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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).
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
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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Volume 219 April 2020
The Congenital Diaphragmatic Hernia Program at Boston as number and percentage and continuous variables were
Children’s Hospital is staffed by a multidisciplinary team of represented by median and IQR.
pediatric surgeons, pulmonologists, radiologists, develop- To detect possible selection bias of treating physicians in
mental specialists, dieticians, and nurses who are specialized ordering follow-up V/Q studies, baseline characteristics
in the care of these highly complex patients. Children who were compared between patients who had a single study
receive care at our CDH clinic undergo serial V/Q scans as and those who had multiple V/Q measurements with appro-
a part of their follow-up protocol, with the first one at priate statistical tests. Comparisons of categorical variables
approximately 6 months to 1 year of age. We sought to pro- were performed with a Fisher exact or c2 test and continuous
vide a longitudinal assessment of V/Q progression in patients variables with a Wilcoxon rank-sum test. Next, adjustment
with CDH followed at our institution and to identify peri- for selection bias was performed with inverse probability
natal risk factors that correlate with severity as well as deteri- weighting.11 In brief, a logistic regression model was fitted
oration of V/Q mismatch over time. Our hypothesis was that to predict the probability of having multiple studies based
patients with CDH have a persistent perfusion defect of the on defect size, ECMO utilization, and baseline V/Q measure-
ipsilateral lung throughout life which can worsen, and ment. This probability was then inversed to obtain the selec-
that this perfusion defect correlates with severity of CDH at tion weight, which was used in all subsequent statistical
birth. models of the study. By utilizing this selection weight, results
of longitudinal analyses could be generalized to the entire
Methods cohort as if all patients had been followed up beyond their
baseline V/Q study.
This study included all patients with CDH born between
1991 and 2016 with at least one V/Q measurement. Data Statistical Analyses
collection was continued until December 31, 2018. For A generalized linear model (GLM) was used to fit the longi-
each patient, only complete V/Q studies with both ventila- tudinal V/Q data. Parameters of the model were estimated
tion and perfusion measurements were included. Exclusion with the generalized estimating equations technique. This is
criteria included incidental diagnosis of CDH, Morgagni- a semiparametric regression method that allows for estima-
type defect, and surgical correction at an outside institution. tion of the average V/Q response of the entire cohort over
The initial V/Q study was typically obtained between time, taking into account the correlation in repeated mea-
6 months and 1 year of age. V/Q studies were repeated within surements within each individual patient. Besides age, cova-
the next 1-2 years if the initial results showed significant riates of the GLM were chosen a priori and included sex,
mismatch. Otherwise, repeat studies were done from 3 to defect side, ECMO utilization, as well as surrogate markers
5 years of age. Further follow-up studies were done at various for the degree of pulmonary hypoplasia (ie, defect size) and
time points at the discretion of the multidisciplinary treat- pulmonary hypertension (ie, oxygen requirement at
ment team. Throughout this study, all reported V/Q mea- discharge from index hospitalization). The GLM allowed
surements referred to the ipsilateral side. for assessment of the trends of V, Q, and V/Q measurements
Demographic and perinatal characteristics of CDH were of the cohort over time by estimating regression coefficients,
recorded for each patient in the cohort and included sex, 95% CIs, and P values. Subsequently, an interaction term be-
gestational age, birth weight, prenatal diagnosis of CDH, Ap- tween defect size and time was introduced into the GLM to
gar score at 1 and 5 minutes, cardiopulmonary resuscitation assess for the effect modification of defect size on the longi-
at birth, defect size, patch usage at surgical correction, extra- tudinal trends of V, Q, and V/Q.
corporeal membrane oxygenation (ECMO) utilization, To correlate V/Q ratio with growth, body mass index
structural cardiac abnormality, and oxygen requirement at (BMI) and BMI percentile were calculated for each patient
discharge from index hospitalization. Diaphragmatic defect at the time of every V/Q measurement using the Center for
size was assessed at surgical correction based on the CDH Disease Control and Prevention calculator. BMI percentile
Study Group Staging System.10 CDH Study Group defect calculation was only performed between the age of 2 and
size, which is highly correlative with clinical outcomes,10 as- 20 years, according to the formula’s restriction. A GLM was
signs a grading scale of A-D for the smallest to the largest dia- subsequently fitted with BMI percentile as the outcome and
phragmatic defect. For patients born before the V/Q ratio as the main exposure. Other covariates included
implementation of the CDH Study Group Staging System, sex, age, defect size, defect side, ECMO utilization, and oxy-
defect size was retrospectively assessed by 2 blinded pediatric gen at discharge.
surgeons who specialized in the surgical management of Because of the lack of a validated classification system for
CDH. Discordant assessments were resolved by an indepen- cardiopulmonary functional status in children, a modified
dent third surgeon. Cardiac anomalies included congenital version of the New York Heart Association (NYHA) Classifi-
cyanotic heart diseases and major defects such as hypoplastic cation was used. This modified version of NYHA Classifica-
left heart syndrome, coarctation of the aorta, and double tion was based on the authors’ experience with the CDH
outlet right ventricle. Dichotomous variables were expressed cohort; it has not been validated in other studies. Class I:
161
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THE JOURNAL OF PEDIATRICS www.jpeds.com Volume 219
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April 2020 ORIGINAL ARTICLES
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Table III. Prediction of ventilation/perfusion ratio, ventilation, and perfusion by baseline characteristics
V/Q V Q
Variables Effect estimate (95% CI) P value Effect Estimate (95% CI) P value Effect Estimate (95% CI) P value
Age* 0.17 (0.04, 0.30) .010 0.6% ( 3.1, 1.8) .605 3.0% ( 5.4, 0.7) .012
CDHSG defect size C/D 0.30 (0.14, 0.45) <.001 1.3% ( 7.7, 5.0) .681 7.0% ( 11.2, 2.9) .001
Oxygen at discharge 0.20 (0.07, 0.32) .002 10.0% ( 16.2, 3.7) .002 6.2% ( 9.3, 3.1) <.001
Male 0.20 (0.07, 0.32) .003 4.6% ( 10.6, 1.3) .128 1.8% ( 4.4, 0.8) .174
ECMO 0.02 ( 0.16, 0.20) .847 6.8% ( 14.4, 0.8) .081 0.7% ( 5.5, 4.0) .757
Left-sided defect 0.01 ( 0.20, 0.17) .949 11.0% (1.1, 20.9) .029 3.4% ( 7.0, 0.2) .064
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 for poor functional outcome. It should also be emphasized
ipsilateral perfusion deficit. The severity of V/Q mismatch that although there was a correlation between V/Q mismatch
also positively correlated with measures of CDH severity and functional classification, the majority of patients in this
such as defect size and oxygen requirement at index hospital study had good functional status during the study period,
discharge. In the secondary analyses, V/Q ratio further which was reflected by the generally low probability of
demonstrated a negative association with growth as well as poor functional classification (Figure 5).
functional status. Results from this study are also in agreement with reports
This study extends previous reports on the CDH cohort from other groups. Studies conducted on Italian and French
followed at our institution.9,12 Despite being derived from cohorts of survivors of CDH have demonstrated persistently
a different statistical model, the findings in this study were poor pulmonary perfusion on follow-up measurements,
largely consistent with previous analyses and demonstrated although the follow-up duration and sample size in these
a trend of worsening of V/Q mismatch with time. In the studies were smaller compared with our study.21,22 Factors
earlier reports, ECMO requirement and patch usage at surgi- that correlate with poor perfusion and V/Q mismatch in
cal repair were found to predict the severity of V/Q other studies are also indicators of disease severity, such as
mismatch. Both of these predictors were summarized by patch usage, liver transposition into the chest, pulmonary hy-
defect size, which has been shown to correlate with patch us- pertension, supplemental oxygen, and ECMO usage.23,24 In
age, ECMO utilization, and overall postnatal morbidity.13,14 addition, poor V/Q mismatch has been associated with
Perhaps one of the most interesting results of this study increased pulmonary morbidity, such as repeated pneu-
was the effect of defect size on the severity of V/Q mismatch. monia, and poor growth during short-term follow-up.20
When the CDH Study Group Staging System was proposed Conversely, a few other reports have demonstrated a trend
in 2013, defect size was considered a surrogate marker for of improved perfusion over time in survivors of CDH.7,8
the degree of pulmonary hypoplasia.10,15 Although there is However, it should be noted that these studies had smaller
still a scarcity of information on the pathogenesis of CDH, sample sizes and selected for less severe cases of CDH (ie, pa-
evidence suggests that both pulmonary hypoplasia and the tients who did not require ECMO8 or patch usage).7 Taken
diaphragmatic defect result from early disturbances in lung together, published data are largely consistent with our find-
organogenesis,16 the so-called “dual-hit hypothesis.”17 Our ings and these results highlight the continuing stress endured
study suggests that these early genetic or molecular aberra- by the respiratory system in survivors of CDH.
tions can set survivors of CDH on different trajectories that A limitation of our study was its retrospective design and
affect future development of pulmonary ventilation and single institutional nature. The study demonstrated selec-
perfusion. However, it also opens the door for adjunct ther- tion bias, given that follow-up V/Q measurements were
apies that can potentially modify the course of the disease, contingent upon parental assent and clinical judgement
such as angiogenic growth factors to improve capillary for- of the treating physicians. Follow-up was less likely if pa-
mation and alveolarization18,19 and early and intensive car- tients were deemed “low-risk” and demonstrated adequate
diopulmonary rehabilitation programs. results on initial V/Q studies. Although inverse probability
We also sought to establish an association between V/Q weighting was used to adjust for this bias, it is possible that
mismatch and metrics of clinical outcome, such as growth the results were still biased by residual and unmeasured
and functional status. Although a short-term association be- factors. In addition, selection bias may have existed be-
tween nutritional status and V/Q mismatch has been re- tween patients who did and did not undergo V/Q testing.
ported,20 we explored the effect of V/Q ratio on BMI in a Compared with 103 children who did not have a V/Q
longitudinal fashion and attempted to link V/Q ratio with study, those with V/Q measurements were more likely to
cardiopulmonary function. The negative association between be inborn (62% vs 49%; P = .042) and carry a prenatal
V/Q mismatch and relevant clinical outcomes suggests that diagnosis of CDH (71% vs 53%; P = .003), but less likely
V/Q studies, in addition to other clinical assessment modal- to have structural cardiac defect (12% vs 22%; P = .026).
ities, could be helpful in identifying a subset of patients at risk Interestingly, there was no difference between the 2 groups
164 Dao et al
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April 2020 ORIGINAL ARTICLES
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
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Longitudinal Analysis of Ventilation Perfusion Mismatch in Congenital Diaphragmatic Hernia Survivors 165
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166 Dao et al
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Longitudinal Analysis of Ventilation Perfusion Mismatch in Congenital Diaphragmatic Hernia Survivors 166.e1
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Model-based average values and 95% CIs were obtained from a GLM.
166.e2 Dao et al
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