Pulmonary vascular disease

ORIGINAL ARTICLE

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Pulmonary hypertension in children with congenital
heart disease (PAH-CHD, PPHVD-CHD). Expert
consensus statement on the diagnosis and
treatment of paediatric pulmonary hypertension.
The European Paediatric Pulmonary Vascular Disease
Network, endorsed by ISHLT and DGPK
Rainer Kozlik-Feldmann,1 Georg Hansmann,2 Damien Bonnet,3 Dietmar Schranz,4
Christian Apitz,5 Ina Michel-Behnke6

For numbered affiliations see ABSTRACT PH associated with CHD.2 CHDs with volume
end of article. Pulmonary arterial hypertension associated with load to the pulmonary arteries have been grouped
Correspondence to congenital heart disease (PAH-CHD) is a complex disease in class 1.4.4 ‘Congenital heart diseases’ (see the
Dr Rainer Kozlik-Feldmann, that presents with a broad spectrum of morphological consensus statement on ‘diagnostics, monitoring,
Department of Paediatric and haemodynamic findings of varying severity. Recently, outpatient care’3). PH associated with left heart
Cardiology, University Heart the aspect of paediatric pulmonary hypertensive vascular congestive diseases can now be found in class 2.4
Center, University Medical
disease (PPHVD) has been introduced to expand the ‘Congenital/acquired left heart inflow/outflow tract
Center Hamburg-Eppendorf,
Martinistr. 52, Hamburg understanding of the full spectrum of pulmonary obstruction and congenital cardiomyopathies’. And
20246, Germany; hypertension and increased pulmonary vascular finally, segmental PH that does not affect all seg-
[email protected] resistance. Evaluation and treatment of PAH-CHD/ ments of the lung is allocated to group 5.
PPHVD-CHD can be divided into in different topics. First, The difficulty in the management of PH in paedi-
This article is a product of the
writing group of the European defining criteria for operability and initiation of advanced atric CHD is further augmented by the complexity
Paediatric Pulmonary Vascular therapies preoperatively and postoperatively is an of the underlying CHD and the frequent comorbid-
Disease (PVD) Network unresolved issue. Second, management of Eisenmenger ities. Certainly, comorbidities that include prematur-
(Writing Group Chair: syndrome is still an important question, with recent ity, neonatal lung diseases (bronchopulmonary
G Hansmann, Writing Group
Co-Chair: C. Apitz); ISHLT,
evidence on the severity of the disease and a more dysplasia and lung hypoplasia), chromosomal anom-
International Society of Heart rapidly progressive course than previously described. alies and polymalformations syndromes may puzzle
and Lung Transplantation; Third, the Fontan circulation with no subpulmonary the healthcare provider in the evaluation of the aeti-
DGPK, German Society of ventricle requires a distinct discussion, definition and ology and pathophysiology of elevated pulmonary
Paediatric Cardiology. classification since even a mild rise in pulmonary vascular resistance (PVR) in CHD. In order to meet
Received 10 July 2015 vascular resistance may lead to the so-called failing the complexity of paediatric PH with increased
Revised 11 October 2015 Fontan situation. Patients with CHD and single-ventricle PVR, a more detailed and age-dependent classifica-
Accepted 14 October 2015 physiology (Fontan/total cavopulmonary anastomosis) tion has been proposed by the Paediatric Taskforce
require a particularly stepwise and individualised of the Pulmonary Vascular Research Institute
approach. This consensus statement is on the current (Panama 2011) that expanded the term pulmonary
evidence for the most accurate evaluation and treatment arterial hypertension (PAH) to paediatric pulmonary
of increased pulmonary artery pressure and resistance, as hypertensive vascular disease (PPHVD).4–6
well as ventricular dysfunction, in children with In the Netherlands, the incidence and prevalence
congenital heart defects, and provides according of idiopathic pulmonary arterial hypertension
practical recommendations. To optimise preoperative and (IPAH) was estimated to be 0.7 and 4.4 per million
postoperative management in patients with PAH-CHD, children, respectively, whereas PAH associated with
diagnostic and treatment algorithms are provided. congenital heart disease (PAH-CHD) had an
assumed incidence of 2.2 and a prevalence of 15.6
per million.7
Pathophysiology of CHD with intra-cardiac and
INTRODUCTION extra-cardiac shunts may differ greatly in pre-
Pulmonary hypertension (PH) associated with con- tricuspid versus post-tricuspid lesions (ie, proximal
genital heart disease (CHD) is commonly associated or distal to the subpulmonary atrioventricular valve
with left-to-right shunt defects, or left heart in the bloodstream).
obstructive disease causing postcapillary PH.1 Pre-tricuspid shunts are left-to-right (or bidirec-
However, such simple grouping of CHD features tional) shunts at a low-pressure level, which lead to
To cite: Kozlik-Feldmann R, does not reflect the heterogeneity of paediatric PH volume load on the right ventricle (RV) and pulmon-
Hansmann G, Bonnet D, in the setting of CHD. The most recent update ary circulation, without immediate or midterm
et al. Heart 2016;102: from the 5th World Symposium on PH (WSPH) in increase of pulmonary arterial pressure (PAP). In
ii42–ii48. Nice 2013 proposed a more detailed approach for pre-tricuspid lesions, the development of
ii42 Kozlik-Feldmann R, et al. Heart 2016;102:ii42–ii48. doi:10.1136/heartjnl-2015-308378
 Pulmonary vascular disease

PAH-pulmonary vascular disease (PVD)/PPHVD may occur DIAGNOSIS OF PULMONARY HYPERTENSION ASSOCIATED
beyond the forth decade of life in 6–17%.8 The risk of developing WITH CONGENITAL HEART DISEASE

Heart: first published as 10.1136/heartjnl-2015-308378 on 6 April 2016. Downloaded from http://heart.bmj.com/ on 9 December 2018 by guest. Protected by copyright.
PVD is not only associated with the size of the atrial septal defect A modified clinical classification of PAH associated with CHD,
(ASD) but also dependent on the compliance of the RV (→magni- based on the most recent WSPH recommendations (2013),2 is
tude of the left-to-right shunt). The same considerations apply to given in box 1. Detailed recommendations on the evaluation of
partial anomalous pulmonary venous return (PAPVR). The patients with PAH by echocardiography are given by
volume load of the pulmonary circulation will be strongly influ- Koestenberger et al.34 within this issue. Echocardiography is the
enced by additional left heart lesions and left ventricular dysfunc- most valuable tool to describe morphology, haemodynamics and
tion. However, Eisenmenger syndrome in adults with ASD is rare ventricular function. In addition, an estimation about precapil-
and was estimated to occur in only 2% of patients.9 lary or postcapillary PH can be made. Even though cardiac cath-
Post-tricuspid lesions are left-to-right shunts at a high-pressure eterisation is the gold standard for diagnosing PH with and
level, which lead to volume load on the left ventricle and pul- without PVD, echocardiography may predict PAP and PVR and
monary circulation. If the post-tricuspid defects are large is a valuable routine tool. In complex CHD, or suboptimal
enough, the pulmonary pressure will increase to systemic blood echocardiographic windows, cardiac MRI or chest CT may be
pressure level ( pressure-unrestrictive ventricular septal defects performed to determine ventricular mass and volumes, valvular
(VSDs)). In post-tricuspid lesions, the development of regurgitation or any obstruction in single or biventricular circu-
PAH-PVD/PPHVD will occur during the first years of life. lation.35 Furthermore, patients with PH should be evaluated for
Untreated, ≈50% of the patients with post-tricuspid lesions will concomitant diseases (heart, lung, abdomen) with implications
develop suprasystemic PVR with shunt reversal to a right-to-left on management and prognosis, especially in patient groups with
shunt through the preformed shunt lesions, that is, the so-called comorbidities increasing the risk of developing PPHVD.3
Eisenmenger complex. While adults with Eisenmenger-PAH have
a better survival than those with idiopathic/heritable PAH, chil-
Surgery and operability of patients with PAH-CHD and
dren with PAH-CHD and PVD (ie, PPHVD) have a 5-year mor-
biventricular circulation
tality that appears to be comparable to those with idiopathic/
For correctable CHD, timely surgical repair is paramount
heritable PAH (29% vs 25%).10 The severity of adult
to prevent pulmonary hypertensive vascular disease14 32 33 36
PAH-CHD tends to be underestimated because the apparent sur-
(figure 1). Consequently, corrective or palliative surgery with
vival is related to the immortal bias selection of patients in
CHD and significant left-to-right shunt is performed mostly in
reported registries.1
the first six months of life to prevent persisting or evolving pres-
The particular haemodynamics of the Fontan circulation is
sure load on the pulmonary vasculature. Nevertheless, PAH
fragile (total cavopulmonary connection: no subpulmonary ven-
after surgical repair of CHD has been reported in 7.4% of adult
tricle, systemic veins surgically connected to the pulmonary cir-
patients with CHD.37 Today, there is no clear consensus on cri-
culation). In fact, there are potentially several reasons for a
teria for operability in left-to-right shunts with elevated PVR.
‘failing Fontan’ situation to occur. The single-ventricle dysfunc-
However, operability is of utmost importance as it has been
tion, chronically elevated central venous pressure, elevated PVR
shown that prognosis of postoperative PAH-CHD, which can be
(for passive pulmonary blood flow) or obstructions in the
prevented by timely shunt closure in the majority of cases, is
venous or arterial pathway may cause heart failure or specific
identical or worse than that of IPAH.38 No consensus exists on
complications such as plastic bronchitis or protein-losing enter-
the management of PAH in patients with CHD who do not
opathy. ‘Failing Fontan’ patients do not fulfil standard criteria
meet operability criteria or who have persisting PAH after cor-
for PH but may have an increased PVR, as judged by the trans-
rection of the defect (box 1).
pulmonary pressure gradient.2 There has been recent evidence
of a potential clinical response to specific PAH therapies in
Fontan patients, which needs further exploration before thera- So-called ‘simple shunt defects’
peutic recommendations can been made.2 The aim of this In ‘simple’ left-to-right shunt defects (ASD, VSD, patent ductus
article is to present the current evidence for the most accurate arteriosus (PDA)), which are diagnosed in neonates/infants with
evaluation and treatment of PAH-CHD, PHVD associated with clinical signs of heart failure (due to volume overload and shunt
CHD in children and adolescents, including according consen- related low systematic cardiac output) and normal oxygen satur-
sus recommendations. ation, cardiac catheterisation and acute vasoreactivity testing
(AVT) can be omitted and patients should be referred for surgical
METHODS shunt closure (figure 1). Undiagnosed CHD that is asymptomatic
The recommendations given in table 1 relate to the grading for years and does not present with PAH until adulthood, for
system currently suggested by the European Society of example, ASD in the adult, represents a special entity and cannot
Cardiology (ESC) and the American Heart Association, and was be compared with an ASD in childhood.39 For those adult
based on paediatric data only (class, level of evidence). The patients with pre-tricuspid left-to-right shunts (eg, ASD, PAPVR),
grading and voting process within the writing group is outlined complete assessment of pressures, oxygen transport and utilisa-
in this issue.11 Computerised searches of the PubMed/ tion, and the derived calculated variables is mandatory before
MEDLINE bibliographic database from 1990 to June 2015 considering surgery. A combination of precapillary and postcapil-
were conducted. The developer searched using the terms ‘paedi- lary PH may be present especially in the adult with chronic PH,
atric pulmonary hypertension’, ‘congenital heart disease’, ‘pul- which requires expert decision-making in terms of surgery or
monary arterial hypertension’, ‘vasoreactivity in pulmonary medical treatment, or pharmacotherapy before surgery (‘treat to
hypertension’, ‘cavopulmonary anastomosis pulmonary hyper- close’ concept, see Hansmann and Apitz40).
tension’, ‘Fontan circulation and pulmonary vascular disease’, In post-tricuspid shunts (‘simple’: VSD, PDA; or more complex
‘operability in congenital heart disease in children’, ‘nitric oxide CHD that allows shunt closure), early surgical correction of CHD
in pulmonary hypertension in children’, ‘Eisenmenger syndrome within the first two years of life is essential to avoid irreversible
and pulmonary hypertension’. remodeling of the pulmonary vasculature. For patients with an
Kozlik-Feldmann R, et al. Heart 2016;102:ii42–ii48. doi:10.1136/heartjnl-2015-308378 ii43
 Pulmonary vascular disease

Table 1 Recommendations on the evaluation and management of pulmonary hypertension (PH) in children and adolescents with
congenital heart disease (PAH-CHD, PPHVD-CHD)

Heart: first published as 10.1136/heartjnl-2015-308378 on 6 April 2016. Downloaded from http://heart.bmj.com/ on 9 December 2018 by guest. Protected by copyright.
Recommendations COR LOE
Children/adolescents with clinically confirmed CHD should undergo specific transthoracic echocardiographic (TTE) screening for pulmonary arterial I C
hypertension (PAH) and/or ventricular dysfunction. TTE cannot reliably distinguish between PAH with increased PVR (PPHVD) and without elevated
PVR4 12
In children and adolescents with PAH/PPHVD-CHD, a complete diagnostic workup needs to be performed in order to determine whether PAH is I C
associated or causally related to concomitant CHD12
Operability/catheter intervention: surgery or interventional closure for CHD with simple post-tricuspid shunts (VSD, PDA) and significant left-to-right I C
shunting should preferably be performed within the first six months of life13
Children with PAH-CHD and significant left-to-right shunting, congestive heart failure (pulmonary congestion), failure to thrive and SpO2 >95% (lower IIa C
extremities) can be considered ‘operable’ for shunt closure, however, perioperative PH crisis may occur
Children with PAH-CHD, significant left-to-right shunting and uncertainties regarding the PVR are recommended to undergo comprehensive right and left I C
heart catheterisation regardless of the patient’s age
Operability: children with CHD and simple defects (VSD, PDA) beyond the typical date of surgery (see main text) or those with shunts and cyanosis should I C
undergo comprehensive right and left cardiac catheterisation (see figure 1)14 15
Children with PVRI <6 WU×m2 and a PVR/SVR ratio <0.3 in the absence of additional risk factors are eligible for standard management/surgery/ I C
percutaneous interventional device closure
Children with PVRI ≥6 WU×m2 and a PVR/SVR ratio ≥0.3 have to be evaluated by acute vasodilative testing (AVT) I C
Operability in complex CHD has to be judged individually, considering age, size and type of lesions and associated syndromes I C
In children/adolescents with single-ventricle physiology, the haemodynamic threshold for operability pre-Fontan surgery is probably a mean TPG IIa C
≤6 mm Hg4
In clinically asymptomatic children/adolescents with single-ventricle physiology and total cavopulmonary connection (Fontan), a PVRI ≤3 WU×m2 and IIa C
mean TPG ≤6 mm Hg is consistent with acceptable haemodynamics4
In children/adolescents with total cavopulmonary connection (Fontan) signs of increased PVRI and/or low Qp and/or hepatic congestion should undergo IIa C
complete diagnostic workup, including comprehensive cardiac catheterisation
In children/adolescents with total cavopulmonary connection (Fontan) and PHVD (TPG is >6 mm Hg), or those Fontan patients with symptoms irrespective IIa C
of haemodynamics, targeted PH therapies should be considered to improve exercise capacity4
In inoperable children/adolescents with Eisenmenger syndrome, targeted pharmacotherapy as single drug or combination therapy (sequential, upfront) IIa C
may be used, depending on WHO functional class and symptoms16
In inoperable children/adolescents with Eisenmenger syndrome, iron supplementation (orally, intravenous) may be administered if iron deficiency is IIb C
present17–20
In inoperable children/adolescents with Eisenmenger syndrome, supplemental oxygen may be considered to reduce symptoms, after careful examination IIb C
(when PaO2 <60 mm Hg)21 22
In inoperable children with Eisenmenger syndrome and neurological symptoms (headaches, TIA, stroke), phlebotomy may be indicated in severe IIb C
hyperviscosity syndrome (MCV >80 fl)
In inoperable children/adolescents with Eisenmenger syndrome, anticoagulation may be considered in the absence of hemoptysis23 24
IIb C
In children/adolescents with PAH/PPHVD-CHD and left heart congestion either due to obstruction or secondary due to myocardial dysfunction, it is I C
recommended to perform full haemodynamic evaluation by comprehensive right and left heart catheterisation25–32
CHD, congenital heart disease; LOE, level of evidence; MCV, mean corpuscular volume; PAH, pulmonary arterial hypertension; PDA, patent ductus arteriosus; PH, pulmonary
hypertension; PPHVD, paediatric pulmonary hypertensive vascular disease; PVR, pulmonary vascular resistance; PVRI, PVR index; Qp, pulmonary blood flow; SVR, systemic vascular
resistance; TIA, transient ischaemic attack; TPG, transpulmonary pressure gradient; VSD, ventricular septal defect; WU, Wood units.

additional (genetic) risk for PPHVD, PPHVD severity or post- two different diseases with variable susceptibility to medical
operative persistent PPHVD, as in Down’s syndrome, surgery treatment.17 43 Due to improved diagnostics and timely treat-
should occur within the first six months of life in most instances. ment, it can be expected that the Eisenmenger complex in
These typical dates of surgery indicating an optimal time frame to patients with CHD will become a rare entity in advanced
prevent persisting or progressive PAH-CHD are well accepted and healthcare systems in the future.
should eliminate or decrease (eg, fenestrated VSD patch) the flow/
shear-stress related elevation of PAP and PVR.36 41 Postcapillary pulmonary hypertension
Valvular heart disease, such as mitral stenosis, may lead to post-
Advanced PAH-CHD and Eisenmenger’s syndrome capillary PH but usually responds to surgical repair with gradual
There are patients with PAH-CHD (eg, from developing coun- decrease and normalisation of pulmonary pressure, whereas in
tries) who present beyond the optimal age for surgery when restrictive physiology of the ventricles associated with postcapil-
admitted for evaluation. In these cases, a complete evaluation of lary PH, reversibility of PH is less clear. The evaluation of these
the pulmonary and systemic haemodynamics has to be per- patients with predominantly postcapillary PH should follow the
formed. If the physiology is already that of the Eisenmenger syn- same recommendations of complete haemodynamic assessment
drome, defect closure at this stage is associated with elevated (including AVT) as for PAH/PHVD-CHD in this issue,42
mortality and should not be pursued.8 Patients with PAH-CHD whether they occur isolated or in combination with lesions that
without a right-to-left shunt who are responsive to AVT42 may may cause precapillary PH (ie, PAH). A subset of these patients
have prolonged periods until they convert shunt direction and with left heart obstruction and left atrial hypertension do have
turn from pink to blue. Until now it has not been proven reactive pulmonary vasoconstriction. Such a situation charac-
whether every patient with PAH-CHD, persisting post-tricuspid terised by predominantly postcapillary PH with a precapillary
left-to-right shunt, and variable degree of PHVD-CHD, neces- component is accompanied by a marked elevation of the dia-
sarily develops an Eisenmenger syndrome or whether there are stolic pulmonary artery pressure and increased diastolic
ii44 Kozlik-Feldmann R, et al. Heart 2016;102:ii42–ii48. doi:10.1136/heartjnl-2015-308378
 Pulmonary vascular disease

closure in patients with PAH-CHD, healthcare providers may

Box 1 Clinical classification of pulmonary arterial consider lung biopsy in addition to chest CT to rule out or

Heart: first published as 10.1136/heartjnl-2015-308378 on 6 April 2016. Downloaded from http://heart.bmj.com/ on 9 December 2018 by guest. Protected by copyright.
hypertension associated with congenital heart disease confirm additional parenchymal lung disease such as alveolar
(modified from Simonneau et al 2) capillary dysplasia.46

1. Eisenmenger’s syndrome Acute vasoreactivity (AVT) testing in PAH/PHVD-CHD and

▸ Includes all large intra-cardiac and extra-cardiac defects implications for surgical repair
systemic-to-pulmonary shunts, which may progress with AVT in paediatric PH includes inhalative nitric oxide
time to severe elevation of PVR and to reversal (iNO), oxygen, iNO+oxygen and/or (ideally) inhalative
( pulmonary-to-systemic) or bidirectional shunting; iloprost13 25–28 47 (for details, see Apitz et al42). For patients
cyanosis, secondary erythrocytosis and multiple organ with CHD, it has not been proven that AVT can predict long-
involvement are usually present. Post-tricuspid shunts term prognosis, neither has it been shown that cut-off values
such as VSD, PDA and aortopulmonary window progress indicate absolute contraindications for surgery. Nevertheless,
more frequently and earlier to severe pulmonary there has been an agreement to evaluate and predict risk for
vascular disease, shunt reversal and Eisenmenger development or persistence of PAH early and late after surgery
physiology, than pre-tricuspid shunt lesions (eg, ASD). for CHD.13 While in biventricular circulations with pulsatile
2. Pulmonary arterial hypertension associated with prevalent pulmonary flow the diagnostic mPAP limit of <25 mm Hg is
systemic-to-pulmonary shunts valuable in children beyond neonatal age, the ratio of systolic
▸ correctable* and mean pulmonary artery pressures between the pulmonary
▸ non-correctable and systemic circulation, and the ratio of PVR and systemic vas-
▸ Include moderate to large defects; PVR is mildly to cular resistance (SVR), especially in the young age group, are
moderately increased, systemic-to-pulmonary shunting important for judgement of operability or heart transplant-
is still prevalent, whereas cyanosis at rest is not a ation.29 48 Vasoreactivity testing covers the response to vasodila-
feature. tive drugs and, moreover, the discrimination of pulmonary
3. Pulmonary arterial hypertension with small/coincidental† endothelial dysfunction.28 49
defects Based on the limited published clinical studies and our own
▸ Marked elevation in PVR in the presence of small experience, we suggest a structured catheterisation protocol and
cardiac defects, which themselves do not account for two separate definitions of positive AVT: (1) AVT to assess prog-
the development of elevated PVR; the clinical picture is nosis and indication for specific PH therapy and (2) AVT to
very similar to idiopathic PAH. Defect closure is assess operability of associated pulmonary hypertension (APAH)
contraindicated. with CHD (ADAH-CHD).12 The AVT protocol and the latter
4. Pulmonary arterial hypertension after correction of definitions can be found in Apitz et al.42 The haemodynamic
congenital cardiovascular defects change that defines a positive response to AVT in PAH asso-
▸ Congenital heart disease is repaired, but PAH either ciated with a shunt defect (Qp:Qs >1.5; APAH-CHD-shunt)
persists immediately after correction or recurs/develops for children should be considered as a >20% fall in PVR-index
months or years after correction in the absence of and PVR/SVR with respective final values <6 WU × m2 and
significant postoperative haemodynamic lesions. <0.3. Nevertheless, operative safety in APAH-CHD with a
*With surgery or intravascular percutaneous procedure. shunt cannot be guaranteed (the approximate grey zone is PVR-
†The size applies to adult patients. index 6–8 WU × m2, and PVR/SVR ratio 0.3–0.5) and an
ASD, atrial septal defect; PAH, pulmonary arterial hypertension; element of clinical subjectivity is inevitable. Further investigation
PDA, patent ductus arteriosus; PVR, pulmonary vascular is warranted in selected populations, such as the growing
resistance; VSD, ventricular septal defect. number of children with CHD complicated by chronic lung
disease of prematurity,46 and in the developing world where
patients are more likely to present late with advanced pulmon-
ary hypertensive vascular disease and often shunt reversal
transpulmonary pressure gradient (>7 mm Hg in adults) (for (right-to-left, ie, Eisenmenger syndrome).
details, see Apitz et al42). The precapillary component is called
‘reactive’ PH, and the combined condition was formerly often Postoperative pulmonary hypertension in patients with
called ‘out of proportion’ PH. Possibly, this subgroup of patients PAH-CHD
with both precapillary and postcapillary PH develops more If postoperatively elevated PAP suspicious for PHVD-CHD is
severe PVD with time.44 observed early after surgical repair and is not thought to be
transient with intensive care measures,50 comprehensive left and
Lung biopsy right heart catheterisation may be indicated to evaluate the need
Lung biopsies in patients with PAH-CHD with advanced, most for specific PAH therapy. The latter invasive diagnostics is cer-
likely irreversible pulmonary hypertensive vascular disease show tainly indicated in late postoperative PAH-CHD, that is, years
intimal proliferation and vessel narrowing associated with after surgery, be it persistent/progressive or ‘de novo’.
impaired endothelial cell apoptosis and antiapoptotic signaling
from perivascular inflammatory cells.45 Because of the low like- Transcatheter interventions and surgical treatment creating
lihood of altering the diagnosis and treatment and the substan- a right-to-left shunt
tial risk of morbidity and mortality, open or thoracoscopic lung Finally, innovative surgery and transcatheter interventions have
biopsies are not recommended for patients with PAH-CHD/ been proven to be helpful in purposely turning PAH patients to
PHVD-CHD33 in most instances. However, in certain situations Eisenmenger physiology: creating an interatrial communica-
when PAP and PVR remains high or even worsen after shunt tion51 52 and/or establishment of a Potts shunt (left pulmonary
Kozlik-Feldmann R, et al. Heart 2016;102:ii42–ii48. doi:10.1136/heartjnl-2015-308378 ii45
 Pulmonary vascular disease

Heart: first published as 10.1136/heartjnl-2015-308378 on 6 April 2016. Downloaded from http://heart.bmj.com/ on 9 December 2018 by guest. Protected by copyright.
Figure 1 Algorithm for the management of patients with congenital heart disease associated with PAH/PPVD and congenital shunt lesions
(modified from Lopes et al13 and the PVRI PAH-CHD taskforce ( pdf on PVRI website). The indication for invasive diagnoses and eligibility for
surgery/operability by comprehensive left and right heart catheterisation includes basic evaluation and AVT, the latter especially in the grey zone of
forecast uncertainty. ASD, atrial septal defect; AVT, acute vasodilative testing; CHD, congenital heart disease; PAH, pulmonary arterial hypertension;
PDA, patent ductus arteriosus; PH, pulmonary hypertension; pre OP, preoperatively; PVR, pulmonary vascular resistance; PVRI, PVR index; Qp,
pulmonary blood flow; Qs, systemic blood flow; SVR, systemic vascular resistance; VSD, ventricular septal defect; WU, Wood units.

artery to descending aorta) or stenting an evident ductus anastomosis) and in a second step the connection of the IVC to
arteriosus.52 53 the pulmonary arteries (total cavopulmonary anastomosis
Taken together, the criteria for closure of shunts in CHD are (TCPC)/Fontan).
implemented within the WSPH Nice statements (2013)2 and The measurements of mean transpulmonary pressure gradient
ESC/ERS guidelines (2015),33 but do not differentiate markedly (mTPG=mPAP−LAP mean) and PVR index (PVRI) are crucial
between children and adults. Despite levels of evidence that do for an appropriate selection of patients for the TCPC/Fontan
not exceed the level of expert opinion (C), a valuable algorithm circulation. Accepting the limitations of calculating and inter-
for decision-making, including AVT, has been recently suggested preting PVR in univentricular circulations, a mTPG of
by Lopes et al.13 We suggest a similar approach, following clin- ≤6 mm Hg with a PVRI ≤3 WU×m2 probably marks the limit
ical, non-invasive and haemodynamic data (algorithm, figure 1). for completion of palliative separation of the pulmonary and
Whether AVT is able to predict long-term normalisation of pul- systemic circulation in univentricular hearts.4 If the measure-
monary artery pressures and resistance cannot be ultimately ments are beyond these limits, it has been proposed to pre-treat
answered. with vasodilators such as PDE5-inhibitors or endothelin recep-
tor antagonist to decrease PVR with the intention to reach the
PULMONARY HYPERTENSIVE VASCULAR DISEASE IN THE criteria for TCPC/Fontan palliation. However, clinical efficacy
CONTEXT OF SINGLE-VENTRICLE PHYSIOLOGY of such pharmacotherapy has not been proven.
Patients with hypoplastic left ventricle (LV) or RV, and patients There are no standards on how to properly estimate TCPC/
in whom the left and right heart cannot be separated for other Fontan haemodynamics during cardiac catheterisation. It is
reasons, undergo the (modified) Fontan procedure, leading to unknown whether patients should be studied in general anaes-
single-ventricle physiology and non-pulsatile pulmonary blood thesia, sedation or local anaesthesia only. Transducer systems are
flow (no subpulmonary ventricle). In most cases, a first step is sometimes unreliable in measuring the non-pulsatile pressure
required to secure and define the pulmonary perfusion and to inside the pulmonary arteries. Additionally, aortopulmonary col-
ensure an unobstructed systemic perfusion (stage 1 surgery, laterals, residual antegrade flow from the ventricle and venove-
Norwood with classical BT-shunt or RV-PA shunt). This is fol- nous collaterals (to the pulmonary veins) or arteriovenous
lowed by two cavopulmonary surgeries by connecting the sys- shunts make it difficult to estimate the correct Qp/Qs ratio.
temic veins to the pulmonary arteries. First is a bidirectional However, standard procedures overcoming these questions
anastomosis between superior vena cava (SVC) and pulmonary have to be found because failure of TCPC/Fontan and decreased
arteries ( partial cavopulmonary anastomosis, syn. Glenn exercise tolerance in the absence of severe ventricular
ii46 Kozlik-Feldmann R, et al. Heart 2016;102:ii42–ii48. doi:10.1136/heartjnl-2015-308378
 Pulmonary vascular disease

dysfunction or atrioventricular valve regurgitation may be attrib- Kinderherzzentren (W-H-001-2014) and Stiftung Kinderherz (2511-6-13-011). DB
uted primarily to increased PVR.29 currently receives grants from the Agence Nationale de la Recherche and from the
Fédération Française de Cardiologie and received fees for consulting, advisory boards

Heart: first published as 10.1136/heartjnl-2015-308378 on 6 April 2016. Downloaded from http://heart.bmj.com/ on 9 December 2018 by guest. Protected by copyright.
and steering committee membership from Actelion Pharmaceuticals EliLilly, Pfizer
PHARMACOTHERAPY OF PAH-CHD and Bayer. CA currently receives grant funding from Stiftung Kinderherz
A brief overview of the actual treatment strategies with their (2511-10-13-001) and Behring-Röntgen-Stiftung (59-0018).
effects on decrease of PVRI,54 55 improvement of quality of life This Heart supplement was produced with support from an unrestricted
educational grant from Actelion Pharmaceuticals Germany GmbH, Bayer Pharma AG,
and exercise tests has been published by others12 and is further
and Pfizer Inc. None of these organisations had any influence on the composition of
outlined in our according expert consensus on paediatric PH the writing group or the content of the articles published in this supplement. Open
therapy.40 Access publication of this article was sponsored by Actelion Pharmaceuticals
For PAH-CHD patients in the grey zone of PVRI estimation Germany GmbH.
(6–8 WU×m2, figure 1), medical treatment prior to closure of Provenance and peer review Commissioned; externally peer reviewed.
the shunt defect may be pursued (‘treat to close concept’), and Open Access This is an Open Access article distributed in accordance with the
closure of the defect can be considered if in a subsequent haemo- Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
dynamic study the PVR index is < 6 WU×m2. Convincing long- permits others to distribute, remix, adapt, build upon this work non-commercially,
term data for this strategy remain scarce. If the patient remains in and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http://creativecommons.org/
the grey zone of indexed PVR, a modified surgery with, for licenses/by-nc/4.0/
example, fenestrated defect closure may be considered.56
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ii48 Kozlik-Feldmann R, et al. Heart 2016;102:ii42–ii48. doi:10.1136/heartjnl-2015-308378