L

Long-term pulmonary sequelae of severe

bronchopulmonary dysplasia
Sheila V. Jacob, MD, Allan L. Coates, MD, Larry C. Lands, MD, PhD, Clair F. MacNeish, BSc, RRT,
S. Patricia Riley, MD, Laura Hornby, MSc, Eugene W. Outerbridge, MD, G. Michael Davis, MD,
and Robert L. Williams, MD

pared with normal term infants4-8 and

Objective: To evaluate the long-term pulmonary sequelae of survivors of bron- ongoing morbidity and persistent chest
chopulmonary dysplasia (BPD) of sufficient severity to have required supple- radiographic abnormalities.2,3 Smyth et
mental oxygen for at least 1 month after term. al.9 found a very high incidence of air-
Study design: Fifteen patients with a mean age of 1.1 years were matched to
preterm infants of similar gestational age and age at time of study. Pulmonary See related articles, p. 171
function testing included spirometry, plethysmographic lung volumes, carbon and p. 188.
monoxide diffusion capacity, and in 9 of 15 subjects with BPD, measurement of
lung static elastic recoil pressures. way hyperactivity (6 of 8 tested) and a
Results: The subjects with BPD had a mean expiratory volume in 1 second mean forced expiratory volume in 1 sec-
(FEV1) of 64% ± 21% predicted (4 had an FEV1 <50% predicted) compared ond of 68% of predicted in 9 school-age
with 85% ± 11% (P < .01) for the preterm children in the control group. Subjects survivors of BPD whose mean gestation-
with BPD had a significant degree of gas trapping with a residual volume to total al age was 30 weeks. Northway et al.,4
lung capacity ratio of 37% ± 13% compared with 25% ± 4% for the control group studying 26 adolescents and young
adults who had been born during the
(P < .01). An inverse relationship was seen between the FEV1 and the time on
same era as those studied by Smyth et
supplemental oxygen (r = –0.84, P < .0001), with 3 of the 4 children whose FEV1
al.,9 found a mean FEV1 of 75% of pre-
was <50% requiring oxygen for more than 900 days. Those with the greatest de-
dicted in survivors of BPD whose mean
gree of airflow limitation and gas trapping had the greatest abnormalities in both gestational age was 33 weeks. More en-
shape and position of the pressure volume curves of the lung. couraging is a report by Hakulinen et
Conclusion: Severe BPD may result in moderate to severe long-term abnor- al.10 of prematurely born children with a
malities in pulmonary function tests. (J Pediatr 1998;133:193-200) mean gestational age of 28 weeks and
relatively mild BPD; they found values
of FEV1 that were close to normal.
Bronchopulmonary dysplasia is a chron- toms and abnormal pulmonary function
ic lung disease related to injury induced has been reported. Survivors of prema- BPD Bronchopulmonary dysplasia
by mechanical ventilation and oxygen turity and respiratory distress syndrome DLco Diffusion capacity of carbon monoxide
FEF25-75 Forced expiratory flow between 25%
therapy in prematurely born infants.1 have an increased incidence of hospital- and 75% of vital capacity
Smaller infants are surviving premature ization during the first year of life.2,3 It FEV1 Forced expiratory volume in 1 second
birth and respiratory distress syndrome has been shown that prematurely born IUATLD International Union Against Tuberculosis
and Lung Disease
because of advances in neonatal care; infants both with and without respirato- PV Pressure volume
however, a significant degree of morbidi- ry distress syndrome have subtle but sig- RV Residual volume
ty in terms of ongoing respiratory symp- nificant differences in lung function com- TLC Total lung capacity

From the Divisions of Respiratory Medicine, Newborn Medicine and Medical Imaging, McGill University Montreal Previous long-term follow-up stud-
Children’s Hospital-Research Institute, Montreal, Quebec, Canada. ies4,9,11 have either included a heteroge-
Supported in part by Health Canada through the National Health Research and Development Program.
neous group of infants with BPD or a
Received for publication Mar 10, 1997; revisions received Sept 12, 1997, Jan 9, 1998; accepted Mar 23,
1998.
group with relatively mild BPD, in that
Reprint requests: Allan Coates, MD, Division of Respiratory Medicine, Hospital For Sick Children, 555 birth weights were on the order of 1500 g
University Ave, Toronto, Ontario, Canada. and there was no need for prolonged
Copyright © 1998 by Mosby, Inc. oxygen administration. This study was
0022-3476/98/$5.00 + 0 9/21/90614 designed to evaluate children with severe

193
 JACOB ET AL THE JOURNAL OF PEDIATRICS
AUGUST 1998

Table I. Perinatal and anthropometric data to identify all infants who had been dis-
charged home receiving supplemental
Subjects Premature members oxygen between 1981 and 1987. Inclu-
with BPD of control group sion criteria for this study were as fol-
(N = 15) (N = 15) lows: (1) premature birth at 34 weeks’
gestational age or less, (2) clinical and
Mean ± SD Mean ± SD
radiologic diagnosis of BPD (see follow-
or median or median
ing text), (3) requirement for supple-
(interquartile range) (interquartile range)
mental oxygen (to maintain a saturation
Age (yr) 10.6 ± 1.7* 11.2 ± 1.5 of at least 90% both awake and asleep or
Gestational age (wk) 28.7 ± 2.1 28.5 ± 2.6 a transcutaneous PO2 >55 mm Hg before
Birth weight (g) 1110.0 ± 328.0 1044.0 ± 262.9 the availability of oximetry) for at least 1
Days of ventilatory assistance 56.0 (21.0-77.0)* 8.0 (4.0-32.0) month after term, and (4) discharge
Age O2 discontinued (days) 631.0 (339.0-928.0)* 11.0 (7.0-32.0) home receiving supplemental oxygen.
Height (cm) 137.9 ± 12.4* 147.3 ± 12.0 Because of the birth dates and the thera-
Weight (kg) 35.4 ± 13.9 39.0 ± 7.1 peutic options of that era, none of these
% Ideal body weight 108.5 ± 21.2 97.7 ± 15.8 children had received artificial surfactant
Lean body mass (kg) 27.6 ± 7.5 31.7 ± 6.1 or postnatal steroids for the management
% Body fat 19.3 ± 9.7 18.7 ± 5.5 of BPD. Exclusion criteria were (1) con-
*P
genital heart disease other than patent
< .02 for BPD versus premature members of control group.
ductus arteriosus, (2) an ongoing oxygen
need related to a primary respiratory di-
agnosis other than BPD, and (3) an in-
Table II. Pulmonary function data ability to perform pulmonary function
tests. Each child with BPD whose family
Premature members was willing to participate in the study
Subjects with BPD of control group was matched with a child of the same
(N = 15) (N = 15) chronologic age (±12 months) who had
Mean ± SD Mean ± SD been born prematurely at the same ges-
tational age (±2 weeks) and who re-
FVC (% pred) 83.1 ± 18.2 93.7 ± 8.3 quired either continuous positive airway
FEV1 (% pred) 63.6 ± 20.6* 85.1 ± 10.8 pressure or assisted ventilation in the im-
FEV1/FVC (%) 69.2 ± 9.0* 84.1 ± 7.7 mediate neonatal period but who did not
FEF25%-75% (% pred) 40.3 ± 24.5* 78.7 ± 22.7 have BPD defined by an ongoing re-
TLC (% pred) 104.7 ± 13.2 97.1 ± 7.5 quirement for supplemental oxygen be-
FRC (% pred) 122.6 ± 35.8* 93.8 ± 13.4 yond 36 weeks’ postconceptional age.13
RV (% pred) 181.8 ± 84.3* 114.8 ± 20.2 These children were recruited from the
RV/TLC (%) 36.7 ± 12.8* 25.3 ± 4.2 neonatal follow-up programs at the
DLCO (% pred) 83.4 ± 10.5† 92.4 ± 13.0† Montreal Children’s Hospital and the
DLCO/VA (% pred) 119.5 ± 11.3† 117.0 ± 18.0† Royal Victoria Hospital (a McGill Uni-
FVC, Forced vital capacity; FRC, functional residual capacity; VA, alveolar volume. versity perinatal center).
*P < .01 for BPD versus premature members of control group.
The study was approved by the Insti-
†N = 12.
tutional Review Board of the McGill
University Montreal Children’s Hospi-
tal-Research Institute, and 1 parent and
BPD whose discharge was facilitated by not have BPD during the neonatal peri- the child signed a consent form before
supplemental oxygen at home and whose od, and (2) pressure volume curves of they participated.
requirement for supplemental oxygen their lung would show a loss of elastic re- Chart reviews were performed by a
persisted past 44 weeks’ gestational age. coil pressure in keeping with the patho- person unaware of the results of pul-
The hypotheses were as follows: (1) logic characteristics of severe BPD.12 monary function testing. The charts of
school-age children who had severe the subjects and the control group were
BPD would have abnormal airway ob- reviewed for gestational age and birth
struction, hyperinflation, and increased METHODS weight, duration of ventilation, age at
airway reactivity compared with a pre- which supplemental oxygen was discon-
maturely born control group matched for Records from the Montreal Children’s tinued, and number of readmissions for
chronologic and gestational age who did Hospital Home Care Service were used respiratory exacerbations. Supplemental

194
THE JOURNAL OF PEDIATRICS
VOLUME 133, NUMBER 2
oxygen was discontinued only when it
could be demonstrated that the SaO2 was
≥90% while the subjects were asleep.
Parents of subjects and members of the
control group filled out a modified Inter-
national Union Against Tuberculosis and
Lung Disease bronchial symptoms ques-
tionnaire14 in either French or English.
The IUATLD questionnaire was chosen
because it had previously been validated
in French, the language of many of the
participants.15 The questionnaire had a
maximum possible respiratory symptom
score of 8 and included questions related
to symptoms of airway hyperactivity, his-
tory of recurrent pneumonia, and family
history of atopy.
Height and weight of subjects and
members of the control group were mea-
sured, and lean body mass was estimated
from skinfold thicknesses as described
by Slaughter et al.16 Pulmonary function
testing was performed at least 6 weeks
after the most recent respiratory tract in-
fection. β-agonists were withheld for
both subjects and the control group dur-
ing the 4 hours before testing, but long-
acting medications such as theophylline,
sodium cromoglycate, and steroids were
not. Subjects and members of the control
group performed standard spirometry
with American Thoracic Society guide-
lines,17 with forced vital capacity, FEV1,
and forced expiratory flow between 25%
and 75% of vital capacity being mea-
sured and expressed as percent predict-
ed for sex and height.18 For black sub-
jects 15% was subtracted from the
predicted value for spirometry.19 Lung
volumes (vital capacity, total lung capac-
ity, functional residual capacity, and
residual volume) were measured by
whole body plethysmography, with re-
sults again being expressed as percent
predicted for sex and height.18
For those children who agreed to the
procedure, with the aid of a topical anes-
thetic, lung elastic recoil pressure was
measured by a quasistatic expiratory ma-
neuver with an esophageal balloon placed
in the lower third of the esophagus20 and
was validated by the occlusion test.21
Pressures at the airway opening and in
the esophagus were measured with a
Validyne MP45 and a Sanborn 297AC
differential transducer. Changes in vol-
Fig 1. Relationship between FEV1 and duration of supplemental oxygen therapy. Correlation coefficient
was r = –0.84 (P < .0001).
ume were measured with a pressure-com-
pensated volume-displacement plethys-
mograph22 (Emerson, Cambridge, Mass)
and recorded along with the transpul-
monary pressure as the subject was in-
structed to take an inspiration to TLC
followed by a slow exhalation to RV, dur-
ing which several brief occlusions were
performed. Volume was expressed as a
percent of TLC and plotted against
transpulmonary pressure on a graph that
included the limits of normal for pressure
volume curves based on age.23
The diffusion capacity of carbon
monoxide (expressed as a percent pre-
dicted24) was measured by the single
breath technique, correcting for lung vol-
ume (DLCO/alveolar volume)25 to study
alveolar gas exchange and to assess the
function of the pulmonary vasculature.26
All subjects and members of the con-
trol group were given a nebulized dose of
albuterol, 2.5 mg in 2.5 cc to assess re-
sponse to a bronchodilator as a measure
of their airway reactivity. This procedure
was done by comparing spirometry be-
fore and 15 minutes after the albuterol
was given. As an assessment of respira-
tory muscle strength, maximal static
pressures generated on inspiration and
expiration were measured at the mouth
at functional residual capacity and TLC,
respectively, as described by Gauthier
and Zinman.27
JACOB ET AL
The latest chest radiographs of sub-
jects with BPD were reviewed and
scored according to the system of Toce et
al.28 If the last chest radiograph was
taken more than a year before the time
that pulmonary function testing took
place, it was repeated.
Data Analysis
Results were expressed as the mean ±
SD or median (interquartile range) for
non-normally distributed data. The fol-
lowing parameters were compared with
the Student paired t test or the Wilcoxon
matched pairs test: clinical symptom
score as derived from the questionnaire,
perinatal factors including length of time
of ventilation and duration of supple-
mental oxygen, height, weight, and lean
body mass, and pulmonary function re-
sults. For unpaired data either the t test
for independent means or the Mann-
Whitney U test was used. Chi square
testing was used for yes/no questionnaire
responses, radiographic parameters, and
bronchodilator response.
RESULTS
Subject Participation
A total of 27 children with BPD were
admitted to the home oxygen program
during the years included in the study
(1981 through 1987). One child died at
195
 JACOB ET AL
Fig 2. A and B. Actual data points and PV curves for 9 subjects with BPD between ages of 7 and 12
years, with volume plotted as percent of actual TLC and pressure in cm H2O. Dashed lines indicate limits of
normal for age.23 A, A 7-year-old subject (▲) with FEV1 of 68% predicted and RV/TLC of 29%. B, A 9-
year-old subject (▲) with FEV1 of 89% predicted and RV/TLC of 29%.
the age of 6 months. Two children were
deemed ineligible: 1 because of the pres-
ence of a tracheostomy and 1 because of
severe neurologic impairment. Of the re-
maining 24 potential subjects, 1 family
had moved far away, 3 declined to partici-
pate, and 5 could not be located. The
study participants did not differ signifi-
cantly from the 9 eligible children who did
not participate in terms of birth weight,
gestational age, or length of time receiv-
ing mechanical ventilation, but study par-
ticipants were significantly older when
supplemental oxygen was discontinued,
631 (339 to 928) days (median and in-
196
terquartile range) versus 349 (276 to 365)
days, P < .05. Fifteen matched premature-
ly born members of the control group
without BPD were also tested. Six boys
and 9 girls were in each group. All chil-
dren with BPD were white, but 2 of the
members of the control group were black.
Clinical Data
No significant differences were found in
gestational ages and birth weights be-
tween subjects and prematurely born
members of the control group; however,
subjects with BPD underwent ventilation
and received supplemental oxygen for sig-
THE JOURNAL OF PEDIATRICS
AUGUST 1998
nificantly longer time periods than the pre-
mature members of the control group
(Table I). At discharge from the neonatal
intensive care unit, the mean oxygen satu-
ration of the subjects with BPD was 88%
± 5% while awake breathing room air. The
oxygen flow by nasal canula was a mean
of 0.53 ± 0.42 L/min; 42% were receiving
diuretics, and 37% were receiving bron-
chodilator medication. Two thirds were re-
ceiving formula with increased caloric
density to achieve an intake of >120
kcal/kg/day. There was a mean of 2.1 ± 2.7
admissions to hospital during the first 2
years after discharge from the neonatal in-
tensive care unit for respiratory exacerba-
tions. This included one child who was ad-
mitted 8 times during the first year who
subsequently required placement in a fos-
ter home because of her mother’s difficulty
in coping with mild physical problems.
Subjects with BPD were slightly
younger than members of the control
group at the time of the study. They were
significantly shorter than members of the
control group, but no significant differ-
ence was seen in weight, percent of ideal
body weight, lean body mass, or percent
of body fat (Table I).
The IUATLD questionnaire revealed
that more subjects with BPD than mem-
bers of the control group reported having
to stop play or exercise during the previ-
ous 12 months because of shortness of
breath, 9 (60%) of 15 versus 1 (7%) of 15
(P < .01). More subjects (6 [40%] of 15)
than members of the control group (1
[7%] of 15) reported taking medications
for asthma, but this did not reach statisti-
cal significance. A history of pneumonia
was common in both groups, 7 (47%) of
15 versus 6 (40%) of 15 or for 3 or more
episodes of pneumonia, 3 (20%) of 15 ver-
sus 0 (0%) of 15, BPD versus the control
groups, as was a family history of atopy, 7
(54%) of 13 versus 9 (60%) of 15; family
history was unavailable for 2 subjects
with BPD who had been adopted. No sig-
nificant difference was seen in respiratory
symptom scores between subjects and the
control group, 3 (1-4) versus 0 (0-3).
Pulmonary Function Tests
SPIROMETRY AND LUNG VOLUMES . Al-
though forced vital capacity did not dif-
THE JOURNAL OF PEDIATRICS JACOB ET AL
VOLUME 133, NUMBER 2

fer significantly between subjects and the

control group, subjects with BPD had
significantly lower values compared with
the control group for FEV1, FEF25%-75%,
both expressed as a percentage of pre-
dicted, and the FEV1/forced vital capaci-
ty ratio (Table II), with a considerable
variation in the results ranging from nor-
mal to markedly reduced. Four of the
subjects with BPD had values of <50%
of predicted for FEV1. TLC expressed as
a percent of predicted normal was not
significantly different between subjects
with BPD and the control group, but
subjects with BPD had a higher func-
tional residual capacity, RV, and
RV/TLC ratio (Table II).

RESPONSE TO BRONCHODILATOR. One

subject in each of the 2 groups had diffi-
culty performing spirometry after bron-
chodilation. An equal number of subjects
and members of the control group, 8
(57%) of 14 in each group, showed a sig-
nificant response to bronchodilation with
an increase in FEV1 of ≥12% or an in-
crease in FEF25%-75% of ≥25%.
A negative correlation was seen (r =
–0.84, P < .0001) between FEV1 and the
age at which supplemental oxygen was
discontinued (Fig 1). For the subjects
with BPD, there was no correlation be-
tween the symptom score and any pul-
monary function test, but for the control
group the symptom score was correlated
with the change in FEV1 in response to
bronchodilators (r = 0.6, P < .03).

PRESSURE-VOLUME CURVES. A wide

variation was seen in the pressure-vol-
ume curves of the subjects with BPD
(Fig 2), although in general, the curves
were shifted up and to the left when
compared with predicted limits of nor-
mal values for age.23 The elastic recoil
pressure at 90% TLC was lower than ex-
pected, with a mean of 78% ± 26% of
predicted and a range of 43% to 125%.
This result did not correlate with pul-
monary function tests or current radi-
ographic scores; however, the subjects
with gas trapping, as indicated by a high Fig 2. C-E. C, A 10-year-old subject (▲) with FEV1 of 85% predicted and RV/TLC of 19%. D, PV curves
RV/TLC, had curves above the normal for 3 11-year-olds: subject indicated by ■ had FEV1 of 55% predicted and RV/TLC of 45%; FEV1 and
RV/TLC for subject denoted as ▲ were 64% predicted and 23%, respectively; and for subject denoted by
range with little change in pressure at the
h they were 61% predicted and 42%, respectively. E, PV curves for 3 12-year-olds: FEV1 and RV/TLC for
lower lung volumes. Five subjects had subject denoted as ■ were 30% predicted and 64%, respectively; for subject denoted as ▲, it was 67%
PV curves of the lung within the normal predicted and 30%; and for subject denoted as h, it was 41% predicted and 46%.

197
 JACOB ET AL
range or at the limit of normal. These
subjects had a mean FEV1 of 73 ± 15
compared with the 4 with abnormal PV
curves, whose FEV1 was 48 ± 16. In a
similar fashion, the normal PV curves
were associated with an RV/TLC of 28 ±
9 compared with 43 ± 14 for the abnor-
mal curves.
DIFFUSING CAPACITY. No significant
difference in DLco was found between
subjects with BPD and the control
group, either uncorrected or corrected
for lung volume (Table II). For both the
subjects with BPD and the control
group, the DLco correlated with the
FEV1 (r = 0.75, P < .005 and r = 0.79, P <
.002, respectively), but the slope of the
relationship was very different. For the
subjects with BPD compared with the
control group, a threefold greater fall in
DLco occurred for the equivalent de-
crease in FEV1, largely because for those
4 subjects with BPD whose FEV1 was
<50% predicted, the DLco was less than
80% predicted.
M AXIMAL RESPIRATORY PRESSURES .
Maximal inspiratory and expiratory
pressures were successfully measured
in 12 of 15 subjects with BPD and all
15 members of the control group. All
subjects and members of the control
group had maximal inspiratory and ex-
piratory pressures that were within 2
SD of the mean for age. 27 No signifi-
cant differences were found between
the 2 groups.
Review of Chest Radiographs
The mean radiographic score was 6.2 ±
1.1 with a range of 4 to 8 and no signifi-
cant changes from baseline. All subjects
had persistent emphysematous changes
with 1 or more bullae seen in 86% of
films and small areas of hyperlucency
seen in the remaining 14%. Evidence of
fibrosis was also seen in all current radi-
ographs: 71% had multiple fibrotic
strands, and 29% had a few abnormal
streaky densities. No subjects had persis-
tent cardiomegaly on chest radiography.
A negative correlation (r = –0.53, P = .05)
was seen between FEV1 expressed as a
percentage of predicted and the current
radiographic score.
198
DISCUSSION
This study found that children with a
history of severe BPD were left with sig-
nificant pulmonary sequelae at school
age compared with prematurely born
members of the control group, who had
required ventilatory assistance and sup-
plemental oxygen in the neonatal period
but who did not go on to have BPD.
Children with BPD had ongoing respira-
tory symptoms, persistent chest radi-
ographic abnormalities, and significant
airway obstruction and hyperinflation.
Some also had abnormal elastic recoil of
the lungs. The similarity of the neonatal
course between those who participated
in the study and those who did not sug-
gests that the subjects of the study were
representative of all of the children meet-
ing the definition of severe BPD. With
only 1 death in the population after dis-
charge from the hospital, the mortality
rate in the group as a whole is encourag-
ing in light of studies published for in-
fants born in approximately the same era
of neonatal care.29,30
Respiratory Symptoms
Children with BPD and prematurely
born members of the control group had
significant ongoing symptoms as as-
sessed by questionnaire, with children
with BPD having a higher incidence of
activity limitation because of respiratory
symptoms, which is in keeping with the
findings in other studies.2,31 It is interest-
ing that ongoing symptoms did not cor-
relate with pulmonary function testing in
the subjects with BPD. This may be be-
cause the children with BPD have ab-
normal lung function as a result of both
permanent anatomic damage and bron-
chospasm.7,9,32 During their clinical fol-
low-up those with significant improve-
ments in spirometry in response to
bronchodilators were given a trial of cor-
ticosteroids. However, unlike asthmatic
subjects, attempts to improve prebron-
chodilator spirometry with cortico-
steroids, either inhaled or systemic, had
been relatively disappointing in most
subjects. Furthermore these steroid-
unresponsive subjects had only mild
complications concerning respiratory
symptoms with no episodes in later
THE JOURNAL OF PEDIATRICS
AUGUST 1998
childhood that could be described as a
“typical” asthma attack. On the other
hand, those subjects in whom the diag-
nosis of asthma could be supported by
family history and episodic worsening of
symptoms responding to bronchodilators
were much more likely to report annoy-
ing respiratory symptoms. These chil-
dren, however, were not usually those
with the worst pulmonary function tests.
In other words, symptoms seemed to be
more closely related to the reversible
component of airway obstruction rather
than the fixed component, highlighting
the role that ongoing inflammation of the
airways plays in respiratory symptoms.
Spirometry, Lung Volumes, and
Lung Mechanics
With a mean FEV1 of 64% predicted,
most of the subjects with BPD partici-
pating in the study had moderately se-
vere airflow limitation. Of particular
concern were the 4 subjects whose FEV1
was <50% predicted, the lowest being
30% predicted, indicating severe airflow
limitation. These 4 subjects required sup-
plemental oxygen for >700 days, and 3
required it for >900 days (Fig. 1). The
course of these infants was complicated
by recurrent episodes of heart failure
caused by severe pulmonary vascular
disease. There was a correlation between
initial disease severity and long-term pul-
monary function, but it is interesting that
the scatter in the group was such that 2
children who required oxygen for >800
days had FEV1 values of >60% predict-
ed. It should be noted that in the present
age of artificial surfactant and postnatal
steroids for the management of BPD, the
usual duration of oxygen therapy is very
much less than that seen in those chil-
dren in this study.
There have been several reports of
lung function in survivors of
BPD.4,6,9,11,33-35 Most have demonstrat-
ed some abnormality, typically a mild ob-
structive pattern with a component of re-
versibility with bronchodilators, and
hyperinflation. In this study the pattern
of results was similar, although there was
a wide spectrum of impairment. This
study used the response to bronchodila-
tors rather than a provocation test as a
measure of airway reactivity because of
THE JOURNAL OF PEDIATRICS
VOLUME 133, NUMBER 2
ethical concerns about bronchial provo-
cation tests in subjects with already low
spirometric values (mean FEV1 of 64%)
(Table II). However, the results are simi-
lar to those of previous studies that did
use bronchial provocation.9 The similari-
ty of the degree of airway reactivity in
both subjects and the control group is in
keeping with other studies7,8 and sug-
gests that it is associated with prematuri-
ty rather than BPD per se.
The cause of the airway obstruction in
BPD is unclear. Although there may be a
reactive component to the obstruction, as
indicated by the bronchodilator response
in some subjects, there is a large irre-
versible component, which for many of
the subjects in this study has not shown
improvement with inhaled or systemic
steroids. Stocker12 described pathologic
findings on autopsy in patients who had
long-standing or “healed” BPD: on gross
examination the lungs had a cobblestone
appearance as a result of the presence of
hyperexpanded areas alongside units
that were atelectatic and fibrotic, and on
microscopic examination there was evi-
dence of submucosal inflammation in the
bronchi and marked fibrosis of the alveo-
lar septa. Blood vessels showed evidence
of hypertensive changes. Many of these
changes are associated with oxygen toxi-
city,1 which along with barotrauma36
have long been considered to play a role
in acute lung injury. Based on this patho-
logic condition, one would expect to
have airflow limitation associated with
hyperinflation, which was indeed found
in this study. Furthermore the presence
of fibrosis could be expected to give rise
to increased elastic recoil forces: in other
words, stiffer lungs. In this study those
subjects whose FEV1 was <50% predict-
ed and in whom PV curves were mea-
sured had marked hyperinflation and flat
curves that at low lung volume were well
above the normal range, but they had a
loss of elastic recoil at high lung volumes.
Those with less hyperinflation tended to
have much more normal PV curves with
less loss of elastic recoil, especially at low
lung volumes. This picture of mixed and
seemingly contradictory findings is likely
due to the coexistence of emphysematous
changes and fibrosis. The final pattern is
often a curve that is shifted up and to the
right in keeping with hyperinflation and
loss of elastic recoil but which is flatter,
representing the stiffer lungs found in
pulmonary fibrosis. No literature ad-
dresses elastic recoil forces in patients
with milder forms of BPD, so it is not
possible to decide which factor, shift of
the curve or change in compliance, is
most responsible for the changes in pul-
monary function.
The mean FEV1 of the control group
in this study was 85%, and the RV/TLC
was 25%, which is virtually identical to
findings in previous studies of prema-
turely born infants with no lung disease.7
Previously, these findings have been at-
tributed to increased airway reactivity
seen in prematurely born infants.7,8 The
response to bronchodilators seen in the
premature members of the control group
in this study would be in keeping with
this explanation. The normal values for
respiratory muscle strength seen in both
groups would suggest that the respirato-
ry muscles played little or no role in the
abnormalities of pulmonary function.
Diffusing Capacity
Normally, airflow limitation in the ab-
sence of any abnormality in the pul-
monary vascular bed or impairment to
gas diffusion would result in an “artifi-
cial” elevation of values for DLco37 be-
cause of an increase in blood volume in
the pulmonary vascular bed, as is com-
monly seen in children with asthma. In
contrast, parenchymal disease, even in
the presence of airflow limitation, is usu-
ally associated with a lower DLco,38
which has been attributed to abnormali-
ties in the pulmonary vascular bed and
has been associated with exertional de-
saturation.38 The 4 subjects with BPD
with values for FEV1 of <50% predicted
all had values of DLco of <80% predict-
ed, and the 2 in whom it was measured
had PV curves suggesting extensive
parenchymal damage. Hakulinen et al.10
showed no differences and virtually
identical values for DLco in both subjects
with mild BPD and the preterm mem-
bers of the control group, with both
these groups significantly different from
the term born children. Such data would
suggest some abnormalities in lung
growth in prematurely born infants
JACOB ET AL
rather than a specific defect in diffusion
resulting from neonatal lung disease.
Radiology
The children with BPD in this study
all continued to have radiographic ab-
normalities at school age consisting of
emphysematous changes in the form of
small areas of hyperlucency and bullae
and fibrotic or atelectatic changes.
In conclusion, children who had severe
BPD as defined by this study had persis-
tent pulmonary abnormalities at school
age, mainly obstruction to airflow with air
trapping, that ranged from minimal to se-
vere. The reason for the differences in out-
come between subjects and the control
group was not explained by birth weight
or degree of prematurity, but for children
with BPD the duration of supplemental
oxygen appeared to be a good predictor of
later abnormalities in pulmonary function.
PV curves and radiographic findings sup-
ported the known pathologic findings of
distorted pulmonary architecture. Of par-
ticular concern are the 4 children whose
FEV1 was <50% predicted. Because a nat-
ural decline in pulmonary function occurs
with increasing age, these children with
severe abnormalities at the time of school
age are at significant risk for respiratory
problems during adult life, particularly if
they smoke. Finally, the corollary is that
those caring for adults with obstructive
lung disease should seek a birth history
and use this information to interpret pul-
monary function and disease severity.
The authors are grateful to Dana Greer for her
organizational skills and data management and
to Akis Smountas for his statistical support and
preparation of the article.
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