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European Heart Journal (1997) 18, 1816-1822
Cardiopulmonary physiology after surgical closure of
asymptomatic secundum atrial septal defects in
childhood
Exercise performance is unaffected by age at repair
M. Rosenthal, A. Redington and A. Bush
Departments of Paediatric Pulmonary and Cardiac medicine, The Royal Brompton Hospital, London, U.K.
Aims Most secundum atrial septal defects, once diagnosed,
are corrected at a young age. The evidence to justify early vs
delayed or even non-closure is equivocal and little is known
regarding long-term effects of later closure. This is particularly pertinent to those patients awaiting transcatheter
closure of their defect for whom a device is only just
becoming available. We examined the exercise cardiorespiratory physiology of children surgically treated for an
isolated secundum defect.
Methods and results One hundred and six healthy control children and 22 children more than 6 months after
surgical repair for an isolated secundum atrial septal defect
were studied. All were asymptomatic. Measurements of
effective pulmonary blood flow, stroke volume, arteriovenous oxygen difference, minute ventilation, heart rate,
oxygen consumption and carbon dioxide production were
made using a quadrupole mass spectrometer during rest
and graded exercise. Data from the normal children
allowed calculation of z scores for the atrial septal defect
group matched for age, sex, pubertal stage and surface area.
Introduction
'It is widely but not universally accepted that atrial
septal defects with a pulmonary to systemic flow ratio
> 1-5:1 should be closed. The evidence to justify this
policy is weak', ran a recent review1'1. The secundum
atrial septal defect represents 10% of congenital heart
defects at birth and 22% of those seen in adults. The
long-term survival of those surgically closed before the
Revision submitted 5 May 1997, and accepted 16 May 1997.
Correspondence: Andrew Bush, Department of Paediatric
Respiratory Medicine, Royal Brompton Hospital, London
SW3 6NP. U.K
This study was funded in part from a grant by Innovision PLC,
Odense, Denmark.
0195-668X/97/111816+07 S18.00/0
Maximal exercise performance was equal between control
and atrial septal defect groups, however, the atrial septal
defect group had a significantly greater effective pulmonary
blood flow and stroke volume but a lower heart rate than
controls at a given exercise stage. Stroke volume abnormalities were most closely related to duration of follow-up
(29% of the variance explained, /><001) rather than age at
surgery.
Conclusions We were unable to show a medium term
benefit from early surgery for an asymptomatic secundum
atrial septal defect during exercise. The clinical relevance
of the haemodynamic differences that do exist remains
unclear.
(Eur Heart J 1997; 18: 1816-1822)
Key Words: Atrial septal defect,
physiology, children.
cardiopulmonary
age of 25 years is excellent'21. However, the long-term
survival of those not surgically treated also appears
good'31. Nevertheless, the practice of closing such defects
at a progressively earlier age is widespread. This is
supported by one study of unselected children which
suggested that those operated <5 years of age have a
superior cardiopulmonary exercise physiology on
follow-up than those operated on later'41. There are
relatively few data, however, and the optimal age at
repair is yet to be determined. There are also an
increasing number of children waiting for transcatheter
closure of their defect and the effect of this delay is
uncertain.
We studied the rest and exercise cardiopulmonary physiology of children with isolated secundum atrial
septal defects surgically closed at different ages using
respiratory mass spectrometry.
4, 1997 The European Society of Cardiology
A trial septal defects and age at repair
Methods
1817
Table 1 Descriptive summary of test groups
Control
The study received local ethical committee approval and
written informed consent from all the subject's parents
was obtained.
ASD
Number
Male
Female
106
55
51
22
6
16
8-50-10-50 years
1051-12 60 years
12-61-14-50 years
> 14-50 years
PreEarly
Late
23
24
37
22
30
36
40
4
7
7
4
11
4
7
Age at study
The control group
One hundred and six healthy children were recruited
from three local London schools. The entry criteria were
(i) at least 7-5 years old — the minimum age which
ensured cooperation with the exercise protocol; (ii) at
least 125 cm tall, the minimum height for using the
exercise bicycle; (iii) no history of acute or chronic
respiratory illness and receiving no medications. To
ensure the control group was not biased towards more
physically active children, volunteers were targeted to
undertake studies on how the heart and lungs worked
together rather than on the basis of testing their fitness;
members of school athletic clubs were excluded.
Puberty
Age at surgery
0-4 years
4-1-8-0 years
8-1-12-0 years
121-160 years
6
9
4
3
0-2-5 years
2-6-5-0 years
5-1-7-5 years
>7-5 years
3
6
6
7
Time from surgery
ASD = atrial septal defect.
The study group
The entry criteria were the finding of an isolated
secundum defect repaired at least 6 months prior to
study and no pre- or post-operative complaints of
symptoms referable to the defect. There was to be no
residual interatrial shunt. In addition, the entry criteria
for the control group were also applied. Children were
excluded if there were associated defects such as atrioventricular valve anomalies, pulmonary outflow tract
narrowing, right ventricular muscle bands or a patent
arterial duct. Forty-four children were identified, 27
were traceable (15/44 lived abroad) and 22/27 agreed to
participate. Subject details are summarized in Table 1.
All children had their height, weight, two site
skinfold thickness and pubertal stage assessed. Resting
lung function (Compact Vitallograph, Lenexa, Kansas,
U.S.A) was also measured according to American
Thoracic Society standards'61.
up and then forwards, at 25 W . m 2, increasing in
1 5 W . m ~ 2 increments every 3 min until exhaustion.
During the last 20 s of each 3 min stage, children performed a 12 s rebreathing manoeuvre whilst continuing
to pedal. At exhaustion, children stopped pedalling but
remained on the bicycle for a further 9 min performing
three further 12 s rebreathing manoeuvres. During the
initial rest, exercise and recovery phases, continuous
mixed expired gas analysis was undertaken when the
subjects were not performing rebreathing manoeuvres.
A typical study lasted 75 min during which the child
performed 12-16 rebreathing manoeuvres.
During the study the subject had continuous
pulse rate and arterial saturation measured using a
surface oximeter (Nellcor, Hayward Ca., U.S.A) placed
over the right supraorbital artery.
Respiratory mass spectrometry
Protocol
This has been fully described previously17'. Briefly,
following a 1 h fast, anthropometric and spirometric
measurements were obtained. The subjects then practised with the mass spectrometry equipment, rested
for lOmin and then performed, seated, five 20 s rebreathing manoeuvres (bag volume: 40% of predicted
vital capacity) from functional residual capacity, every
3 min for 15 min.
After the resting measurements, the subject
exercised using an electromagnetic bicycle (Seca 100,
Birmingham, U.K.). After a 3 min rest, the subject
performed a 12s rebreathing manoeuvre, and then
began cycling, initially backwards at zero load to loosen
An Innovision 2000 quadrupole mass spectrometer
(Odense, Denmark) was used to sample the subjects
ventilated gas and analyse it on the basis of its
massxharge ratio. The hardware and physiological
measurements are fully described elsewhere'710^16'. 0-3%
acetylene was used to measure effective pulmonary
blood flow and helium was the dilution gas used to
measure the ventilatory parameters'15161.
Analysis
All traces were visually checked to ensure the correct
point of complete mixing of the rebreathing and lung
Eur Heart J, Vol. 18, November 1997
1818 M. Rosenthal et al.
Workload (W.m"
Figure 1 Effective pulmonary blood flow z score (mean; 95%
confidence interval vs workload ( W . m ~ 2 ) for healthy children
( T ) and those after an atrial septal defect repair (A).
gases, and to exclude pulmonary recirculation. Only the
middle 40% of the exhaled breath was analysed as this
best represents alveolar gas concentrations'71.
The healthy controls were used to derive age,
surface area and sex-determined mean results for all
the parameters at rest and during each exercise stage.
Resting values were the average of the last three
rebreathing measurements'101. Children were divided
into four age groups (8-10-5, 10-6-12-5, 12-6-14-5 and
> 14-5 years) and three pubertal groups: pre, early and
late puberty based on Tanner stages 1, 2-3 and 4-5,
respectively. From these normal results, z scores were
calculated such that for all control children taken
together, their mean z score for any parameter during
rest or any stage of exercise was 0 with an SD of 1. Thus,
during exercise, even though all raw parameter values
may increase in the control group, their mean z score
remains zero. A deviation from mean zero in a patient
group during exercise is interpreted as the patient group
failing to match the changes expected rather than an
absolute or fall in that parameter. This methodology
allows comparison of the atrial septal defect group
corrected for gender, age, surface area and pubertal
stage.
The maximum work performed by the patients
was expressed as a percentage of the median maximum
work performed by each control sex and age group.
Z-score differences within each patient group
were analysed using a two-way ANOVA with the subject
as a blocking variable and Bonferroni's correction for
multiple contrasts and / > <005 rejected the null hypothesis. Z-score differences between patient groups at each
rest and exercise stage were analysed using the unpaired
student t-test and /><0-05 rejected the null hypothesis.
This methodology was used to strike a balance between
the effects of multiple contrasts and the maximum
reduction in the residual variance.
Eur Heart J, Vol. 18, November 1997
Results
There was no differences in height z score (control: mean
0-43, 95% confidence interval 0-24 to 0-63; atrial septal
defect: - 0 0 9 , -0-55 to 0-36) or mean skinfold thickness z score (control: mean 0-73, 95% confidence interval
0-58 to 0-89; atrial septal defect: 0-40, 0-1 to 0-7) between
controls and the disease group. This suggests that their
lean body mass is similar.
In children with a surgically corrected atrial
septal defect, the effective pulmonary flow (Fig. 1),
similar to controls at rest, was higher than controls
at all stages of exercise. At rest this blood flow difference amounted to approximately 0-2 1. min" ' . m~ 2
2
and
rising to 0-61 min ' . m
by 55 W . m "
at 70 W . m . In addition, there
111. min"
m
was a significant positive relationship between blood
flow z score and length of follow up (/><003, 23%
explained variance) but not with age at surgery. Heart
rate (Fig. 2), initially marginally higher at rest, demonstrates mild chronotropic incompetence with exercise, at
55 W. m~ 2 the discrepancy being 12 beats. min~'. As
a result, the stroke volume (Fig. 3) in these atrial septal
defect treated children deviated progressively from
normal such that at 55 W . m ~ 2 their stroke volume was
4-5ml" ' . beat. m~ 2 greater than controls. Time from
surgery contributed 29% of the variance of stroke
volume (P<001, Fig. 4) thus, the greater the time
from surgery, the greater the stroke volume. There was
no relationship between the degree of chronotropic
incompetence and length of follow-up, age at testing or
age at repair. As oxygen consumption mirrored the
change in effective pulmonary blood flow (Fig. 5), there
was no difference in arteriovenous oxygen difference
between the groups (Fig. 6).
There was no significant difference in the
anaerobic threshold z score (control: mean 000, 95%
Atrial septal defects and age at repair
1819
0.8
0.6 —
0.4 -
o
0.2 -
T-
0.0
-0.2 -
x
1
-0.4 -
1
-0.6 -0.8
N=
1
102 22
Rest
1
103 22
103 22
25
40
Workload
1
96 20
55
1
70 13
70
Figure 2 Heart rate z score (mean; 95% confidence interval vs
workload (W. m"2) for healthy children (T) and those after an
atrial septal defect repair (A).
1.5
£ 1.0
d
2 0.5
1
s
B
£ o.o
1
N = 103 22
Rest
1
1
103 21
103 22
96 20
25
40
55
Workload (W.nT2)
1
70 13
70
Figure 3 Effective stroke volume z score (mean; 95% confidence
interval vs workload (W.m~ 2 ) for healthy children (T) and
those after an atrial septal defect repair (A).
confidence interval — 0-2 to 0-2; atrial septal defect:
0-43, - 0 1 7 to 104, P=00S) though the trend was for
post-atrial septal defect children to have a higher
threshold. There was a significant relationship between
anaerobic threshold z score and age at testing (Fig. 7)
but not age at or time from surgery. The equation: z
score = 5-36-0-39 (age at testing, years) explained 43% of
the variance (P<00006).
Maximum exercise performance was no different
to controls and bore no relation to either age at or time
from surgery.
Discussion
This study is the first systematic investigation of cardiopulmonary haemodynamics in patients after closure of
an atrial septal defect. We used mass spectrometry to
assess effective pulmonary blood flow during graded
exercise and our results show important differences to
previously published data obtained using different techniques. In this study, maximum exercise performance
was indistinguishable from normal regardless of age at
surgery or duration of follow-up. In addition, age at
Eur Heart J, Vol. 18, November 1997
1820 M. Rosenthal et al.
4
6
Follow-up (years)
10
12
Figure 4 The relationship of effective stroke volume z score to duration
of follow-up after correction of a secundum atrial septal defect. This
relationship is after completing 3 min of exercise at 40 W . m ~ 2 (9 min
exercise in total). /><001; r2 = 0-2886.
-0.5
N=
103 22
Rest
Workload (W.irf)
Figure 5 Oxygen consumption z score (mean; 95% confidence
interval vs workload ( W . m ~ 2 ) for healthy children ( • ) and
those after an atrial septal defect repair ( • ) .
surgery could not be shown to affect any haemodynamic
parameter of performance, rather it was follow-up and
age at testing that influenced haemodynamics. This does
not confirm the findings of Reybrouck et a/.[4' who
demonstrated a lower ventilatory threshold (a difficult
parameter to obtain in children) in those operated after
the age of 5 years. In contrast to Reybrouck et al's
study, the anaerobic threshold, which precedes the ventilatory threshold demonstrated a trend to be greater
than normal and there was a relationship between
anaerobic threshold and age at testing rather than age
at, or time from surgery. Furthermore, children with
treated atrial septal defects in our study had a higher
effective pulmonary blood flow both at rest and during
exercise. We, like Reybrouck et al., found mild chronotropic incompetence, however, and so there was a markedly increased effective stroke volume after atrial septal
defect repair. As the chronotropic incompetence did not
Eur Heart J, Vol. 18, November 1997
significantly vary with follow up, the rise in pulmonary
blood flow for a given exercise load is therefore due to
an increasing stroke volume.
Epstein et a/.[l8], studying healthy corrected atrial
septal defect patients (youngest 14 years) demonstrated
a reduction in the rise in cardiac output (measured using
peripheral arterial and pulmonary arterial oxygen concentrations) during exercise due mainly to a failure to
augment the stroke volume. PeterssonII9) reported
that although cardiac output was low normal at rest, it
rose in proportion to exercise and therefore remained
low normal with a raised arteriovenous oxygen difference. The results of this study are difficult to interpret
however as the author did not compare their results with
contemporary normal data obtained with the same
technique.
The mechanism for the findings in our study are
unclear. One important possibility are problems with the
Atrial septal defects and age at repair
1821
-0.1
N = 103 22
Rest
Workload (W.nT
Figure 6 Arteriovenous oxygen difference z score (mean; 95%
confidence interval vs workload (W . m ~ 2 ) for healthy children
( T ) and those after an atrial septal defect repair (A).
10
12
14
Age at testing (years)
16
18
Figure 7 Relationship of anaerobic threshold z score to age at testing in
22 children following repair of a secundum atrial septal defect.
/»<00006; r 2 =0-456.
matching of the control and atrial septal defect children,
i.e. atrial septal defect children may be more sedentary
and thus require a higher oxygen consumption and
effective pulmonary blood flow at a given exercise load.
Control children were recruited 'for a study examining
the way the heart and lungs work together' and not to
assess athleticism, and we avoided recruits from athletic
clubs. Not all control children (15%) owned a bicycle
and all lived in inner London which may bias the control
population towards sedentary behaviour. In contrast,
the atrial septal defect children all owned bicycles and
most lived outside London in more rural areas which
may bias this group towards athleticism or at least
counteract the negative psychological effects of having
congenital heart disease. Age at detection of an atrial
septal defect murmur is influenced by many factors
other than the presence of symptoms. It is also possible
that the children treated at a young age had more
symptoms or had easier access to better health care
services and it was not possible to match patients so
that left to right shunts were equal. All studies were
performed under identical conditions by a single
investigator (M.R.) in an albeit non-formal random
order. We therefore believe that the observed differences
are not due to experimental error.
The finding of a trend towards a raised anaerobic
threshold in atrial septal defect children points towards
superior athleticism in atrial septal defect children, but
is at odds with the increased oxygen requirement,
increased pulmonary blood flow but similar arteriovenous oxygen differences to controls at a given workload. This combination points to an increased oxygen
requirement by skeletal muscle in atrial septal defect
children, which is serviced by a raised pulmonary blood
Eur Heart J, Vol. 18, November 1997
1822 M. Rosenthal et al.
flow. That no differences in arteriovenous oxygen difference occurs implies that the circulation is better able to
supply oxygen to the skeletal muscle in atrial septal
defect than control children, again going along with
superior cardiovascular fitness. This may be a legacy of
the pre-operative abnormal circulation. The reduced
pre-operative systemic circulation may alter skeletal
muscle metabolism to improve oxygen extraction. Postoperatively these mechanisms may persist in a setting
where the systemic circulation is now near normal. The
ability of the circulation to now supply the muscle's
increased oxygen needs is now met by persisting changes
in right ventricular performance and size rather than
increased oxygen extraction. In the early follow-up
period, this superior supply is sufficient to keep the
anaerobic threshold higher than normal but with
increasing follow-up this benefit is progressively lost
(Fig. 7) and with this falling anaerobic threshold, the
stroke volume and pulmonary blood flow rise in compensation to maintain skeletal muscle oxygen supply.
This mechanism must remain speculative, however;
nonetheless, indirect evidence in support of this comes
from Meyer et al.[20] who demonstrated increased right
ventricular dimensions and abnormal septal motion in
>90% of patients preoperatively. Post-operatively, their
children showed an early reduction in right ventricular
size although not to normal, and it remained increased
5 years post-operatively as did the left ventricular
shortening fraction. Indeed there was a trend for both
parameters to return to pre-operative values by 5 years
follow-up. Haemodynamic changes may even begin
before birth. Wagenvoort et al.[2X] in support of this,
reported that the medial surface area index (ratio of the
pulmonary arterial medial smooth muscle surface area
to the lung parenchymal surface area) was markedly
raised in fetuses found to have atrial septal defects
although it is difficult to envisage the fetal haemodynamic differences of a patent foramen ovale and
secundum atrial septal defect as being more than minor.
Whatever the mechanism, the clinical importance of our data is clear; correction of an asymptomatic
secundum atrial septal defect before the age of 5 years
confers no medium term physiological advantage with
regard to exercise although the psychological effects of
delay and the risks of late arrhythmias are factors in
considering the timing of closure. With these caveats,
our findings are reassuring for atrial septal defect
patients who may already have been waiting several
years for transcatheter closure.
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