of fractures in infancy, and bone diseases
associated with increased bone fragility can be subtle or
difcult to diagnose. Bone diseases include OI, osteopenia
of prematurity, rickets, copper deciency, disuse demineralization, Menkes syndrome (kinky hair syndrome), scurvy,
osteopetrosis, hypophosphatasia, congenital syphilitic periostitis, osteomyelitis, leukemia, vitamin A toxicity, and
metabolic and kidney diseases that cause calcium wasting
and demineralization.
OI needs to be distinguished from intentional trauma.
Both intentional trauma and OI can present with multiple or
recurrent fractures, fractures that do not match the history
of trauma, and the nding of fractures of varying ages and at
different stages of healing. Metaphyseal and rib fractures
once thought pathognomonic for child abuse can occur in OI.
The presence or absence of blue sclerae is unreliable because
they may be seen in unaffected infants until age 18 months
and may not be seen in OI type IV. Testing for OI should be
performed when there is a reasonable clinical suspicion for
the presence of OI or a similar bone fragility disorder.
MANAGEMENT
Treatment of OI involves a coordinated multidisciplinary
approach that consists of physical and occupational therapy,
orthopedic surgical interventions, and medications to reduce
fracture rates, prevent long-bone deformities and scoliosis,
minimize pain, and maximize mobility and other functional

capabilities. Physical and occupational therapists can design
programs to assist in mobility and reduce fracture risk.
Orthopedic specialists are needed to manage fractures and
may need to place telescoping intramedullary rods in the
femurs and tibiae to prevent or correct malformations.
Service of an otolaryngologist may be needed to address
hearing loss. Genetic counseling should be provided to the
family regarding risk for subsequent children.
In many centers worldwide, bisphosphonate administration to children with moderate and severe forms of OI has
been adopted as part of routine clinical care. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast
function. Although bisphosphonates are not currently
approved by the US Food and Drug Administration for this
indication because of a lack of long-term safety data, this
therapy has arisen from more than 15 years of experience
with these agents in this condition.
Various bisphosphonates have been found to prevent
skeletal deformities, preserve mobility, decrease fracture
rate and bone pain, and improve bone strength and quality
of life of OI patients. Although there is no consensus on the
optimal agent, dosage, or duration of therapy, pamidronate
administered intravenously has the most published evidence of benecial effects. The greatest gains from intravenous pamidronate treatment take place in the rst 2 to 4
years of therapy. However, continued skeletal growth in
children places them at risk for being unable to maintain
the positive gains in mineralization made during the initial
therapy. Despite there being no completed randomized
trials to help guide the clinician, at-risk children may indeed benet from longer-term bisphosphonate therapy to
preserve the gains realized in the initial therapy phase
and lessen the chance of fractures occurring at adjoining
bisphosphonate-treated and bisphosphonate-naive bone.
There are important short-term and long-term safety
concerns with the use of bisphosphonates. In the short term,
transient hypocalcemia, inuenza-like symptoms, and esophageal irritation are common. Nephrotoxicity, anterior uveitis,
and atrial brillation can occur uncommonly. The risk of
hypocalcemia can be mitigated by maintenance of a normal
vitamin D status and ongoing provision of adequate calcium
and vitamin D supplementation during therapy.
Bisphosphonates have an extremely long half-life. Children continue to release pamidronate from their skeleton 4
to 10 years after therapy. Potential long-term adverse effects
include radiographic metaphyseal bands, iatrogenic osteopetrosis, fractures after discontinuation of bisphosphonate
therapy in growing children, delayed healing at osteotomy
sites, esophageal cancer, and osteonecrosis of the jaw. No
cases of some of these adverse effects (eg, esophageal cancer

and osteonecrosis of the jaw) secondary to bisphosphonate
use have been seen in children with OI to date.
Because of the adverse effects, bisphosphonate therapy is
not justied in children with very mild forms of OI. However,
bisphosphonate therapy should be offered to patients who
have long-bone deformities, vertebral compression fractures,
or frequent fractures. Because the effect of bisphosphonates
on the skeleton is clearly growth dependent, referral to
a pediatric endocrinologist to begin bisphosphonate therapy
as early as possible in severely affected patients is warranted.
PROGNOSIS
The prognosis for an individual with OI varies greatly,
depending on the number and severity of symptoms. Patients with type I (mild type) typically experience most of
their fractures before puberty. It is uncommon to have bone
deformities, and they are usually of normal or near-normal
stature. Hearing loss is a major concern.
PATIENT COURSE
This child had 4 additional fractures in his feet and legs
during the next 2 years. He was then referred to the pediatric
endocrinology department at age 2 years. A bone density
scan revealed reduced bone mineral density of the lumbar
spine (z score 2.0) (Figure 3). His 25-hydroxyvitamin D
level was 20 ng/mL (50 nmol/L) (borderline for vitamin
D deciency), and treatment was initiated with vitamin D
(ergocalciferol) at 2000 IU/d. His 25-hydroxyvitamin D
level normalized to 35 ng/mL (87 nmol/L) within 2 months.
In addition, intravenous pamidronate treatment was initiated for 3 days every 3 months, and consideration is currently being given to placing intramedullary telescoping
rods in both lower extremities.
Figure 3. Bone mineral density of the lumbar spine was 0.361 g/cm2 at
age 2 years, demonstrating moderate osteopenia (z score 2.0).
Vol. 35 No. 11
NOVEMBER 2014
e59
Summary
Pediatricians play an important role in diagnosing OI as a cause of
fracture and may be asked to differentiate this uncommon
genetic diagnosis from intentional trauma and other causes of
fracture.
Early referral to a pediatric endocrinologist, physical therapist,
and orthopedic surgeon for the evaluation and treatment of low
bone mass and recurrent fractures is important because early
medical and surgical intervention may help to minimize the rate
of future fractures, even within the rst year of life.
Continued follow-up with physical and occupational therapy,
audiology testing, and regular evaluations of dental health are all
essential for children with OI.
e60
Note: The views expressed in this article are those of the

authors and do not reect the ofcial policy or position of the
US Department of the Army, US Department of Defense, or the
US government.
Suggested Reading
Rauch F, Glorieux FH. Osteogenesis imperfecta, current and future
medical treatment. Am J Med Genet C Semin Med Genet. 2005;139C
(1):3137
Ruck J, Dahan-Oliel N, Montpetit K, Rauch F, Fassier F. Fassier-Duval
femoral rodding in children with osteogenesis imperfecta receiving
bisphosphonates: functional outcomes at one year. J Child Orthop.
2011;5(3):217224
van Dijk FS, Cobben JM, Kariminejad A, et al. Osteogenesis
imperfecta: a review with clinical examples. Mol Syndromol.
2011;2(1):120
2015
AAP CME Schedule
JANUARY
FEBRUARY
Clinical Pediatric
MARCH
APRIL
Workshop on
CME Course
San Francisco, CA
May 22-24
Perinatal Practice
Strategies
Scottsdale, AZ
March 27-29
CME Course
Lake Tahoe, CA
Neonatal/Perinatal
CME Course
Santa Fe, NM
April 24-26
Coding Seminar
Scottsdale, AZ
March 27
Register Online
www.aap.org/
livecme
Pediatric Academic
San Antonio, TX
February 21-25
AUGUST
SEPTEMBER
PREP:ID
and Toxic Stress

in Pediatrics
San Francisco, CA
July 30-August 2
OCTOBER
NOVEMBER
National Conference
& Exhibition
Washington, DC
October 24-27
Infectious Diseases
Chicago, IL
August 17-22
Violence, Abuse
Call Toll-Free
866/THE-AAP1
(866/843-2271)
Societies Annual
Meeting
San Diego, CA
April 25-28
PREP The Course
JULY
JUNE
CME Course
May 22-24
CME Course
Orlando, FL
March 13-15
Hospital Medicine:
Caring for Newborns
and Children in the
Hospital Setting
San Diego, CA
January 16-18
MAY
DECEMBER
tracheotomy.

Henry M. Adam, MD
Editor, In Brief
CME Course
Nashville, TN
December 11-13
October 23
CME Course
Chicago, IL
September 4-6
CME Course
Phoenix, AZ
November 13-15
PREP The Course

Atlanta, GA
September 26-30

CME Courses
Appropriate for the
in the topic.

Vol. 35 No. 11
NOVEMBER 2014
499
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Visual Diagnosis:
6-Month-Old Boy With
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Pediatric Hearing Loss

Spirometry for the Primary

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Pediatric Hearing Loss

Spirometry for the Primary Care Pediatrician

Vol. 35 No. 11 November 2014

Phuong Vo, Virginia S. Kharasch

Case 1: Recurrent Epistaxis in a 4-Year-Old Boy

Case 2: Eosinophilia in a 5-Year-Old Boy

Case 3: Feeding Intolerance in a 3-Month-Old Girl

Nutritional Considerations in Pediatric

Visual Diagnosis: 8-Day-Old Hypotonic

Visual Diagnosis: 6-Month-Old Boy With

Pediatrics in Review is supported, in part, through an educational

Answer Key appears on page 496.

Pediatric Hearing Loss

After reading this article, the reader will be able to:

1. Provide a basic overview of the anatomy of the ear and discuss

AUTHOR DISCLOSURE Dr. Grindle has

many others. The main focus of care should always be on

middle ear becomes lled with something other than air

DIAGNOSIS OF HEARING LOSS

born in the United States had completed a newborn hearing

affected by outer ear and middle ear disease, although to

screens. However, they are a useful adjunct in identifying

High-Risk Criteria for Children

Birth to Age 28 Days

cooing and babbling until ages 6 to 9 months. They will,

CAUSES OF HEARING LOSS

Figure 1. Summary of causes of prelingual

Regardless of cause, they all lead to abnormal function of the

may lead to hearing loss. Hearing loss typically occurs early in

Common Syndromic Causes of Hearing Loss

Most common type of autosomal dominant syndromic hearing loss

Second most common autosomal dominant hearing loss

Hallmark is bilateral vestibular schwannomas

Most common autosomal recessive syndromic hearing loss

Variable SNHL and euthyroid goiter

Jervell and Lange-Nielsen syndrome

Congenital severe to profound SNHL

Progressive hearing loss

SNHL. Fractures through the ossicles can disarticulate these

Last, hearing loss may be caused by otitis media with

For those individuals with persistent chronic otitis media with

MANAGEMENT OF HEARING LOSS IN CHILDREN

and development. Often, simple seating rearrangements,

4. Berlin CI, Morlet T, Hood LJ. Auditory neuropathy/dyssynchrony: its

9. Teele DW, Klein JO, Rosner BA. Epidemiology of otitis media

7. Kutz JW, Simon LM, Chennupati SK, Giannoni CM, Manolidis S.

12. Tranebjaerg L, Samson RA, Green GE. Jervell and Lange-Nielsen

8. Merkus P, Free RH, Mylanus EA, et al; 4th Consensus in Auditory

Parent Resources from the AAP at HealthyChildren.org