Seminars in Fetal and Neonatal Medicine 27 (2022) 101383

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Seminars in Fetal and Neonatal Medicine

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Diagnosis & management of pulmonary hypertension in congenital

diaphragmatic hernia
Shazia Bhombal a, Neil Patel b, *
a
Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
b
Department of Neonatology, Royal Hospital for Children, Glasgow, G51 4TF, United Kingdom

A B S T R A C T

Congenital diaphragmatic hernia (CDH) contributes to neonatal morbidity and mortality worldwide. Pulmonary hypertension (PH) is a key component of CDH
pathophysiology and critical consideration for management and therapeutic options. PH associated with CDH has traditionally been attributed to pulmonary vascular
maldevelopment and associated lung parenchymal hypoplasia, leading to pre-capillary increase in pulmonary vascular resistance (PVR). However, there is increasing
recognition that left ventricular hypoplasia, dysfunction and elevated end diastolic pressure may contribute to post-capillary pulmonary hypertension in CDH
patients.
The interplay of these mechanisms and associated dysfunction in the right and left ventricles results in variable hemodynamic phenotypes in CDH. Clinical
assessment of individual phenotype may help guide personalized management strategies, including effective use of pulmonary vasodilators and extra-corporeal
membrane oxygenation. Ongoing investigation of the underlying mechanisms of PH in CDH, and efficacy of physiology-based treatment approaches may support
improvement in outcomes in this challenging condition.

1. Introduction
Congenital diaphragmatic hernia (CDH) affects 2.3 in 10,000 live
born infants globally and continues to be a major contributor to
morbidity and mortality in neonatal populations [1,2].
A developmental defect in the diaphragm, most commonly on the left
side, permits herniation of abdominal contents into the fetal thorax. The
associated findings of pulmonary hypertension (PH) and pulmonary
hypoplasia are principal components of CDH pathophysiology and de­
terminants of disease severity [3,4].
Despite many decades of study and a growing armoury of treatments,
PH remains one of the most challenging aspects of CDH care [5]. To help
address this challenge, we aim to provide a “state-of-the-art” review of
PH pathophysiological mechanisms and current, precision-medicine
approaches for individualized diagnosis and management.
2. Defining PH in CDH
In children and adults, PH is defined based on mean pulmonary
arterial pressure (PAp) (>20 mmHg) and pulmonary vascular resistance
indexed to body surface area (PVRI), with gold standard assessment by
right heart catheterization [6,7]. In newborns with CDH, as with any
neonatal disease, a simple pressure-based definition is not feasible; all
infants have elevated PAp during the normal transitional period, and
invasive measurement of PAp is neither practical nor safe [8]. Classifi­
cations of PH in CDH based on echocardiographic parameters are widely
reported but rely on indirect, subjective measures of PAp [9].
In clinical practice the term “pulmonary hypertension” in CDH is
typically used to describe a clinical syndrome of raised PAp and asso­
ciated features of hypoxemia, cardiac dysfunction and systemic hypo­
tension. Future development of a standardized definition of clinically
significant PH in CDH incorporating oxygenation, ventricular function
and systemic hemodynamics may be more clinically relevant and is a
priority.
3. Epidemiology of PH and relationship to outcome
Serial echocardiographic studies in the early neonatal period have
demonstrated that PAp decreases gradually over the first weeks of life in
the majority of CDH cases, but in some cases can remain pathologically
elevated for many months [10]. Lusk et al. observed that PAp was
elevated in 94% of CDH cases in the first week of life, 43% in the third
week, and 28% at the sixth week [9]. In the same series, persistent
elevation of PAp from the second week of life was associated with
increased mortality and/or prolonged respiratory support.
Non-resolution of PH at the time of death or discharge was associated
with other markers of CDH severity including lower fetal lung volumes

* Corresponding author.
E-mail addresses: sbhombal@stanford.edu (S. Bhombal), neil.patel@ggc.scot.nhs.uk (N. Patel).

https://doi.org/10.1016/j.siny.2022.101383

Available online 12 August 2022

1744-165X/© 2022 Elsevier Ltd. All rights reserved.

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S. Bhombal and N. Patel
Abbreviations
CDH congenital diaphragmatic hernia
ECMO extra-corporeal membrane oxygenation
LAp left atrial pressure
LV left ventricle
LVEDP left ventricular end diastolic pressure
PAAT pulmonary artery acceleration time
PAp pulmonary artery pressure
PH pulmonary hypertension
PVR pulmonary vascular resistance
RV right ventricle
SBP systemic blood pressure
TAPSE tricuspid annular plane systolic excursion
and liver in the chest. However, a more recent retrospective analysis by
Basurto et al. fetal lung volumes were not associated with the presence
of PH after day 1 of life [11].
The absolute level of early PAp may also be predictive of outcome. A
recent registry analysis of >1400 CDH cases observed that moderate or
severe PH (PAp >2/3 systemic pressure) in the first 48 h of life was
associated with increased risk of death or oxygen therapy at 30 days of
life [12].
The natural history and incidence of PH in CDH beyond the neonatal
period is not well understood. A recent review by Lewis et al. identified
wide variability of PH rates at 2 years (4.5–38%) likely reflecting vari­
ation in cohort size, PH definition, and the technical limitations of
echocardiographic measures to estimate PAP [13]. Cardiac catheteri­
zation has been useful in a limited number of cases of infants and chil­
dren post-CDH repair to assess PAP, PVR, cardiac anatomy and systemic
hemodynamics, and may be a useful technique in selected cases when
significant ongoing PH is suspected [14–16].
3.1. Pathophysiological mechanisms of PH in CDH
PAp is the product of pulmonary blood flow (PBF) and pulmonary
vascular resistance (PVR).
PH in CDH has been traditionally attributed to pre-capillary in­
creases in PVR associated with disease-specific changes in the pulmo­
nary vasculature [4]. However, there is growing recognition that
post-capillary increases in PVR associated with left ventricular
dysfunction may be important, particularly during the transitional
period.
We now discuss these mechanisms highlighting the dynamic inter­
play between the pulmonary vasculature, heart and lungs during the
fetal, transitional and neonatal periods that contribute to PH and wider
circulatory dysfunction in CDH.
3.2. Fetal origins of PH in CDH
3.2.1. Developmental abnormalities of the pulmonary vasculature in CDH
Abnormalities of the fetal pulmonary vasculature in CDH are well-
described [17]. Decreased arborization is accompanied by thickening
of the muscular media and adventitia in the pulmonary arterioles
leading to reduced vessel calibre and increased resistance [18]. Struc­
tural changes are accompanied by reduced functional vasoreactivity
[19,20]. Multiple modulating pathways including disrupted pericyte
function, vascular growth factors, and candidate microRNAs are impli­
cated in this disordered vasculogenesis [21–24]. These changes persist
into postnatal life and have historically been considered to be the
principal cause of increased pre-capillary PVR and PH in CDH.
Consistent with these morphological changes, functional analysis of
fetal pulmonary artery flow has demonstrated increased Doppler
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Seminars in Fetal and Neonatal Medicine 27 (2022) 101383
pulsatility index, considered to reflect increased prenatal PVR and
reduced pulmonary blood flow [25]. This parameter appears to be
independently predictive of postnatal outcome in CDH, and may
augment the prognostic value of established measures of fetal lung
volume [26].
3.2.2. Cardiac hypoplasia in fetal CDH
Changes in the fetal pulmonary vasculature are accompanied by
relative hypoplasia of the heart, particularly the left ventricle [27,28].
LV hypoplasia is characterized by narrowing and elongation of the
ventricle and is associated with a reduction in fetal left ventricular
output [29,30].
Fetal LV dimensions, and the ratio of right:left ventricle dimensions
(RV:LV), correlate with other measures of CDH severity including fetal
lung volumes [29,31]. Proposed mechanisms of fetal LV hypoplasia in
CDH include direct mechanical compression by herniating abdominal
contents, and reduced pulmonary blood flow, restricted by primary
changes in the pulmonary vasculature discussed above, leading to
reduced LV flow and growth [32,33]. In addition, mediastinal shift is
hypothesized to cause redirection of ductus venosus and inferior vena
cava streaming away from the foramen ovale and LV, and toward the
RV. This change in flow pattern is thought to hamper flow-dependent LV
growth and conversely increases RV flow and size [34].
In prenatal life, CDH-related reductions in pulmonary blood flow, LV
flow and hypoplasia may not be functionally significant, as gas exchange
occurs in the placenta, and cardiac output is maintained by the RV via
the patent ductus [35]. However, both abnormalities of the pulmonary
vasculature and LV morphology are potentially important contributors
to postnatal PH in CDH, as now discussed.
3.3. Pathophysiology of postnatal PH in CDH
The mechanisms and clinical consequences of postnatal PH in CDH
arise from disrupted ventriculo-arterial and inter-ventricular in­
teractions, detailed below and summarized in Fig. 1.
3.3.1. Pre-capillary elevation of PVR
The structural and functional abnormalities in the pulmonary arte­
rioles, originating in fetal life, prevent the acute vasodilation and
reduction in pre-capillary PVR that usually accompany the first breaths
[35]. As a result, the normal increase in pulmonary blood flow and
associated increase in LV filling and output are impeded [36].
In infants with CDH, this persistent elevation in PVR after birth has
been demonstrated non-invasively using proxy measures including
Doppler analysis of pulmonary artery acceleration time (PAAT). Rela­
tive shortening of PAAT, indicating increased PVR, is associated with
CDH severity and adverse outcomes including mortality [37,38].
This pre-capillary mechanism of increased PVR has traditionally been
considered as the principal cause of PH in CDH, both in the acute
transitional period and in the subacute period over the first weeks and
months of life [4]. However, the precise nature and timing of
re-modelling of the pulmonary vasculature after birth in CDH is poorly
understood, due to a lack of suitable imaging modalities or post-mortem
data.
3.3.2. Right Ventricular and Pulmonary Circulation interaction in CDH
In normal postnatal life, the right ventricle is a wedge-shaped
structure, crescenteric and thin-walled in cross-section, and designed
to work at low operating pressures, coupled to the low-resistance pul­
monary circulation [39]. Performance of the compliant RV is largely
determined by pre-load, or venous return [40,41].
In CDH, as in other PH states, increased afterload elicits an adaptive
response in the RV with two components [42]:
1. Homeometric adaptation: increased RV contractility accompanied by
remodelling and hypertrophy of the myocardium.
S. Bhombal and N. Patel Seminars in Fetal and Neonatal Medicine 27 (2022) 101383

Fig. 1. Pathophysiology of Pulmonary Hypertension in CDH: role of ventriculo-arterial interactions and ventricular interdependence. a: Normal circulation.
Legend: The right ventricle operates at low pressure, coupled to the low-resistance pulmonary circulation. The right and left ventricles support each other’s function
via mechanisms of interventricular interdependence including shared muscle fibres, septum and pericardium.
b: Contributing mechanisms of pulmonary hypertension and associated cardiac dysfunction in congenital diaphragmatic hernia.
Legend: Structural and functional abnormalities of the pulmonary arteries result in increased pre-capillary pulmonary vascular resistance (PVR). Maladaptive
hypertrophy, dilation and tachycardia in the right ventricle (RV) lead to dysfunction, uncoupling and reduced pulmonary blood flow (PBF). Septal dysfunction and
displacement impair LV function and filling. Primary LV dysfunction arises due to fetal hypoplasia and acute increase in afterload at birth. Increases in left atrial
pressure (LAp) and pulmonary venous pressure (PVp) lead to post-capillary increase in PVR. Reduced LV output results in systemic hypotension and metabolic
acidosis, and exacerbates coronary hypoperfusion and myocardial ischaemia.

2. Heterometric adaptation: dilation of the ventricle, to increase stroke
volume, accompanied by an increase in heart rate.
In the face of severe or prolonged elevation of PVR these adaptive
responses in the RV become mal-adaptive and normal coupling is dis­
rupted [43,44]. RV hypertrophy reduces compliance and diastolic
filling, whilst increasing myocardial oxygen demand [45]. Increased RV
pressures also lead to reduced coronary perfusion gradient and potential
myocardial ischaemia [46,47]. Tachycardia further impairs diastolic
filling and coronary flow. Changes in ventricular size and shape lead to
leftward septal shift impacting left ventricular performance, as discussed
below. The net result is impaired RV function, reduced pulmonary blood
flow, and “uncoupling” from the pulmonary circulation [48].
These components of RV dysfunction have been demonstrated in
CDH. Agarwal et al. have observed shortened diastolic time intervals,
whilst Moenkemeyer et al. observed impaired early diastolic relaxation
in the RV using tissue Doppler imaging within the first 48 h of life [49,
50]. Reduced RV systolic strain has also been observed using
speckle-tracking echocardiography early after birth and in the
post-operative period [51–53]. In large, multi-center cohorts 34% of
infants had RV dysfunction on initial echocardiogram [54].
Coupling of the RV and pulmonary circulation in CDH has recently
been assessed using novel composite echocardiographic measures of RV
systolic function (tricuspid annular plane systolic excursion, TAPSE) and
PVR (PAAT and ductal flow), by Aggarwal et al. Abnormal coupling in
this cohort was associated increased ECMO use and mortality [55].
Beyond the immediate transitional period and into the post-
operative period RV function may improve with resolution of pre-
capillary PH, or remain at risk if PVR remains elevated [49]. Recent
investigation by Avitabile and colleagues observed that persistent

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S. Bhombal and N. Patel
abnormalities of RV strain post-operatively were associated with
increased mortality [53]. Egan et al. have observed evidence of ongoing
RV diastolic dysfunction, which may be sub-clinical and of uncertain
significance, in childhood CDH survivors up to 6 years of age [56].
3.3.3. Left ventricular dysfunction in CDH PH
There is increasing recognition of the left ventricle both as a medi­
ator of the down-stream effects of PH in CDH and as a primary instigator
of increased PVR.
The maladaptive response of the RV to increased afterload, previ­
ously described, can lead to secondary LV dysfunction via mechanisms
of ventricular interdependence, specifically [57]:
• Systolic dysfunction of shared myocardial fibres [58]. Massolo et al.
have observed increased correlation of LV and RV strain indicating
increased interdependence in CDH cases compared to controls [59].
• Diastolic dysfunction due to leftward septal shift, altering the
pressure-volume relationship of the LV, reducing end-diastolic vol­
umes, and increasing end-diastolic and left atrial pressure [60,61].
Septal shift has been quantified in CDH using the eccentricity index,
a ratio of ventricular dimensions in the short axis, and associated
with adverse outcome [62,63].
• Reduced diastolic filling due to the tachycardic response initiated in
the RV to increased PVR.
• Regional dys-synchrony of myocardial segments in the RV disrupting
LV synchrony [59,64,65].
However, not all LV dysfunction in CDH is secondary to RV
dysfunction. In large multi-center registry analysis of >1100 CDH cases,
5% had early LV dysfunction in the absence of RV dysfunction [54]. In a
smaller single-center cohort Patel et al. observed isolated impairment of
LV systolic strain, and normal RV systolic strain, in 20% of cases [52].
Furthermore, regional analysis of early LV function has observed systolic
impairment in septal and free wall segments [59]. Taken together these
findings indicate the potential for primary LV dysfunction in CDH.
Factors contributing to primary LV dysfunction during the transi­
tional period may include:
1. Fetal LV hypoplasia. This is supported by a number of cohort studies
which observed an association between reduced fetal LV dimensions
and adverse outcome in CDH [29,31,66].
2. Acute changes in LV loading; due to the removal of the low-resistance
placenta leading to increased systemic vascular resistance and LV
afterload, combined with failure of the normal increase in pulmo­
nary blood flow and left ventricular filling [67].
3. Developmental abnormalities in LV myocardial structure and meta­
bolism [68].
4. Generalised acidosis and hypoxemia, due to right to left shunting at
atrial or ductal level, as well as altered patterns of coronary blood
flow [47].
Early LV dysfunction results in impaired left ventricular output,
systemic blood flow and oxygen delivery, contributing to the clinical
findings of systemic hypotension and metabolic acidosis characteristic
of CDH [69]. Associated reductions in coronary flow will further exac­
erbate biventricular oxygen delivery and function.
3.4. LV dysfunction and post-capillary PVR
Diastolic LV dysfunction, whether primary or secondary in origin,
and reduced LV end diastolic volume (due to LV hypoplasia and septal
shift) will increase left atrial and pulmonary venous pressure, and in
turn lead to a post-capillary increase in PVR.
This is a key consideration with therapeutic implications; that the
mechanism of increased PVR and PAP in CDH, particularly during the
first hours at birth, may be due not only to pre-capillary changes in
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Seminars in Fetal and Neonatal Medicine 27 (2022) 101383
pulmonary vascular structure or function, but also due to LV dysfunction
and post-capillary effects on the pulmonary circulation [70].
Importantly, LV dysfunction appears to be a transient phenomenon
which resolves rapidly in the first days of life even in severe cases [71].
Thus whilst LV dysfunction may be an important cause of PH and he­
modynamic instability in the first hours of life, it is less likely to
contribute to ongoing PH thereafter. This too has important therapeutic
considerations, as we discuss later.
3.5. Clinical significance of cardiac dysfunction in CDH PH
The clinical significance of postnatal RV and LV function as de­
terminants of CDH severity and outcome has been demonstrated in
number of recent analyses.
In single center cohort studies RV and LV dysfunction, assessed by
both conventional measures (including diastolic time interval, tissue
Doppler imaging, LVEF, RV TAPSE and fractional area change) and
strain imaging in the early neonatal period and after surgical repair have
been associated with increased mortality, ECMO use, and duration of
respiratory support in survivors, ([49–53,62,69]) ([52,62,69]).
Recent analysis in the International CDH Study Group confirmed
these findings in a cohort of >1100 CDH cases. Patients with any
dysfunction in the RV, LV, or both had higher mortality overall
compared to the 61% of patients with normal function. LV dysfunction
independently predicted mortality and ECMO use, increasing risk of
death two-fold [54].
Ventricular dysfunction in CDH is associated with other measures of
disease severity including fetal lung size, liver position and defect size/
stage determined at surgery [52,54]. However, Duy et al. recently
observed that RV and LV ventricular dysfunction can also occur in
“low-risk” CDH cases with small diaphragmatic defects, and are inde­
pendent predictors of mortality in these cases. [72].
3.6. Cardio-respiratory interactions and CDH PH
The lungs in CDH are hypoplastic and highly compliant, prone to
barotrauma and volutrauma. As a result, clinical changes in respiratory
status and management, particularly during positive pressure ventila­
tion, will additionally impact PVR in CDH via a number of mechanisms
of cardio-respiratory interaction [73]:
• Direct effect on pulmonary vasculature and PVR: De-recruitment and
over-distension will increase PVR by differential effects on extra-
alveolar vessels and pulmonary capillaries.
• Altered loading conditions on heart: increasing pleural pressure will
reduce the gradient for systemic venous return and RV preload, and
reduce LV preload and afterload. Direct changes in PVR will affect
RV afterload.
• Direct impact on myocardial performance due to changes in pleural
pressure.
3.7. Hemodynamic phenotypes in CDH PH
Differentiating the contributing pathophysiologies to PH in CDH is
integral to management of this complex patient population. Varying
degrees of pulmonary hypoplasia, PH, and ventricular compromise
affect clinical presentation, or phenotype, and responsiveness to indi­
vidual therapies.
CDH physiology can be broadly differentiated into three phenotypes,
Fig. 2:
1. Mild or no PH with a compliant, coupled RV
2. Pre-capillary PH and no cardiac dysfunction, or primary RV
dysfunction with or without secondary LV dysfunction
3. Post-capillary PH phenotype with significant primary LV dysfunction
S. Bhombal and N. Patel
Fig. 2. Three hemodynamic phenotypes indicating relative contributions of pulmonary hypoplasia and ventricular compromise in PH in CDH; image
copyright Satyan Lakshminrusimha.
Historically, the absence of a phenotypic approach may have
affected the findings of therapeutic trials, including studies of inhaled
nitric oxide (iNO). iNO promotes relaxation of pulmonary artery smooth
muscle and is the only FDA approved therapy for neonates >34 weeks
gestational age with PH. In theory, iNO should benefit the CDH popu­
lation by promoting vasodilation in the altered pulmonary vasculature.
And yet, no such benefit has been observed in randomized trials to date.
The multi-center NINOS study (Neonatal Inhaled Nitric Oxide Study
Group) randomized term and near-term infants with CDH and hypox­
emic respiratory failure to 20 ppm iNO or 100% FiO2 and observed no
difference in the need for ECMO or death [74].
Similarly, a large CDH registry study demonstrated that the wide­
spread use of iNO was frequently unrelated to a clinical diagnosis of PH;
though 70% of iNO recipients had recorded PH, 26% of patients with
recorded PH did receive iNO, and 36% of patients without PH received
iNO. In addition, the use of inhaled nitric oxide in this population was
independently associated with increased mortality [75].
These investigations have led to uncertainty and re-consideration of
the role of iNO and other pulmonary vasodilators in CDH. However, a
targeted, pathophysiology-based approach to PH assessment and man­
agement, based on the mechanisms discussed already may help to
address this uncertainty going forward.
3.8. Echocardiographic as component of PH and hemodynamic
assessment in CDH
Serial echocardiography, from the early transition onwards, can
provide information to distinguish underlying pathophysiological phe­
notypes and guide treatment. The initial echo combines structural
assessment for congenital heart disease, and functional hemodynamic
assessment of PAp, ventricular size and function, and shunt physiology.
Subsequent serial functional echocardiography combined with assess­
ment of clinical status provides additional information of changing
physiology to guide and assess response to treatment.
Comprehensive functional echocardiographic assessment in CDH
combines qualitative and quantitative techniques of PAp, RV and LV
size, shape and function according to current recommendations [76,77].
No measure is a gold standard, their limitations should be appreciated
and practical care taken to perform short, targeted scans to prevent
clinical instability [78]. Table 1 summarises existing echo parameters
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Seminars in Fetal and Neonatal Medicine 27 (2022) 101383
reported in CDH.
Shunting patterns at the patent ductus arteriosus (PDA) and atrial
septum may be useful indirect indicators of PAp, ventricular function in
CDH. Low velocity left-to-right shunt in a small PDA, bidirectional, or
right-to-left flow patterns are all indicators of significant pulmonary
hypertension, with PAp close to or, or in excess of systemic blood
pressure (SBP) [79].
Atrial level shunting is dependent on relative RV to LV compliance
and associated atrial pressures. Accordingly, in the setting of a poorly-
compliant RV, elevated end diastolic pressure (RVEDP) and right
atrial pressures (RAp) and preserved LV function, shunting at the atrial
level will be right-to-left. Conversely, reduced LV compliance and
increased left atrial (LA) pressure promote a left-to-right atrial shunt
[80].
Combined assessment of atrial and ductal shunting patterns provides
important insights to the phenotypic types, for example:
1. Phenotype 1: Mild or no PH with a compliant RV: predominantly left-to-
right shunting at the PDA and atrial level, normal biventricular
function and interventricular septal geometry indicative of low PAp
2. Phenotype 2: Pre-capillary PH and no cardiac dysfunction or primary RV
dysfunction with or without secondary LV dysfunction: predominant
right-to-left PDA and atrial shunting
3. Phenotype 3: Post-capillary PH with primary LV dysfunction, elevated
LVEDP and LAp: predominantly right-to-left PDA and left-to-right
atrial shunts.
3.9. Therapeutic strategies for CDH PH based on pathophysiological
phenotype
Once the underlying pathophysiology has been elucidated this can
guide therapeutic strategies, Fig. 3. In phenotype 1, a patient with left to
right shunting at both the ductal and atrial level and preserved ven­
tricular function, hypoxia may be related to alveolar gas exchange
associated with parenchymal disease and respond to adjustments in
ventilator strategy.
3.9.1. Phenotype 2: pre-capillary PH and RV dysfunction
In phenotype 2, pre-capillary, pulmonary arterial hypertension
phenotype with normal or uncoupled RV function, the echocardiogram
S. Bhombal and N. Patel Seminars in Fetal and Neonatal Medicine 27 (2022) 101383

Table 1 reflects elevated pulmonary pressures, with septal flattening, elevation

Echocardiographic measures reported in the post-natal assessment of CDH PH
and cardiac function.
Measure
Pulmonary artery pressure or pulmonary vascular resistance
Patent ductus arteriosus flow [9]
Velocity time integer ratio of PDA flow
[55,83]
Septal position [9]
Tricuspid regurgitation maximal velocity
[9,49]
Pulmonary artery acceleration time: right
ventricular ejection time (PAAT:ET)
[37,118]
Pulmonary - systemic shunting patterns
Inter-atrial and ductal shunting [80]
Right ventricular function
Tricuspid Annular Systolic Plane
Excursion [55]
Tricuspid valve flow velocities (E′ and A′ ) Load dependent measures of diastolic
[119]
Tissue Doppler imaging (TDI) of diastolic
and systolic myocardial velocities [49]
RV systolic: diastolic duration ratios [50] Time interval assessment, load
Myocardial Performance Index (MPI)
[120]
RV Fractional area change (FAC) [55]
Strain assessment using Speckle Tracking
Echocardiography (STE) [51–53,59]
Right ventricular output [83]
Right ventricle - pulmonary circulation coupling
TAPSE:PAAT [55]
Left ventricular function
TDI myocardial velocities [71]
Strain assessment using Speckle Tracking
Echocardiography (STE) [51,52,62]
Myocardial performance index (MPI)
[121]
Left ventricular ejection fraction [102]
Comment
Qualitative assessment of PAp relative
to SBP
Quantifies PDA shunt.
Qualitative assessment of leftward
septal shift
Used to estimate peak RV pressure.
Quantitative measure of PVR. Patency
of ductus should be considered in
interpretation.
Qualitative assessment of PH
phenotype
Quantifies RV systolic function, load
dependent.
function
Quantifies longitudinal function. Load-
dependent.
dependent
Composite measure. Highly load-
dependent.
Load dependent and high observer
variability.
Quantifies regional and global
function.
Composite measure. High observer
variability.
Composite of RV function and PVR.
Degree of load dependency
Quantitative assessment of regional
and global function and rotational
dynamics.
Time-interval based composite
measure
Established, regional measure of LV
function
of tricuspid regurgitant jet velocity, right-to-left PDA and atrial shunts.
The latter can exacerbate pre-ductal hypoxemia which may worsen
pulmonary vasoconstriction and PVR.
Management strategies are based on reducing pre-capillary PVR and
include optimization of sedation and lung recruitment (avoiding over­
distension and de-recruitment) and pulmonary vasodilator therapies.
The latter target the three main cytokine pathways between pulmonary
arterial endothelium and smooth muscle cells:
I. Nitric oxide pathway: iNO augments endogenous, vasodilatory NO
production, and in a significant minority (approximately 30%) of
CDH infants in the early neonatal period elicits an acute improve­
ment in oxygenation [81,82]. Sildenafil, a phospho-diesterase in­
hibitor acts on the same pathway to prevent breakdown of cyclic
GMP and augment NO’s action. Similarly, its early use in CDH is
associated with improved oxygenation, but as Kipfmueller et al.
recently observed, only 40% are responders [83,84].
The variable response to these pulmonary vasodilators may explain
the lack of net benefit in historic controlled trials of iNO, and may be due
to existing maximal activation of these cytokine pathways, variable
pharmacokinetics, and non-responsive phenotypes of post-capillary PH
secondary to LV dysfunction (phenotype 2), as discussed below.
II. Prostacyclin pathway: Endogenous prostacyclin promotes relaxation
of pulmonary artery smooth muscle, via a cyclic-AMP (cAMP)
mediated pathway. Prostacyclin analogues including epoprostenol
and treprostinil in inhaled, intravenous and subcutaneous prepara­
tions have been used in acute, sub-acute and chronic PH in CDH with
reported benefits in responders, but have not as yet been exposed to a
controlled trial [85–87].
Milrinone inhibits phosphodiesterase 3, to prevent breakdown of
cAMP and augment this pathway [88]. As well as pulmonary vaso­
dilating actions, it has direct positive inotropic and lusitropic (diastolic)
actions, which make it theoretically ideally suited to RV dysfunction in
phenotype 2. Limited case series have demonstrated improved oxygen­
ation and RV function, though in mild and moderate CDH Mears et al.
did not observe a response in oxygen index or PAp [89,90].

III. Endothelin pathway: Endothelin-1 is a natural pulmonary artery

vasoconstrictor. Elevated plasma levels of ET-1 are associated
with adverse outcome and chronic PH in CDH [91]. A recent RCT

Fig. 3. CDH management based on hemodynamic phenotype.

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S. Bhombal and N. Patel
of ET-1 receptor antagonists in non-CDH PH failed to demon­
strate benefit [92].
Recent analysis in a multi-center North American cohort observed
that 63% of cases received at least one pulmonary vasodilator, including
in order of frequency; iNO (62%), milrinone (33%), sildenafil 22%
(intravenous. 10%, oral 17%), epoprostenol 7%, treprostinil 3%,
bosentan (ET antagonist) 3% [93]. In the same cohort, 15% of infants
received prostaglandin E1. The latter is both a pulmonary vasodilator,
but also importantly maintains ductal patency. This may be important in
the setting of both phenotypes 2 and 3 to reduce RV afterload and to
maintain systemic blood flow respectively [94–96].
3.9.2. Phenotype 3: post-capillary PH and LV dysfunction
In phenotype 3, postcapillary pulmonary venous hypertension and
primary LV dysfunction, the echocardiogram often demonstrates right to
left PDA shunting reflecting supra-systemic PH and left-to-right atrial
level shunting, consistent with elevated LVEDP, LAp and pulmonary
venous pressure, combined with LV, or biventricular, dysfunction.
In this phenotype pulmonary vasodilator therapies could lead to
clinical deterioration by increasing filling of the failing LV [97].
Consistent with this hypothesis, Lawrence et al. recently observed that
the presence of LV dysfunction was the sole factor associated with lack of
improved oxygenation after a trial of iNO in CDH cases [82].
Instead, this phenotype may be better managed by supporting LV
function directly using inotropic therapies such as low dose epinephrine
whilst avoiding excessive LV afterload [98]. Recently Schroeder et al.
have reported exploratory use of a novel agent for this purpose, levo­
simendan a calcium sensitizing agent, who’s use was associated with
improved LV function and PAp in CDH cases [99,100].
Milrinone and PGE1 may be useful in phenotype 3, as well as
phenotype 2, but for different reasons. In the setting of LV dysfunction,
milrinone may improve LV performance directly as a positive inotrope,
lusitrope, and peripheral vasodilator reducing LV afterload [88,101]. By
maintaining the ductus and permitting right-to-left shunting PGE1 may
augment systemic flow in the setting of low LV output, albeit simulta­
neously contributing to lower post-ductal oxygen saturations.
3.10. Use of systemic vasoconstrictors in CDH phenotypes
Historic treatment approaches to neonatal PH have included
aggressive vasoconstriction, to increase systemic blood pressure and
promote left-to-right ductal shunting. This practice is likely to be
detrimental, exposing infants to side effects of high dose catecholamines
and ultimately impeding systemic blood flow and oxygen delivery.
Furthermore, in patients with severe LV dysfunction (phenotype 3)
excessive afterload may worsen LV function.
However, careful, targeted use of lower-dose systemic vasocon­
strictors may be beneficial in specific phenotypes. Acker et al. have re­
ported that vasopressin use in CDH patients with catecholamine
resistance hypotension prevented ECMO in six of eleven cases [102].
Whether this beneficial response was due to systemic vasoconstriction or
direct pulmonary vasodilation is an area for ongoing investigation.
Similarly norepinephrine has been demonstrated to improve PAp:
SBP ratios in non-CDH neonatal PN [103].
These systemic vasoconstrictors may improve CDH hemodynamics
via a number of mechanisms:
• Improved gradient for coronary blood flow, particularly in the
setting of RV dysfunction or mild LV dysfunction (phenotype 2) [47].
• Improved LV myocardial performance in response to increased
afterload, the Anrep effect [42].
• Increased LVEDP which may theoretically reverse leftward septal
shift [104].
Dopamine is a non-specific vasoconstrictor used ubiquitously in the
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Seminars in Fetal and Neonatal Medicine 27 (2022) 101383
neonatal population, including in some centers treating CDH. In lambs
with PPHN remodelled pulmonary arteries appeared sensitive to dopa­
mine with increases in both systemic and PA pressure [105]. For these
reasons, as well as its chronotropic and central properties, dopamine
may not be an optimal vasopressor in patients with reactive pulmonary
vasculature including CDH [106].
3.11. PH and timing of surgery in CDH
A binary focus on early versus late repair strategies has failed to
identify an optimal time for surgery in CDH [107,108]. A
physiology-guided approach may be more appropriate. Pulmonary ar­
tery pressure, RV and LV function typically improve in the first 3–4 days
of life in CDH, spontaneously or in response to therapy [49,54,71]. It
therefore makes sense to await this improvement before performing
potentially destabilising surgery. Accordingly, current international
treatment guidelines recommend an individualized approach based on
achieving specific pre-operative criteria incorporating oxygenation,
lactate, blood pressure and pulmonary artery pressure [109]. Serial
echocardiographic assessment of PAp and ventricular function is a key
tool during this decision-making process.
Higher pre-operative pulmonary artery pressures appear to be
associated with adverse outcome however, as advocated in current
guidelines, if PAp remains elevated above supra-systemic levels beyond
the first two weeks of life then a decision to proceed to surgery may be
necessary [110]. Of note, severe, early and disproportionate PH com­
bined with high lactate levels and bilious nasogastric aspirates may
indicate a rare complication of bowel compromise in CDH and may be
an indication for immediate exploratory surgery and repair [111].
3.12. ECMO for PH and cardiac dysfunction in CDH
Extra-corporeal membrane oxygenation is a rescue support for
cardio-respiratory failure, used globally in around 30% of CDH cases per
year [112]. However, controversies remain in relation to patient selec­
tion, timing of initiation and timing of surgical repair on ECMO. Recent
international guidelines highlight the importance of PH and cardiac
function assessment to guide management strategy before and during
ECMO [113]. In our experience patients with severe LV dysfunction
(phenotype 3) exhibit rapid improvement during short ECMO runs and
are amenable to repair after decannulation from ECMO. However, in
patients with associated severe PH or ventilatory failure unresponsive to
optimal medical management spontaneous recovery is unlikely and
early repair on ECMO may be warranted [71].
3.13. Targeted, phenotype-based therapy and outcomes
Could early and precise cardiovascular support, targeting individual
phenotypes, impact outcomes in the CDH population? An ongoing multi-
center, randomized controlled trial is evaluating early use of milrinone
in the CDH population, with the primary outcome as oxygenation
response determined by a change in oxygenation index at 24 h after
initiation [114]. Trials in CDH are challenging due to the relative rarity
of the condition and this will be the first to investigate hemodynamic
strategies specifically.
Future investigation of combination therapies addressing both car­
diac function and pre-capillary pulmonary arterial hypertension may
also be important. Kumar et al. observed that iNO in combination with
milrinone may be associated with improved oxygenation response and
survival after ECMO in infants with CDH [81].
4. Management of long-term PH and cardiac dysfunction in CDH
Between 11 and 17% of CDH survivors are discharged on pulmonary
vasodilator therapies, predominantly enteral sildenafil, but also bosen­
tan and more rarely intravenous or subcutaneous treprostinil [85,115].
S. Bhombal and N. Patel
In a single center series Behrsin et al. observed that median duration of
sildenafil therapy was 343 days [116]. The absence of longitudinal
studies and standardized guidance for assessment and treatment of
sub-acute and chronic PH are a source of ongoing variation in practice
and clinical uncertainty relating to indications, timing, dosing and
weaning of pulmonary vasodilator therapies.
Patients with suspected PH post-discharge are likely to benefit from
multi-disciplinary follow-up, including cardiology expertise, with care­
ful attention to contributing co-factors including gastro-esophageal
reflux, respiratory compromise, and nutrition [117].
5. Conclusion
Pulmonary hypertension and cardiac dysfunction are key, inter-
related pathophysiological components, therapeutic targets and de­
terminants of outcome in CDH. Pre- and post-capillary mechanisms of
increased pulmonary vascular resistance contribute to variable clinical
phenotypes of right and left ventricular dysfunction.
Structured clinical assessment of PAp, PVR and ventricular function
can reveal individual phenotypes at each point in the disease course and
guide targeted therapy, including appropriate use of pulmonary vaso­
dilators, inotropes, vasopressors and ECMO.
Future collaborative investigation is required to fully understand the
pathogenesis and mechanisms of PH in CDH, and whether this
pathophysiology-based clinical management approach can contribute to
improved short and long-term outcomes.
Authorship
Both authors (SB and NP) have made equal and substantial contri­
butions to all of the following: drafting the article or revising it critically
for important intellectual content, final approval of the version to be
submitted.
Funding
None.
Practice points
• Increased pulmonary vascular resistance in CDH may be due to a
combination of pre-capillary abnormalities of the pulmonary
vasculature and post-capillary increase in pulmonary venous pres­
sure due to left ventricular dysfunction.
• Pulmonary hypertension is associated with variable hemodynamic
phenotypes, characterized by the extent of right ventricular, left
ventricular, and biventricular dysfunction.
• Functional echocardiography is a key clinical tool in CDH manage­
ment enabling serial assessment of hemodynamic phenotype to help
guide targeted, physiology-based treatment strategies.
• Right ventricular dysfunction phenotypes are likely to benefit from
strategies to minimize PVR, including pulmonary vasodilators,
whilst supporting systemic blood pressure to optimize coronary
blood flow. Left ventricular dysfunction phenotypes, in the early
transitional period, improve with time and may be best supported by
inotropic therapy and mechanical ECMO support if required. LV
dysfunction may predict non-response to pulmonary vasodilators.
Future research directions
• Investigation of the cellular, metabolic and genetic mechanisms of
PH and associated cardiac dysfunction in fetal and postnatal life
• Consensus definitions and standardized objective measures of PH
and cardiac function in CDH to enable robust multi-center in­
vestigations, and as core outcomes for future interventional trials.
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uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.
Seminars in Fetal and Neonatal Medicine 27 (2022) 101383
• Development of improved early prognostic indicators incorporating
measures of pulmonary vascular resistance, cardiac morphology and
function in combination with existing measures of fetal lung volume.
• Investigation of the natural history, prognostic and clinical signifi­
cance of PH and associated cardiac dysfunction in the post-operative
period and later life.
Declaration of competing interest
The authors (SB and NP) have no financial and personal relationships
with other people or organisations that could inappropriately influence
(bias) the content of this article.
Acknowledgements
We are grateful to Satyan Lakshminrusimha for providing Fig. 2.
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