The Respiratory Course of Extremely Preterm Infants: A Dilemma
for Diagnosis and Terminology
Eduardo H. Bancalari, MD1, and Alan H. Jobe, MD, PhD2
A
ntenatal corticosteroids, postnatal surfactant treatment, and new strategies for respiratory care have
modified the clinical presentation, lung outcome,
and survival of extremely low birth weight (ELBW) infants.
These changes over the last 10-20 years have resulted in a large
population of ELBW survivors that have clinical courses that
are quite different from those observed before the general use
of surfactant and antenatal corticosteroids. The classic definitions and diagnoses for respiratory problems developed for
larger preterm infants may not be accurate for this ELBW
population. Hence, clinicians often find themselves without
the proper terms to describe and code the clinical course in
many of these patients.
The Respiratory Course: A History
Before the introduction of mechanical ventilation in the 1960s,
many of the preterm infants who died soon after birth with respiratory failure were diagnosed with hyaline membrane disease (HMD) at autopsy.1 The relatively mature survivors
generally recovered with normal pulmonary function. With
the introduction of mechanical ventilation an increasing number of premature infants survived, but many did so with severe
lung damage, described initially by Northway et al in 1967 as
bronchopulmonary dysplasia (BPD).2 These infants initially
had severe HMD and persistent respiratory failure that evolved
into BPD. With increased survival, the term respiratory distress
syndrome (RDS) replaced HMD as the clinical diagnosis. With
the introduction of surfactant treatment after 1990,3 and the
more widespread use of antenatal corticosteroid therapy after
1994,4 severe RDS became less frequent. Although after the introduction of these therapies many of ELBW infants needed
minimal early respiratory support and had much better respiratory outcomes, they were still managed with mechanical
ventilation and often had the default diagnosis of “RDS”.5
The Initial Respiratory Diseases of ELBW
Infants
One of the diagnostic dilemmas that clinicians face now is
what to call the mild initial respiratory course that is observed
BPD
CPAP
CPIP
ELBW
HMD
RDS
RIP
Bronchopulmonary dysplasia
Continuous positive airway pressure
Chronic pulmonary insufficiency of prematurity
Extremely low birth weight
Hyaline membrane disease
Respiratory distress syndrome
Respiratory instability of prematurity
in many ELBW infants today.6,7 The respiratory failure in
premature infants immediately after birth can result from
poor postnatal adaptation, birth hypoxia causing central respiratory depression, or lung inflammation associated with
chorioamnionitis.7,8 Although many of these ELBW infants
need some form of initial respiratory support and supplemental oxygen, this need may result from retained lung fluid,
structural immaturity of the lungs, or insufficient respiratory
effort. Ideally, the diagnosis of RDS should be limited to respiratory failure occurring in preterm infants when there are
clinical and radiographic findings consistent with surfactant
deficiency. However, there is no clinically acceptable way to
securely diagnose surfactant deficiency. The RDS diagnosis
is imprecise at best because many of these infants are intubated and ventilated shortly after birth and are given surfactant. These interventions can mask the clinical and
radiographic signs of RDS. The converse problem is that
these infants are frequently diagnosed as RDS, even when
they do not have significant lung disease, because they are
ventilated. Infants who require respiratory support primarily
because of poor respiratory effort, but without significant
lung involvement, should be diagnosed as respiratory depression or apnea rather than RDS and should not be routinely
treated with surfactant.
A survey of recent clinical experiences will illustrate the diagnostic problems of determining who has RDS and who does
not have RDS (Table). The National Institute of Child Health
and Human Development Neonatal Research Network
reported an incidence of RDS of 63% for infants with birth
weights of 500-1000 g for 1997-2002.9 The diagnosis
required oxygen use from 6-24 hours of life, respiratory
support to 24 hours, and a chest radiograph consistent with
RDS. However, for the more recent interval from 20032007 for infants <28 weeks’ gestation (approximately the
same population as for the earlier interval), 95% of infants
had a diagnosis of RDS because the less stringent criteria of
oxygen use or respiratory support for $6 hours of the first
24 hours without a chest radiograph requirements were
used.5 These are quite minimal criteria for a diagnosis of
RDS in ELBW infants. The variability in the diagnosis of
RDS can also result from the use of surfactant treatment as
From the 1Division of Neonatology, Department of Pediatrics, University of Miami,
Miller School of Medicine, Miami, FL; and the 2Division of Pulmonary Biology,
Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati,
OH
Funded in part by National Institutes of Health (HL-101800 to A.J.) and the University
of Miami Project New Born. The authors declare no conflicts of interest.
0022-3476/$ - see front matter. Copyright ª 2012 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.05.054
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www.jpeds.com
Table. Incidence of RDS in very low birth weight infants
Study
Infants
reported
% RDS
% treated
with surfactant
Danish Experience13
NICHD 1997-20029
NICHD 2003-20075
COIN Trial11
NICHD Support Trial12
Vermont-Oxford CPAP Trial10
27 2 wk
500-1000 g
22-28 wk
950 g average
24-27 wk
26-29 wk
63%
95%
-
30%
62%
76%
38% (CPAP arm)
67% (CPAP arm)
15% (CPAP arm)
NICHD, National Institute of Child Health and Human Development; COIN, continuous positive
airway pressure or intubation at birth.
a criterion to diagnose RDS.5,9-13 Clinicians are re-evaluating
the liberal use of noninvasive continuous positive
airway pressure (CPAP) as a way to manage RDS and avoid
BPD, as first reported in 1987 by Avery et al,14 and
extensively used in Scandinavia in the 1990s.13 The use of
early CPAP can stabilize spontaneous ventilation for very
low birth weight infants and eliminate the need for
surfactant treatment in many of them. Another diagnostic
problem is that premature infants are frequently born to
mothers with symptomatic or asymptomatic infections
(chorioamnionitis).15 Is the initial respiratory failure in
these infants due to surfactant deficiency, antenatal
pulmonary infection/inflammation, or a combination of
both? This is a difficult differential diagnosis because the
clinical and radiographic manifestations of RDS and
pneumonia in this population can be very similar and often
both conditions may coexist. The use of tests to evaluate the
amount of surfactant in the amniotic fluid has become
uncommon, thus, eliminating one of the tools that were
available to diagnose RDS. Bacteria or elevated cytokine
levels in tracheal secretions collected immediately after
birth,8,16 or other signs of infection such as an elevated
white blood count and C reactive protein may suggest the
diagnosis of pneumonia, but their absence does not exclude
this diagnosis.17 A chest radiograph with an interstitial
pattern or coarse infiltrates in the lungs, early appearance of
pulmonary interstitial emphysema, or pleural effusions also
suggest the diagnosis of pneumonia.18,19 A poor or only
transient response to exogenous surfactant also suggests the
possibility that pulmonary infection/inflammation is
a more important factor than surfactant deficiency as the
cause of the respiratory distress.20 Traditional “pneumonia”
seldom occurs in these infants and the organisms recovered
from chorioamnionitis associated ELBW deliveries are
generally of low pathogenicity and blood cultures are
usually sterile.21 However, colonization of the airway with
Ureaplasma urealyticum has been associated with worse
respiratory outcome.22
Transition from Early Respiratory
Insufficiency to Chronic Respiratory Failure
The transition from the initial respiratory disease to recovery or to the development of BPD in these infants offers an
even bigger challenge in terms of mechanisms of disease
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and terminology. Most of the infants who end up with
BPD today have a clinical course that is quite different
from the evolution described by Northway.2,6,7,23-25 In contrast to the original description where most infants had severe respiratory failure requiring aggressive ventilator
support, the initial respiratory course of many infants today is mild and some infants lack the typical clinical and
radiographic findings required for the diagnosis of RDS.
Initially these infants can be managed with nasal CPAP
and the infants that require mechanical ventilation frequently do so because of poor respiratory effort rather
than severe lung disease. This is reflected by the fact that
they initially require no or very little supplemental oxygen.6,7 However, during the weeks that follow birth many
ELBW infants have a gradual deterioration in gas exchange
and require increasing inspired oxygen concentrations and
respiratory support. The transition between the early respiratory status to either recovery or the development of BPD
is often prolonged and extremely variable. There is no consistency in the way clinicians label this phase of respiratory
insufficiency. Because of the multiplicity of factors that
may contribute to the progressive deterioration of lung
function, different diagnoses are used to describe the 3month period from birth at 24 weeks gestation to 36 weeks
postmenstrual age when moderate or severe BPD is diagnosed.26 In many cases it is difficult to identify a single
cause for the deterioration in respiratory status because
of interactions of multiple pathogenic factors. These may
include lung injury because of increased inspired oxygen
concentration, 12,27 damage from mechanical over distension secondary to positive pressure ventilation,28-31 colonization of the airways with pathogens,22,32 recurrent focal or
segmental atelectasis due to airway obstruction, pulmonary
edema because of a patent ductus arteriosus and increased
pulmonary blood flow, 23,33 or secondary surfactant deficiency.34 In fact, the dominant variable may be how the
processes of lung injury, repair, and growth progress in
any given infant, which are variables that cannot be quantified or predicted. This is an area where more research is
needed to better define the possible role of the different
pathogenic mechanisms.
The problem then is how should the clinician label an
ELBW infant who had no, mild, or severe, surfactant treated
RDS early after birth, but at 1 to 3 weeks is receiving some respiratory support (CPAP, supplemental oxygen, high flow
nasal cannulae, or mechanical ventilation)? RDS is not an appropriate diagnosis after the first week. The infant may still
have a patent ductus arteriosus that has not closed, the airway
might be colonized with several pathogens with or without
other signs of systemic infection, and the chest radiographs
show diffuse haziness with some patchy areas of higher densities that could represent segmental atelectasis or pneumonic infiltrates. These infants frequently have significant
and progressive nonspecific respiratory failure that is not
captured by diagnoses such as pneumonia or BPD. A number
of these infants will eventually be diagnosed as BPD, but this
diagnosis is not established before 28 days and more
Bancalari and Jobe
COMMENTARY
October 2012
commonly at 36 weeks postmenstrual age.26 There is no
agreement as to what to call this transitional period between
the early respiratory course and the point when these infants
either improve and become free of respiratory support or are
diagnosed with BPD. They are too old to have RDS, but not
old enough to meet diagnostic criteria for BPD.
The term chronic pulmonary insufficiency of prematurity
(CPIP) was introduced by Krauss et al in 197535 to describe
a group of premature infants who presented with what was
called delayed progressive respiratory distress that, unlike
RDS, presented toward the end of the first week after birth
in previously healthy preterm infants. The respiratory
symptoms persisted for 2-4 weeks after which most of the
infants recovered. The authors did not mention specific
causes for this respiratory presentation, but because the
progressive deterioration in gas exchange coincided with
a significant loss in lung volume, they speculated that like
RDS, CPIP could be in part due to lack of surfactant. The
clinical presentation in these infants was similar to the infants described by Wilson and Mikity in 1960 who however
had characteristic radiographic changes of coarse infiltrates
and cystic lungs.36 The infants with CPIP had more normal
chest radiographs. These two diagnoses are seldom used
now. Although the clinical presentations of these two entities were different from the respiratory course of ELBW infants today, they may share similar underlying pathogenic
factors.
The Coding Problem
In clinical practice, the infant who is on a ventilator or on nasal CPAP at 2 hours of age on room air needs a diagnosis that
may simply be respiratory distress, which translates to an International Classification of Diseases code for other respiratory problems after birth—unspecified. If the chart
documents tachypnea, that will trigger another International
Classification of Diseases code. If the infant has RDS, then
a specific code is used. However, there are no consistent diagnoses or codes for the respiratory status following RDS
(which should resolve within 1 week) and before the diagnosis of BPD. The problem is compounded in our hospitals by
physicians and hospitals coding simultaneously for different
purposes but with no coordination. The consequence is that
the same patient is likely to have different codes and diagnoses in different data sets. Another source of inconsistency is
that these ELBW infants seldom have normal lung function
by standards applied to healthy children or adults. For example, the spontaneous breathing 900 g infant with a respiratory
rate of 60, a PaCO2 of 52 mm Hg, and an oxygen saturation of
92% breathing room air (PaO2 45 mm Hg) may have impending respiratory failure with tachypnea, a high PaCO2,
and a low PaO2, but is considered to have normal lung function by the neonatal community because there are no good
reference values for lung function at different gestational
and postnatal ages. If the neonatal community does not
have good names for the respiratory syndromes we see,
then data bases will be most problematic.
Proposed Terminology
To unify the terminology used to describe these infants we
propose the term “respiratory instability of prematurity”
(RIP) as a general descriptor for very low birth weight infants
requiring some form of respiratory assistance but with multiple factors contributing to their respiratory failure. We suggest using the term “respiratory” rather than “pulmonary”
because many of the infants require respiratory support not
so much due to their pulmonary disease, but because of inconsistent central respiratory drive and poor inspiratory effort. We propose using the term “instability” rather than
“insufficiency” because many of these infants have a poorly
defined combination of respiratory control problems, mechanical “instability” as well as lung parenchymal disease
that contribute to the respiratory problems, but this is not always accompanied by failure defined by abnormal arterial
blood gases. This is a suggested term that can be considered
by the neonatology community.
Important contributors to early RIP following birth are
respiratory depression and poor respiratory effort, RDS
due to surfactant deficiency, pneumonia/inflammation,
and pulmonary hypoplasia. The factors that contribute
to the transitional RIP in infants who subsequently need
prolonged respiratory support were mentioned earlier.
The clinical evolution of these infants during this transitional period is extremely variable and unpredictable. Although some of them show gradual improvement and
wean from respiratory support and supplemental oxygen
before the end of the first month, others have progressive
respiratory compromise, remain dependent on oxygen
and respiratory support, and are eventually diagnosed
with BPD. The diagnosis of BPD currently depends on
a demonstration of oxygen need,26,37 but there are multiple factors and pathologies contributing to this oxygen
dependence.
The purpose of the proposed terminology, RIP, is not to
replace specific diagnoses when they are clear, but to provide
clinicians with a more encompassing diagnosis in infants in
whom there are several mechanisms contributing to the respiratory failure, but without clear evidence of their relative
contribution or importance. A second purpose is to stimulate
a discussion of the diagnostic and coding difficulties for respiratory diseases in ELBW infants. n
Submitted for publication Feb 8, 2012; last revision received Apr 17, 2012;
accepted May 23, 2012.
Reprint requests: Eduardo H. Bancalari, MD, Department of Pediatrics R131,
University of Miami, Miller School of Medicine, 1611 N W 12th Ave, C740,
Miami, FL 33136. E-mail: [email protected]
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