ORIGINAL

ARTICLES
Longitudinal Analysis of Ventilation Perfusion Mismatch in Congenital
Diaphragmatic Hernia Survivors
Duy T. Dao, MD, MPH1,2, Ali Kamran, MD1, Jay M. Wilson, MD3, Catherine A. Sheils, MD4, Virginia S. Kharasch, MD5,
Mary P. Mullen, MD, PhD6, Samuel E. Rice-Townsend, MD1, Jill M. Zalieckas, MD1, Donna Morash, RN1, Mollie Studley, MS1,
Steven J. Staffa, MS1,7, David Zurakowski, MS, PhD1,7, Ronald E. Becker, MD8, Charles J. Smithers, MD9,*,
and Terry L. Buchmiller, MD1,*

Objective To determine the natural history of pulmonary function for survivors of congenital diaphragmatic hernia
(CDH).
Study design This was a retrospective cohort study of survivors of CDH born during 1991-2016 and followed at
our institution. A generalized linear model was fitted to assess the longitudinal trends of ventilation (V), perfusion (Q),
and V/Q mismatch. The association between V/Q ratio and body mass index percentile as well as functional status
was also assessed with a generalized linear model.
Results During the study period, 212 patients had at least one V/Q study. The average ipsilateral V/Q of the cohort
increased over time (P < .01), an effect driven by progressive reduction in relative perfusion (P = .012). A higher V/Q
ratio was correlated with lower body mass index percentile (P < .001) and higher probability of poor functional status
(New York Heart Association class III or IV) (P = .045).
Conclusions In this cohort of survivors of CDH with more severe disease characteristics, V/Q mismatch worsens
over time, primarily because of progressive perfusion deficit of the ipsilateral side. V/Q scans may be useful in iden-
tifying patients with CDH who are at risk for poor growth and functional status. (J Pediatr 2020;219:160-6).

See editorial, p 7 and related

article, p 167

C
ongenital diaphragmatic hernia (CDH) is a serious disease of the newborn characterized by hypoplasia of the pulmo-
nary parenchyma and vasculature.1 Because of advancements in neonatal intensive care, overall survival has reached
70% at major pediatric centers.2 As death after the index hospitalization is rare, more and more survivors of CDH are
reaching adolescence and adulthood. With prolonged survival, long-term outcomes and morbidities have posed new challenges
in the care of these patients.3 Among the topics that are still poorly understood, the natural history of pulmonary ventilation
and perfusion is of particular interest due to conflicting reports in the literature and its implications on the disease’s pathophys-
iology, clinical management, and even therapeutic strategies.4-6
In an Italian study that followed patients with CDH until early adulthood, Arena et al reported rapid improvement of pul-
monary perfusion after CDH repair despite evidence of continuing pulmonary hypoplasia on ventilation (V)/perfusion (Q)
studies.7 Similarly, in another study from India, the authors used serial V/Q scin-
tigraphy to conclude that there was pulmonary vascular growth in patients with
CDH over time.8 However, in an initial study of patients followed in our CDH
1
clinic, V/Q mismatch worsened over time, primarily because of progressive From the Department of Surgery, Boston Children’s
2
Hospital, Boston, MA; Vascular Biology Program,
9
perfusion deficit in the ipsilateral lung. In these and other studies that aim to Boston Children’s Hospital, Boston, MA; Department of 3

Pediatric Surgery, McGovern Medical School at

investigate the trend of pulmonary ventilation and perfusion in survivors of UTHealth and Children’s Memorial Hermann Hospital,
4
Houston, TX; Division of Respiratory Diseases, Boston
CDH, either a small sample size or lack of longitudinal statistical models limits Children’s Hospital, Boston, MA; Department of 5

the ability to draw definitive conclusions. Pediatrics, Franciscan Children’s Hospital, Brighton, MA;
6
Department of Cardiology, Boston Children’s Hospital,
Boston, MA; 7Department of Anesthesiology, Boston
Children’s Hospital, Boston, MA; 8Division of
Developmental Medicine, Boston Children’s Hospital,
Boston, MA; and 9Department of Surgery, Johns
Hopkins All Children’s Hospital, St. Petersburg, FL
BMI Body mass index
*Contributed equally.
CDH Congenital diaphragmatic hernia
Funded by the National Institutes of Health
ECMO Extracorporeal membrane oxygenation (5T32HL007734 [to D.D.]). The funder had no role in study
GLM Generalized linear model design, data analysis, decision to publish, or preparation
NYHA New York Heart Association of the manuscript. The authors declare no financial con-
flict of interest.
Q Perfusion
V Ventilation 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jpeds.2019.09.053

160

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The Congenital Diaphragmatic Hernia Program at Boston
Children’s Hospital is staffed by a multidisciplinary team of
pediatric surgeons, pulmonologists, radiologists, develop-
mental specialists, dieticians, and nurses who are specialized
in the care of these highly complex patients. Children who
receive care at our CDH clinic undergo serial V/Q scans as
a part of their follow-up protocol, with the first one at
approximately 6 months to 1 year of age. We sought to pro-
vide a longitudinal assessment of V/Q progression in patients
with CDH followed at our institution and to identify peri-
natal risk factors that correlate with severity as well as deteri-
oration of V/Q mismatch over time. Our hypothesis was that
patients with CDH have a persistent perfusion defect of the
ipsilateral lung throughout life which can worsen, and
that this perfusion defect correlates with severity of CDH at
birth.
Methods
This study included all patients with CDH born between
1991 and 2016 with at least one V/Q measurement. Data
collection was continued until December 31, 2018. For
each patient, only complete V/Q studies with both ventila-
tion and perfusion measurements were included. Exclusion
criteria included incidental diagnosis of CDH, Morgagni-
type defect, and surgical correction at an outside institution.
The initial V/Q study was typically obtained between
6 months and 1 year of age. V/Q studies were repeated within
the next 1-2 years if the initial results showed significant
mismatch. Otherwise, repeat studies were done from 3 to
5 years of age. Further follow-up studies were done at various
time points at the discretion of the multidisciplinary treat-
ment team. Throughout this study, all reported V/Q mea-
surements referred to the ipsilateral side.
Demographic and perinatal characteristics of CDH were
recorded for each patient in the cohort and included sex,
gestational age, birth weight, prenatal diagnosis of CDH, Ap-
gar score at 1 and 5 minutes, cardiopulmonary resuscitation
at birth, defect size, patch usage at surgical correction, extra-
corporeal membrane oxygenation (ECMO) utilization,
structural cardiac abnormality, and oxygen requirement at
discharge from index hospitalization. Diaphragmatic defect
size was assessed at surgical correction based on the CDH
Study Group Staging System.10 CDH Study Group defect
size, which is highly correlative with clinical outcomes,10 as-
signs a grading scale of A-D for the smallest to the largest dia-
phragmatic defect. For patients born before the
implementation of the CDH Study Group Staging System,
defect size was retrospectively assessed by 2 blinded pediatric
surgeons who specialized in the surgical management of
CDH. Discordant assessments were resolved by an indepen-
dent third surgeon. Cardiac anomalies included congenital
cyanotic heart diseases and major defects such as hypoplastic
left heart syndrome, coarctation of the aorta, and double
outlet right ventricle. Dichotomous variables were expressed
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Volume 219  April 2020
as number and percentage and continuous variables were
represented by median and IQR.
To detect possible selection bias of treating physicians in
ordering follow-up V/Q studies, baseline characteristics
were compared between patients who had a single study
and those who had multiple V/Q measurements with appro-
priate statistical tests. Comparisons of categorical variables
were performed with a Fisher exact or c2 test and continuous
variables with a Wilcoxon rank-sum test. Next, adjustment
for selection bias was performed with inverse probability
weighting.11 In brief, a logistic regression model was fitted
to predict the probability of having multiple studies based
on defect size, ECMO utilization, and baseline V/Q measure-
ment. This probability was then inversed to obtain the selec-
tion weight, which was used in all subsequent statistical
models of the study. By utilizing this selection weight, results
of longitudinal analyses could be generalized to the entire
cohort as if all patients had been followed up beyond their
baseline V/Q study.
Statistical Analyses
A generalized linear model (GLM) was used to fit the longi-
tudinal V/Q data. Parameters of the model were estimated
with the generalized estimating equations technique. This is
a semiparametric regression method that allows for estima-
tion of the average V/Q response of the entire cohort over
time, taking into account the correlation in repeated mea-
surements within each individual patient. Besides age, cova-
riates of the GLM were chosen a priori and included sex,
defect side, ECMO utilization, as well as surrogate markers
for the degree of pulmonary hypoplasia (ie, defect size) and
pulmonary hypertension (ie, oxygen requirement at
discharge from index hospitalization). The GLM allowed
for assessment of the trends of V, Q, and V/Q measurements
of the cohort over time by estimating regression coefficients,
95% CIs, and P values. Subsequently, an interaction term be-
tween defect size and time was introduced into the GLM to
assess for the effect modification of defect size on the longi-
tudinal trends of V, Q, and V/Q.
To correlate V/Q ratio with growth, body mass index
(BMI) and BMI percentile were calculated for each patient
at the time of every V/Q measurement using the Center for
Disease Control and Prevention calculator. BMI percentile
calculation was only performed between the age of 2 and
20 years, according to the formula’s restriction. A GLM was
subsequently fitted with BMI percentile as the outcome and
V/Q ratio as the main exposure. Other covariates included
sex, age, defect size, defect side, ECMO utilization, and oxy-
gen at discharge.
Because of the lack of a validated classification system for
cardiopulmonary functional status in children, a modified
version of the New York Heart Association (NYHA) Classifi-
cation was used. This modified version of NYHA Classifica-
tion was based on the authors’ experience with the CDH
cohort; it has not been validated in other studies. Class I:
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THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume 219

meeting developmental milestones, following the growth

curve, and minimal need for supportive medications (for in- Table I. Baseline characteristics of patients who had
fants); asymptomatic at rest and no physical limitation with multiple vs 1 V/Q study
exercise (for children). Class II: requirement of supplemental Variables Multiple V/Q studies One V/Q study P value
enteral feeding to achieve appropriate growth, mild- N 104 108
moderate delay in meeting developmental milestones Sex .481
Male 67 (64%) 64 (59%)
without a history of neurological comorbidities, or moderate Female 37 (36%) 44 (41%)
need for supportive medications without pulmonary hyper- Gestational age (wk) 38 (37, 39) 39 (38, 39) .146
tensive treatment (for infants); asymptomatic at rest but Birth weight (g) 3060 (2700, 3575) 3140 (2720, 3415) .559
Prenatal diagnosis 72 (76%) 71 (66%) .164
mild physical limitation with exercise (for children). Class Apgar at 1 min 4 (3, 7) 6 (4, 8) .011
III: falling off the growth curve despite supplemental enteral Apgar at 5 min 7 (6, 8) 8 (7, 8) .056
feeding, severe delay in meeting developmental milestones CPR 7 (7%) 3 (3%) .198
CDHSG defect size .023
without a history of neurological comorbidities, intermittent A/B 57 (55%) 76 (70%)
need for oxygen therapy, or requirement of pulmonary hy- C/D 47 (45%) 32 (30%)
pertensive treatment; asymptomatic at rest but severe phys- Defect side .067
Left 81 (78%) 95 (88%)
ical limitation with exercise (for children). Class IV: Right 23 (22%) 13 (12%)
requirement of constant oxygen therapy (for infants); symp- Patch usage 65 (63%) 51 (47%) .027
tomatic at rest, or requirement of constant oxygen therapy ECMO 42 (40%) 21 (19%) .001
Cardiac abnormality 11 (12%) 12 (12%) 1.000
(for children). Oxygen at discharge 37 (36%) 30 (28%) .240
Cardiopulmonary functional status was retrospectively as- Baseline V/Q 1.29 (1.15, 1.51) 1.35 (1.13, 1.53) .561
sessed for each patient at every point of V/Q measurement
CDHSG, CDH Study Group; CPR, cardiopulmonary resuscitation; ECMO, extracorporeal mem-
based on review of the CDH clinic notes, which included brane oxygenation.
multidisciplinary evaluations from surgery, pulmonology, Comparison of binary variables between the 2 groups was performed with the Fisher exact test
whereas the Wilcoxon rank-sum test was used for continuous variables.
cardiology, developmental medicine, and nutrition. The
reviewer was blinded to the patient’s V/Q measurements.
The classes were then dichotomized into low (class III and
IV) and high (class I and II) functional status. A GLM was favorable perinatal CDH characteristics. Specifically, they
again used to assess the effect of the V/Q ratio on the odds had lower Apgar score at 1 minute (P = .011), higher
of having low functional status, with the same covariates as proportion of defect size C and D (P = .023), more
previously specified. frequent use of patch for repair (P = .027), and more
Throughout this study, a 2-sided a level of 0.05 was frequent employment of ECMO for stabilization
considered statistically significant. All statistical tests were (P = .001). These results were consistent with selection bias
performed with SAS software (v 9.4, SAS Institute, Cary, in the follow-up of V/Q study.
North Carolina). The study was approved by the Institutional After adjustment for selection bias with inverse probability
Review Board at Boston Children’s Hospital (Protocol weighting, longitudinal analysis with the GLM demonstrated
P00019681). progressive mismatch of V/Q over time (Figure 1, A). Even at
1 year of age, patients with CDH already demonstrated
Results significant V/Q mismatch, with an average V/Q ratio of
1.58 (95% CI 1.47, 1.69) (reference range 0.8-1.2)
During the period of 1991 to 2016, a total of 315 patients with (Table II; available at www.jpeds.com). This ratio increased
CDH survived to discharge and 212 had at least 1 complete to 1.82 (95% CI 1.64, 2.01) at 15 years of age. In-depth
V/Q study. The majority of patients in this study were male examination revealed 2 different trends in the ipsilateral
(62%) and had a prenatal diagnosis of CDH (71%). Major ventilation and perfusion percentage of these patients over
cardiac abnormalities were diagnosed in 12%. The majority the follow-up period. Although the ipsilateral ventilation
of CDH defects were left-sided (83%) and more than one- percentage remained relatively constant over time,
third of the defects were classified as size C or D on the perfusion deficit significantly deteriorated over the same
CDH Study Group Staging System. Thirty percent of the pa- period (Figure 1, B and C). The average V of the cohort
tients used ECMO for perinatal stabilization and a similar stayed upward of 40% during the entire study (Table II).
portion required oxygen supplementation at discharge However, the average Q progressively decreased from
from the index hospitalization. 30.7% (95% CI 27.6%, 33.8%) at 1 year to 26.4% (95% CI
Of these 212 patients, 104 had multiple V/Q studies 23.0%, 29.8%) at 15 years of age. Estimation of V/Q trend
(Table I). For those with more than one V/Q study, the over time showed an increase of 0.17 unit (95% CI 0.04,
median follow-up duration between the first and last study 0.30) every 10 years (P = .010) (Table III). This was driven
was 5.1 years (IQR 3.1, 9.1) and patient’s age at the time of by a relatively constant slope for V, 0.6% (95% CI
V/Q measurement ranged from 6 months to 19 years. In 3.1%, 0.3%) per 10 years (P = .605), and a significantly
general, those who had multiple V/Q studies displayed less decreasing slope for Q, 3.0% (95% CI 5.4%, 0.7%)
per 10 year (P = .012) (Table III).
162 Dao et al

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April 2020
Figure 1. Trends of V/Q mismatch. Longitudinal estimate of
the average ipsilateral A, V/Q ratio; B, V percentage; and C, Q
percentage over time was performed with a GLM. Displayed
are the regression lines and 95% confidence bands.
Besides age, certain perinatal CDH characteristics also
influenced V/Q ratio (Figure 2, A [available at www.jpeds.
com] and Table III). Larger defect size (C/D) increased V/
Q ratio compared with smaller defects (coefficient = 0.30;
95% CI 0.14, 0.45; P < .001). Male patients
(coefficient = 0.20; 95% CI 0.07, 0.32; P = .003) and
patients who still required oxygen at discharge from the
index hospitalization (coefficient = 0.20; 95% CI 0.07, 0.32;
P = .002) also had more severe V/Q mismatch.
Longitudinal Analysis of Ventilation Perfusion Mismatch in Congenital Diaphragmatic Hernia Survivors
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ORIGINAL ARTICLES
Oxygen requirement at discharge also correlated
with lower ventilation percentage measurement
(coefficient = 10.0%; 95% CI 16.2%, 3.7%; P = .002)
and left-sided defect showed an opposite association (coeffi-
cient = 11.0%; 95% CI 1.1%, 20.9%; P = .029) (Figure 2, B
[available at www.jpeds.com] and Table III). Factors that
were associated with more severe reduction in perfusion
percentage included large defect size (coefficient = 7.0%;
95% CI 11.2%, 2.9%; P = .001) and oxygen at discharge
(coefficient = 6.2%; 95% CI 9.3%, 3.1%; P < .001)
(Figure 2, C [available at www.jpeds.com] and Table III).
To further assess the effect of defect size on the longitudi-
nal trends of V, Q, and V/Q ratio, an interaction term be-
tween defect size and time was introduced into the
previously fitted GLMs. Compared with patients with defect
size A/B, those with defect size C/D had a faster increase in V/
Q ratio over time (P = .056) (Figure 3, A). Although the
interaction term did not reach statistical significance for V
and Q (P = .168 and .117, respectively), it appeared that
larger defect size also worsened the trajectory of ventilation
and perfusion percentage over time (Figure 3, B and C).
Taken together, these results suggested that large CDH
defect size placed the patients on a different trajectory with
disadvantages in both the starting baseline and rate of
worsening.
When V/Q mismatch was incorporated into the GLM as a
predictor of growth, there was a significant negative correla-
tion between V/Q ratio and BMI percentile. An increase of 1
unit in V/Q ratio was associated with a decrease of 13.6 (95%
CI 21.8, 5.5; P = .001) units in BMI percentile (Figure 4,
A; available at www.jpeds.com). A V/Q ratio of 1.5 and 3.0
corresponded with a BMI percentile of 32.9 (95% CI 27.9,
38.5) and 12.9 (95% CI 1.2, 27.1), respectively (Figure 4,
B; available at www.jpeds.com).
Similarly, there was a correlation between V/Q mismatch
and functional status. Every unit increase of V/Q ratio corre-
sponded to a 2.14-fold increase in the odds of being catego-
rized as functional class III or IV (OR = 2.14; 95% CI 1.02,
4.51; P = .045) (Figure 5, A; available at www.jpeds.com).
In addition, functional status did not change significantly
with age and patients with left-sided defects had better
function status compared with those with right-sided
defects (OR = 0.28; 95% CI 0.09, 0.92; P = .036). Of note,
the probability of having poor functional classification was
generally low during the follow-up period. A V/Q ratio of
1.5 corresponded to a 10.7% (95% CI 4.3%, 23.6%)
probability of having low functional status; this probability
increased to 26.1% (95% CI: 6.4%, 64.6%) at a V/Q ratio
of 3.0 (Figure 5, B; available at www.jpeds.com).
Discussion
We used a large population to investigate the natural history
of V/Q mismatch in survivors of CDH. In the primary
analysis, we determined the temporal trends of V, Q, and
V/Q ratio. Ipsilateral V/Q mismatch worsened over time,
163
THE JOURNAL OF PEDIATRICS  www.jpeds.com
Table III. Prediction of ventilation/perfusion ratio, ventilation, and perfusion by baseline characteristics
V/Q
Variables Effect estimate (95% CI) P value
Age* 0.17 (0.04, 0.30) .010
CDHSG defect size C/D 0.30 (0.14, 0.45) <.001
Oxygen at discharge 0.20 (0.07, 0.32) .002
Male 0.20 (0.07, 0.32) .003
ECMO 0.02 ( 0.16, 0.20) .847
Left-sided defect 0.01 ( 0.20, 0.17) .949
Association between baseline characteristics and ventilation/perfusion ratio (V/Q), ventilation (V), and perfusion (Q) was obtained from the GLM. Effect estimates are shown with 95% CI.
*Effect estimates for V/Q, V, and Q correspond to every 10-year change in age.
an effect that was largely driven by a progressive increase in
ipsilateral perfusion deficit. The severity of V/Q mismatch
also positively correlated with measures of CDH severity
such as defect size and oxygen requirement at index hospital
discharge. In the secondary analyses, V/Q ratio further
demonstrated a negative association with growth as well as
functional status.
This study extends previous reports on the CDH cohort
followed at our institution.9,12 Despite being derived from
a different statistical model, the findings in this study were
largely consistent with previous analyses and demonstrated
a trend of worsening of V/Q mismatch with time. In the
earlier reports, ECMO requirement and patch usage at surgi-
cal repair were found to predict the severity of V/Q
mismatch. Both of these predictors were summarized by
defect size, which has been shown to correlate with patch us-
age, ECMO utilization, and overall postnatal morbidity.13,14
Perhaps one of the most interesting results of this study
was the effect of defect size on the severity of V/Q mismatch.
When the CDH Study Group Staging System was proposed
in 2013, defect size was considered a surrogate marker for
the degree of pulmonary hypoplasia.10,15 Although there is
still a scarcity of information on the pathogenesis of CDH,
evidence suggests that both pulmonary hypoplasia and the
diaphragmatic defect result from early disturbances in lung
organogenesis,16 the so-called “dual-hit hypothesis.”17 Our
study suggests that these early genetic or molecular aberra-
tions can set survivors of CDH on different trajectories that
affect future development of pulmonary ventilation and
perfusion. However, it also opens the door for adjunct ther-
apies that can potentially modify the course of the disease,
such as angiogenic growth factors to improve capillary for-
mation and alveolarization18,19 and early and intensive car-
diopulmonary rehabilitation programs.
We also sought to establish an association between V/Q
mismatch and metrics of clinical outcome, such as growth
and functional status. Although a short-term association be-
tween nutritional status and V/Q mismatch has been re-
ported,20 we explored the effect of V/Q ratio on BMI in a
longitudinal fashion and attempted to link V/Q ratio with
cardiopulmonary function. The negative association between
V/Q mismatch and relevant clinical outcomes suggests that
V/Q studies, in addition to other clinical assessment modal-
ities, could be helpful in identifying a subset of patients at risk
164
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Volume 219
V Q
Effect Estimate (95% CI) P value Effect Estimate (95% CI) P value
0.6% ( 3.1, 1.8) .605 3.0% ( 5.4, 0.7) .012
1.3% ( 7.7, 5.0) .681 7.0% ( 11.2, 2.9) .001
10.0% ( 16.2, 3.7) .002 6.2% ( 9.3, 3.1) <.001
4.6% ( 10.6, 1.3) .128 1.8% ( 4.4, 0.8) .174
6.8% ( 14.4, 0.8) .081 0.7% ( 5.5, 4.0) .757
11.0% (1.1, 20.9) .029 3.4% ( 7.0, 0.2) .064
for poor functional outcome. It should also be emphasized
that although there was a correlation between V/Q mismatch
and functional classification, the majority of patients in this
study had good functional status during the study period,
which was reflected by the generally low probability of
poor functional classification (Figure 5).
Results from this study are also in agreement with reports
from other groups. Studies conducted on Italian and French
cohorts of survivors of CDH have demonstrated persistently
poor pulmonary perfusion on follow-up measurements,
although the follow-up duration and sample size in these
studies were smaller compared with our study.21,22 Factors
that correlate with poor perfusion and V/Q mismatch in
other studies are also indicators of disease severity, such as
patch usage, liver transposition into the chest, pulmonary hy-
pertension, supplemental oxygen, and ECMO usage.23,24 In
addition, poor V/Q mismatch has been associated with
increased pulmonary morbidity, such as repeated pneu-
monia, and poor growth during short-term follow-up.20
Conversely, a few other reports have demonstrated a trend
of improved perfusion over time in survivors of CDH.7,8
However, it should be noted that these studies had smaller
sample sizes and selected for less severe cases of CDH (ie, pa-
tients who did not require ECMO8 or patch usage).7 Taken
together, published data are largely consistent with our find-
ings and these results highlight the continuing stress endured
by the respiratory system in survivors of CDH.
A limitation of our study was its retrospective design and
single institutional nature. The study demonstrated selec-
tion bias, given that follow-up V/Q measurements were
contingent upon parental assent and clinical judgement
of the treating physicians. Follow-up was less likely if pa-
tients were deemed “low-risk” and demonstrated adequate
results on initial V/Q studies. Although inverse probability
weighting was used to adjust for this bias, it is possible that
the results were still biased by residual and unmeasured
factors. In addition, selection bias may have existed be-
tween patients who did and did not undergo V/Q testing.
Compared with 103 children who did not have a V/Q
study, those with V/Q measurements were more likely to
be inborn (62% vs 49%; P = .042) and carry a prenatal
diagnosis of CDH (71% vs 53%; P = .003), but less likely
to have structural cardiac defect (12% vs 22%; P = .026).
Interestingly, there was no difference between the 2 groups
Dao et al
April 2020 ORIGINAL ARTICLES

for the study’s results. Although patient management inevi-

tably evolved over time, some fundamental principles of
CDH management remained constant at our institution
throughout the period of the study. During this time, early
institution of ECMO and early operative repair on ECMO
have been our preferred approach of management. There
were minimal changes in ventilator strategy as well as mini-
mal usage of high-frequency oscillatory ventilation during
neonatal care. In addition, our institution has been a cautious
adopter of minimally invasive surgery for CDH repair and in-
fants on ECMO were surgically corrected with the traditional
open approach. Therefore, it was unlikely that variations in
practice could have confounded the longitudinal trends in
V/Q measurements.
In conclusion, V/Q mismatch continues to worsen in sur-
vivors of CDH, especially those with severe disease character-
istics at birth. This is a result of progressive deficit in relative
perfusion of the ipsilateral lung. Markers of CDH severity,
such as defect size and oxygen supplementation at discharge
from the index hospitalization, are important predictors for
V/Q mismatch severity. As V/Q mismatch severity demon-
strates a negative correlation with growth and functional sta-
tus in this retrospective study, V/Q studies may be a useful
adjunct to pulmonary function test and exercise stress test
to identify a subset of patients who are at risk for poor
long-term functional outcome. n

We thank Mrs Kristin Johnson (Vascular Biology Program, Boston

Children’s Hospital) for her work in preparation of the figures.

Submitted for publication May 27, 2019; last revision received Aug 8, 2019;
accepted Sep 16, 2019.
Reprint requests: Terry L. Buchmiller, MD, Department of Surgery, Boston
Children’s Hospital, 300 Longwood Ave, Fegan 3, Boston, MA 02155. E-mail:
terry.buchmiller@childrens.harvard.edu

Figure 3. Trends of V/Q mismatch as stratified by CDH Study
Group defect size. Longitudinal estimate of the average ipsi-
lateral A, V/Q ratio; B, V; and C, Q over time was performed
with a GLM and stratified by defect size. Displayed are the
regression lines and 95% confidence bands.
with respect to defect size C/D (37% vs 28%; P = .123) or
ECMO usage (30% vs 29%; P = 1.000).
The modified version of NYHA Classification used in this
study was created by the authors and has not been validated
in other studies. Therefore, the secondary analysis that corre-
lated V/Q ratio with functional status should be regarded as
exploratory, and further studies will be needed to confirm
this association.
The 25-year period of this study also raised questions
about changes in management that could have accounted
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April 2020 ORIGINAL ARTICLES

Figure 4. Association between V/Q ratio and growth. A, Es-

timates of the effect of V/Q ratio and other covariates on BMI
percentile were derived from a GLM. The effect of age rep-
resents change in outcome with every 10-year change in age.
B, The association between V/Q ratio and BMI percentile is
demonstrated with the regression line and 95% confidence
bands.

Figure 2. Forest plot of determinants of V/Q measurements.

Estimates of the effect of age and various baseline charac-
teristics on A, V/Q; B, V; and C, Q measurements were
generated from the GLM. The effect of age represents change
in outcome with every 10-year change in age. Shown are ef-
fect estimates and their 95% CIs.

Longitudinal Analysis of Ventilation Perfusion Mismatch in Congenital Diaphragmatic Hernia Survivors 166.e1

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THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume 219

Figure 5. Association between V/Q ratio and functional sta-

tus. A, Estimates of the effect of V/Q ratio and other covariates
on the odds of having low functional status classification were
based on a GLM. The effect of age represents change in
outcome with every 10-year change in age. B, The association
between V/Q ratio and the probability of low functional status
classification is demonstrated with the regression line and
95% confidence bands.

Table II. Estimated average V, Q, and V/Q values over

time
V, Q, V/Q Values Average (%) 95% CI
V
Value at 1 y of age 42.5 (37.7, 47.3)
Value at 5 y of age 42.3 (37.5, 47.0)
Value at 10 y of age 41.9 (37.1, 46.7)
Value at 15 y of age 41.2 (36.2, 46.9)
Q
Value at 1 y of age 30.7 (27.6, 33.8)
Value at 5 y of age 29.4 (26.6, 32.2)
Value at 10 y of age 28.0 (25.1, 30.8)
Value at 15 y of age 26.4 (23.0, 29.8)
V/Q
Value at 1 y of age 1.58 (1.47, 1.69)
Value at 5 y of age 1.65 (1.54, 1.76)
Value at 10 y of age 1.74 (1.60, 1.87)
Value at 15 y of age 1.82 (1.64, 2.01)

Model-based average values and 95% CIs were obtained from a GLM.

166.e2 Dao et al

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