Reproducibility of right-to-left shunt quantification using transthoracic contrast echocardiography in hereditary haemorrhagic telangiectasia
Neth Heart J
Reproducibility of right-to-left shunt quantification using transthoracic contrast echocardiography in hereditary haemorrhagic telangiectasia
V. M. M. Vorselaars 0 1
S. Velthuis 0 1
M. P. Huitema 0 1
A. E. Hosman 0 1
C. J. J. Westermann 0 1
R. J. Snijder 0 1
J. J. Mager 0 1
M. C. Post 0 1
0 Department of Pulmonology, St. Antonius Hospital , Nieuwegein , The Netherlands
1 V. M. M. Vorselaars
Aim Transthoracic contrast echocardiography (TTCE) is recommended for screening of pulmonary arteriovenous malformations (PAVMs) in hereditary haemorrhagic telangiectasia. Shunt quantification is used to find treatable PAVMs. So far, there has been no study investigating the reproducibility of this diagnostic test. Therefore, this study aimed to describe inter-observer and inter-injection variability of TTCE. Methods We conducted a prospective single centre study. We included all consecutive persons screened for presence of PAVMs in association with hereditary haemorrhagic telangiectasia in 2015. The videos of two contrast injections per patient were divided and reviewed by two cardiologists blinded for patient data. Pulmonary right-to-left shunts were graded using a three-grade scale. Inter-observer and inter-injection agreement was calculated with κ statistics for the presence and grade of pulmonary right-to-left shunts. Results We included 107 persons (accounting for 214 injections) (49.5% male, mean age 45.0 ± 16.6 years). A pulmonary right-to-left shunt was present in 136 (63.6%) and 131 (61.2%) injections for observer 1 and 2, respectively. Inter-injection agreement for the presence of pulmonary right-to-left shunts was 0.96 (95% confidence interval (CI) 0.9-1.0) and 0.98 (95% CI 0.94-1.00) for observer 1 and 2, respectively. Inter-injection agreement for pulmonary right-to-left shunt grade was 0.96 (95% CI 0.93-0.99) and 0.95 (95% CI 0.92-0.98) respectively. There was disagreement in right-to-left shunt grade between the contrast injections in 11 patients (10.3%). Inter-observer variability for presence and grade of the pulmonary right-to-left shunt was 0.95 (95% CI 0.91-0.99) and 0.97 (95% CI 0.95-0.99) respectively. Conclusion TTCE has an excellent inter-injection and inter-observer agreement for both the presence and grade of pulmonary right-to-left shunts.
Hereditary haemorrhagic telangiectasia; Pulmonary right-to-left shunt; Transthoracic contrast echocardiography; Pulmonary arteriovenous malformation
Transthoracic contrast echocardiography (TTCE) is used to
screen for the presence of pulmonary arteriovenous
malformations (PAVMs). Over 90% of PAVMs are associated with
Department of Cardiology, St. Antonius Hospital,
Nieuwegein, The Netherlands
hereditary haemorrhagic telangiectasia, an inheritable
disease characterised by abnormal artery-to-vein connections
in the brain, liver or lungs [
]. Most cases are caused
by mutations in the ENG and ACVRL1 gene, leading to
hereditary haemorrhagic telangiectasia type 1 and type 2
respectively. A rarer mutation is located on the SMAD4
gene. PAVMs are frequently described in all subgroups but
more prevalent in hereditary haemorrhagic telangiectasia
type 1. In up to 21% of patients PAVMs are associated with
severe neurologic complications, such as brain abscesses
and ischaemic stroke . Furthermore, PAVMs can result
in hypoxaemia, haemoptysis and migraine. Most patients,
however, remain asymptomatic before the development of
complications, making screening for PAVMs extremely
important in all patients with or suspected of hereditary
haemorrhagic telangiectasia [
TTCE represents a functional measurement in which
PAVMs are visualised as a pulmonary right-to-left shunt.
Pulmonary right-to-left shunt grade on TTCE is a good
predictor for the presence of treatable PAVMs on chest
computed tomography (CT) [
]. Importantly, only moderate to
large right-to-left shunts seem to have clinical implications
3, 8, 9
]. The international hereditary haemorrhagic
telangiectasia guidelines recommend TTCE as first-choice
screenings test for PAVMs. However, the reliability of TTCE is
dependent on the reproducibility in the individual patient.
Although the inter-observer variability has been described
in a few studies, there has been no research evaluating the
reproducibility of TTCE. Therefore, we aimed to
evaluate both the inter-injection and inter-observer variability of
TTCE in this prospective single-centre study.
Material and methods
We included all consecutive persons screened for the
presence of hereditary haemorrhagic telangiectasia and all
consecutive hereditary haemorrhagic telangiectasia patients
visiting the outpatient clinic for a regular 5-year
followup at the Dutch hereditary haemorrhagic telangiectasia
centre between February and November 2015. The clinical
diagnosis was established according to the Curaçao
criteria, which consist of spontaneous and recurrent epistaxis,
telangiectasia at characteristic sites, visceral arteriovenous
malformations, and a first-degree relative with hereditary
haemorrhagic telangiectasia [
]. Genetic testing was offered
to all included patients. A definite diagnosis of hereditary
haemorrhagic telangiectasia was established in case of three
or more Curaçao criteria, or when genetic testing identified
the hereditary haemorrhagic telangiectasia causing gene
mutation (e.g. ENG, ACVRL1 or SMAD4).
Patients were excluded if TTCE was not complete (e.g.
due to intravenous line failure or image storage problems).
The study was approved by the local ethics committee
nected by a bi-directional Luer Lock system. In total, 10 ml
agitated saline (containing microbubbles) was created by
reverse flushing between the connected syringes [
The patient was positioned in the left lateral position and
5 ml of agitated saline was injected at rest while
projecting the four-chamber apical view. After all microbubbles
dissolved, this procedure was repeated.
All TTCE videos were blinded for patient data,
numbered and stored in a database. The observers viewed all
individual contrast injections in random order to minimise
the possibility of bias. Two independent cardiologists
(observer 1: VV and observer 2: SV) quantified each shunt.
All right-to-left shunts that clearly originated out of the
pulmonary vein were classified as pulmonary right-to-left
shunts, and all right-to-left shunts appearing through the
septum as cardiac right-to-left shunts. If shunt origin was
not visible, a delay of four cardiac cycles was used to
distinguish between a pulmonary and cardiac shunt. We
considered the TTCE positive for a pulmonary right-to-left shunt
if microbubbles appeared in the left atrium after four or
more cardiac cycles. The pulmonary right-to-left shunt was
graded based on the maximum number of microbubbles
present in the left ventricle in one still frame. Right-to-left
shunt was graded as 1, 2 or 3 corresponding with 1–29,
30–100 and over 100 microbubbles respectively (Fig. 1 and
video 1–3) [
3, 8, 10–12
We reviewed the technical quality of the studies and
described image quality as good, sufficient or insufficient.
Quantity of contrast in the right ventricle was described
as sufficient when opacification of the right ventricle was
densely filled (with endocardial lining) [
Chest computer tomography
We performed a chest CT examination in all patients with
a pulmonary right-to-left shunt grade ≥2 in at least one
of the injections [
] and used a ≥16-detector CT
scanner (Philips Medical Systems, Best, the Netherlands) with
a high-resolution algorithm and slice thickness of 1 mm. All
CT images were evaluated by an interventional radiologist
and a pulmonologist who were blinded to the TTCE results.
Transthoracic contrast echocardiography
All TTCEs were performed according to the local clinical
protocol. TTCEs were conducted on a Philips IE33
ultrasound instrument (S5-1 transducer; Philips Medical
Systems, Best, the Netherlands) or a General Electronic Vivid
S6 ultrasound instrument (3S transducer; General
Electronic Healthcare, Wauwatosa, The United States).
An intravenous line was inserted in the right antecubital
vein, 1 ml blood was drawn and 8 ml physiological saline
solution and 1 ml air was added. A second syringe was
conWe used descriptive statistics to describe patient
characteristics. Continuous variables were reported as mean ±
standard deviation. Proportions were given by numbers and
corresponding percentages. We measured inter-injection
agreement for the presence and grade of a pulmonary
right-toleft shunt between the two contrast injections at rest in
one patient. Inter-observer agreement was measured for the
presence and grade of pulmonary right-to-left shunts
between observer 1 and observer 2. We used Cohen’s
unFig. 1 Pulmonary right-to-left
shunt (RLS) on transthoracic
contrast echocardiogram. a No
pulmonary RLS. b Pulmonary
RLS grade 1. c Pulmonary RLS
grade 2. d Pulmonary RLS
Table 1 Baseline characteristics
Time of TTCE
Screening for HHTa
Follow-up of pulmonary RLSb
– Type 1
– Type 2
45.0 ± 16.6
Data are presented as number (%) or mean ± standard deviation
HHT hereditary haemorrhagic telangiectasia, RLS right-to-left shunt,
SMAD4 SMAD family member 4, TTCE transthoracic contrast
aTTCE made to screen for pulmonary RLS
bTTCE made at regular 5 year follow-up
cBased on genetic testing or clinical criteria [
weighted kappa coefficient (with 95% confidence
intervals (CI)) for nominal characteristics and Cohen’s weighted
kappa coefficient (with 95% CI) for ordinal characteristics.
Level of agreement was described according to Landis and
]. Odds ratio (OR) with 95% CI was calculated
by performing a binominal logistic regression analyses to
describe predictors for inter-injection differences. For the
statistics we used a statistical software package (SPSS,
version 22; SPSS Inc., Chicago and R (www.r-project.org,
Between February and November 2015, we used TTCE
in 110 patients. After excluding 3 patients (image storage
problem N = 2, intravenous line failure N = 1), 107 patients
(49.5% male, mean age 45.0 ± 16.6 years) were included
for further analysis (Tab. 1). Image quality of TTCE was
good, sufficient and insufficient in 97 (90.7%), 9 (8.4%) and
1 (0.9%) patients/patient respectively. Quantity of contrast
opacification of the right ventricle was sufficient in 197
contrast injections (92.1%). A pulmonary right-to-left shunt
Absolute agreement is described as number with percentage, other agreements are described as kappa with
95% confidence interval. (1): observer 1; (2): observer 2
RLS right-to-left shunt
was present in 136 (63.6%) and 131 (61.2%) injections for
observer 1 and 2 respectively. A cardiac right-to-left shunt
at rest was present in 3 patients (2.8%) for both observers.
Inter-injection agreement (Tab. 2 and 3) for the presence
of pulmonary right-to-left shunt was κ coefficient 0.96;
95% CI 0.90–1.00 (observer 1) and κ coefficient 0.98;
95% CI 0.94–1.00 (observer 2). Inter-injection agreement
for pulmonary right-to-left shunt grade was 0.96; 95%
CI 0.93–0.99 (observer 1) and κ coefficient 0.95; 95%
0.92–0.98 (observer 2). Observer 1 and observer 2
disagreed about right-to-left shunt grade between first and
second contrast injection in 8 and 9 patients respectively.
This included 11 patients (10.3%) in total, technical quality
of the studies showed good image quality in 8 of these
patients (72.7%) and difference in contrast opacification
of the right ventricle in 6 patients (54.4%). Disagreement
between right-to-left shunt grade 1 and 2 occurred in 3 and
5 patients respectively (5 patients (4.7%) in total). CT scans
were taken of all 5 patients and showed a very small PAVM
in 1 patient with no possibility for percutaneous treatment.
Difference between two injections was never more than
one grade. Quantity of contrast in the right ventricle was
a predictor for inter-injection disagreement (OR 6.6; 95%
CI 1.5–29.8, p = 0.01).
Inter-observer agreement (Tab. 2 and 3) for pulmonary
right-to-left shunt presence and grade was κ coefficient
0.95; 95% CI 0.91–0.99 and κ coefficient 0.97; 95% CI
During placement of an intravenous line, one patient (0.9%)
experienced vagal symptoms and an irregular heart rate.
Rhythm on TTCE showed atrial fibrillation, which was
confirmed with a 12-lead electrocardiogram. During TTCE
there were no major complications. One patient (0.9%),
with a right-to-left shunt grade 2, reported dizziness in the
first hour after TTCE with spontaneous full recovery.
This is the first study that describes the reproducibility of
the detection and quantification of pulmonary right-to-left
shunt on TTCE in patients screened for the presence of
PAVM in association with hereditary haemorrhagic
telangiectasia. We found a high level of agreement for the
detection and grading of a pulmonary right-to-left shunt in an
individual patient (κ coefficient 0.95–0.98).
The use of TTCE to detect intra-pulmonary right-to-left
shunts was first described in 1976 [
]. The technique for
TTCE is based on the permeability of the pulmonary
capillary network and the difference in density between
gascontained microbubbles and the surrounding blood [
The capillary network normally measures 8 to 10 µm in
diameter, and therefore the injected microbubbles with a mean
diameter of 27 μm will be trapped in the pulmonary
circulation. If PAVMs are present the filtering capacity of the
capillary network will be diminished, and microbubbles will
pass the pulmonary filter and appear in the left side of the
Clinical implications of the use of TTCE in hereditary
haemorrhagic telangiectasia have emerged in the last few
years. Gazzaniga et al. described an association between
pulmonary right-to-left shunt grade and the occurrence of
complications (haemoptysis, cerebral abscesses and stroke)
]. This was confirmed in a large multicentre study that
included over 1,000 patients and described pulmonary
rightto-left shunt grade 2 and 3 as independent predictors for the
prevalence of a cerebral ischaemic event or brain abscess
(OR 4.78; p = 0.03 and OR 10.4, p = 0.002) [
pulmonary right-to-left shunt grade also predicts the size of
PAVMs on CT and the subsequent feasibility of
]. This suggests that only moderate and large
right-toleft shunts have clinical implications. Therefore, CT can be
safely withheld in patients with a grade 1 pulmonary
rightto-left shunt reducing radiation exposure for many
hereditary haemorrhagic telangiectasia patients [
5 years, no treatable PAVMs develop in patients without
a pulmonary right-to-left shunt at screening. However,
increase in pulmonary right-to-left shunts occurs in
approximately 18%, leading to the need for embolisation in 12%
of patients with initially non-treatable PAVMs at screening
Although the above data already described the
importance of TTCE, reliability of TTCE is based on the
interobserver variability and reproducibility in the individual
patient. Many studies already described a high inter-observer
agreement (κ coefficient 0.85–0.94) for pulmonary
rightto-left shunt detection and, therefore, our results are in line
with the previous [
11, 12, 21
This is the first study describing the inter-injection
agreement for pulmonary right-to-left shunt quantification since
none of the previous studies consecutively performed
multiple injections in one single patient. Although not
completely comparable, repeated injections for the diagnosis
of a cardiac right-to-left shunt have shown to increase the
detection of right-to-left shunts due to a high number of
false negative injections [
]. Differences in
quantification of cardiac right-to-left shunts were mainly based on
the technique of provocation, insufficient contrast in the
right ventricle and poor image quality. The inter-observer
and intra-observer agreements for the detection of a cardiac
right-to-left shunt seem much lower (0.77 and 0.82
respectively) in comparison with those found for pulmonary
rightto-left shunts . This may be explained by the different
mechanisms of both shunts. In contrast to the cardiac
rightto-left shunt, the pulmonary right-to-left shunt represents
a persistent shunt and therefore no provocation is required
to visualise the right-to-left shunt. However, our study
confirms the need for sufficient contrast opacification of the
right ventricle to obtain a reliable result, as it is shown
to be a predictor for inter-injection disagreement (OR 6.6;
95% CI 1.5–29.8, p = 0.01). This confirms the utmost
importance of adequately producing and injecting the agitated
saline. Obtaining a good acoustic window is essential for
reliable right-to-left shunt quantification [
of a second contrast injection should therefore be
recommended when any doubt on right-to-left shunt grade exists.
TTCE may also be used to diagnose a pulmonary
right-toleft shunt related to hepatopulmonary syndrome. Although
there are pathophysiological differences, the results of our
study may be translated to these patients.
Although this study showed an almost perfect level of
inter-injection agreement, it should be emphasised that there
was disagreement between the first and second contrast
injection in 11 patients (10.3%). This might have clinical
implications when treatable PAVMs are missed. Since CT
is withheld in patients with a pulmonary right-to-left shunt
<2, quantification of a right-to-left shunt grade 1 instead
of grade 2 might have consequences. In this study, this
occurred in 5 patients (4.7%). CT did not demonstrate
treatable PAVMs in any of these patients. This reinforces our
previously described recommendation to exclude
right-toleft shunts grade 1 from further CT analysis.
Some clinicians have concerns regarding the safety of
the contrast injection, especially in patients with a
rightto-left shunt. However, the microbubbles in the injected
agitated saline are very small and implode easily. Multiple
recent studies in patients with and without hereditary
haemorrhagic telangiectasia confirm the safety of TTCE and
describe only minor and self-resolving side effects such as
dizziness and migraine in 0–2% [
11, 19, 25, 26
]. In line
with previous studies, our study showed no severe side
At this moment TTCE is the cornerstone in the
diagnostic evaluation of pulmonary right-to-left shunts in the
context of hereditary haemorrhagic telangiectasia. However,
chest CT remains the gold standard for pre- and
post-embolisation evaluation of PAVMs because it provides
essential information on the PAVM anatomy (localisation,
complexity, size of feeding arteries and aneurysmal sac).
Magnetic resonance imaging is also used for PAVM detection.
A big advantage compared with chest CT is the avoidance
of radiation while the anatomy of the PAVMs can still be
demonstrated. Although some studies show promising
results, large comparative prospective studies are lacking and
the lower spatial resolution (compared with CT) is currently
a major limiting factor [
First, this is a single-centre study performed in a tertiary
referral hospital that is highly experienced in hereditary
haemorrhagic telangiectasia and TTCE, therefore the
results may not apply to other centres. Secondly, the level
of agreement could be influenced by the presence of only
a few patients with a large pulmonary right-to-left shunt.
Thirdly, the number of cardiac right-to-left shunts might be
underestimated because we only studied the contrast
injections at rest focussing on the presence of pulmonary
rightto-left shunts. This resulted in a prevalence of 3%
compared with 23% in previous studies [
]. Because we used
the four-beat rule when the shunt origin could not be
visualised, the false positive risk for pulmonary right-to-left
shunt is small.
TTCE has an excellent inter-observer and inter-injection
agreement for both the presence and grading of pulmonary
Take home message
● Moderate to large pulmonary right-to-left shunts are
associated with severe neurologic complications in
hereditary haemorrhagic telangiectasia.
● Transthoracic contrast echocardiography is recommended
for screening of pulmonary right-to-left shunts, although
reproducibility has not been described previously.
● This prospective single-centre study showed that
transthoracic contrast echocardiography has an excellent
interinjection and inter-observer agreement for both the
presence and grade of pulmonary right-to-left shunts.
Acknowledgements We would like to thank J. Kelder for his help with
the statistical analysis.
Conflict of interest V.M.M. Vorselaars, S. Velthuis, M.P. Huitema,
A.E. Hosman, C.J.J. Westermann, R.J. Snijder, J.J. Mager and
M.C. Post declare that they have no competing interests.
Open Access This article is distributed under the terms of the
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link to the Creative Commons license, and indicate if changes were
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