(Circulation. 1995;91:372-378.)
© 1995 American Heart Association, Inc.
Articles |
From the Departments of Paediatric Respiratory Medicine (M.R., A.B.) and Cardiology (A.R.), The Royal Brompton National Heart and Lung Hospital, and the Cardiothoracic Unit, The Hospital for Sick Children (J.D.), London, U.K.
Correspondence to Andrew Redington, The Royal Brompton National Heart and Lung Hospital, Sydney Street, London SW3 6NP, UK.
| Abstract |
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Methods and Results Forty-three children were studied more than 6 months after undergoing a Fontan procedure (23 AP and 20 TCPC); 106 healthy children were also studied as a control group. Measurements of effective pulmonary blood flow, stroke volume, arteriovenous oxygen difference, minute ventilation, heart rate, and oxygen and carbon dioxide consumption were made with an Innovision quadrupole mass spectrometer. Data from the control group allowed calculation of z scores for the Fontan groups matched for age, sex, pubertal stage, and body surface area. Maximal exercise performance was equal in the two Fontan groups, but it was below normal. However, adaptation to exercise was different in the Fontan groups. After 9 minutes of exercise, pulmonary blood flow rose less in the AP group than in the TCPC group (P<.01), and the stroke volume in the AP group also tended to be lower (P=.057) and their arteriovenous oxygen difference was significantly greater (P<.01). Although minute ventilation per unit of carbon dioxide production was similar in the Fontan groups at this level of exercise, children in the TCPC group breathed faster by approximately 10 breaths per minute (P<.005).
Conclusions At submaximal exercise, children who had undergone the TCPC Fontan procedure had pulmonary hemodynamics superior to those of children who had undergone the AP procedure, largely because of respiratory adaptation that permitted blood to be "sucked" into the lungs. To achieve the same maximal exercise performance, children who had undergone the AP procedure had a superior metabolic adaptation to exercise stress.
Key Words: surgery pediatrics spectrometry exercise
| Introduction |
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| Methods |
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Each child had his or her height and weight measured with a Harpenden stadiometer (Holtain Ltd) and electronic scales (SECA), respectively. In addition, the stage of puberty was assessed,13 two-site skinfold measurements (triceps and subscapular) were made with a Holtain skin caliper (Holtain Ltd), and three flow-volume loops were measured (Compact Vitallograph), the best being documented according to American Thoracic Society standards.14
Protocol
After local ethical committee approval was given and
written
informed consent from each subject's parents was obtained, a standard
protocol was used for all children. They arrived at the laboratory
having fasted for 1 hour. After anthropometric and flow-volume loop
measurements were made, the children practiced with the equipment. Once
they were confident with the technique involved, they rested for 10
minutes and then performed, from functional residual capacity, five
20-second rebreathing maneuvers every 3 minutes for 15 minutes; a
metronome was used to control the respiratory rate to 40 breaths per
minute. The rebreathing bag (with a volume of 40% of predicted vital
capacity17 ) contained 35% oxygen, 5% sulfur
hexafluoride, 0.3% acetylene, and 0.3% carbon monoxide labeled with
18O. The balance was nitrogen. At 0.3%, acetylene gives
repeatable results15 and is both odorless and
nonexplosive. Functional residual capacity was determined with a
calibrated pneumotachograph linked to a pair of pneumatic valves that
automatically switched breathing from room air to the rebreathing bag.
During the maneuvers, the continuous pulse rate and arterial saturation
were measured with a surface oximeter (Nellcor) placed over the right
supraorbital artery.
After the resting measurements were made, the subject exercised on an electromagnetic bicycle (Seca 100), electrically calibrated before every study, that produced a constant workload independent of pedal speeds over the range of 6 to 150 rpm. After a 3-minute rest, the subject performed a 12-second rebreathing maneuver (the shortened time ensured that carbon dioxide did not build up sufficiently during rebreathing to cause distress during exercise) and then began cycling, initially backward at zero load to loosen up and then forward at 25 W/m2, increasing in 15-W/m2 increments every 3 minutes until exhaustion. During the last 20 seconds of each 3-minute stage, the subject performed a 12-second rebreathing maneuver while continuing to pedal. For consistency, the child was encouraged to pedal at a rate between 50 and 70 rpm during the entire duration of exercise. At exhaustion, the child stopped pedaling but remained on the bicycle for 9 more minutes, performing three more 12-second rebreathing maneuvers. During the initial rest, exercise, and recovery phases, continuous mixed expired gas analysis was undertaken when the subject was not performing rebreathing maneuvers. A typical study lasted 75 minutes, during which time the child performed 12 to 16 rebreathing maneuvers.
Respiratory Mass Spectrometry
Mass spectrometry is used to
measure the fractional
concentrations of the components of a gaseous mixture on the basis of
their mass-to-charge ratio alone.16 An Innovision 2000
quadrupole mass spectrometer was used to continuously sample each
subject's ventilated gas at a rate of 5 mL/min down a 0.2-mm-ID Teflon
tubing. The individual components of the gas were analyzed
semicontinuously, with each component gas requiring a minimum of 5
milliseconds for analysis, the data from the first 2 milliseconds
being discarded to eliminate errors due to machine equilibration.
During the study, each gas was analyzed for at least 10 milliseconds;
acetylene and carbon monoxide were analyzed for 15 and 20 milliseconds,
respectively. All gases in this study were therefore measured at least
9.7 times per second. The delay from sampling to measurement was 450
milliseconds. The stable isotope of carbon monoxide, CO labeled with
18O, was present to measure transfer factor, but those
data are not part of the present study. During the exercise study
of each subject, the device underwent a two-point calibration three
times, by exposure to both a calibration gas and zero gas (vacuum), and
a one-point calibration at least eight times. The mass spectrometer was
controlled with an IBM clone PC 386DX with a coprocesssor to ensure
rapid data handling during the rebreathing maneuvers, and the results
were downloaded and analyzed by customized software.
The physiological measurements and equations are detailed in the "Appendix." During rebreathing, the absorption of acetylene was used to calculate the effective pulmonary blood flow in contact with ventilated alveoli,17 18 19 20 21 and the absorption of oxygen was used to measure oxygen consumption. With the Fick equation, the ratio of oxygen consumption to pulmonary blood flow can be used to calculate the arteriovenous oxygen content difference. Helium-dilution mixedexpired gas analysis22 allows calculation of oxygen consumption, carbon dioxide production, minute and alveolar ventilation, and the anaerobic threshold.23 The maximum work performed by the patients was expressed as a percentage of the median maximum work performed for each sex and age group.
Analysis
All traces were visually checked to ensure that the
software had
both determined the point of complete mixing of the rebreathing and
lung gases and excluded pulmonary blood recirculation. This was
determined to have occurred correctly in 2933 of 2943 measurements. The
first 40% of each expired breath was excluded from data analysis
because it is composed largely of dead-space gas. The last 20% was
also excluded because it represents underventilated lung elements.
Data from the healthy control subjects were used to derive means, corrected for age, surface area, and sex, for all the parameters at rest and during each exercise stage. Resting values were determined from the average of the last three rebreathing measurements at rest.17 Children were divided into four age groups (8 to 10.5, 10.6 to 12.5, 12.6 to 14.5, and more than 14.5 years) and three pubertal groups (pre-, early, and late puberty based on Tanner stages 1, 2 to 3, and 4 to 5, respectively). From these normal results, z scores were calculated so that for the control children, evaluated as a group, the 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 have increased in the control group, the mean z score remained 0. A deviation from a mean of 0 in a patient group during exercise was interpreted as the patient group's failing to match the changes expected rather than as an absolute fall in that parameter.
z
score results are presented as means with 95%
CIs.24 Other results are expressed as medians with 95%
CIs.25 z score differences between patient
groups and control subjects at rest and at each exercise stage were
analyzed by a one-way ANOVA with Duncan's correction for multiple
contrasts; z score differences within each patient group
were analyzed by a two-way ANOVA with the subject as a blocking
variable and Duncan's correction for multiple contrasts; and
z score differences between patient groups at each rest and
exercise stage were analyzed using the unpaired Student's t
test. The null hypothesis was rejected when P<.05. This
methodology was used to strike a balance between the effects of
multiple contrasts and the maximum reduction in the error. Other group
differences were analyzed by the Mann-Whitney U and
2 tests.
| Results |
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Hemodynamics
At rest, effective pulmonary flow was markedly
lower in subjects
who had undergone a Fontan procedure than in control subjects
(P<.001), as expected. There was no significant difference
between the two Fontan groups (AP mean, 2.2
L · min-1 · m-2; TCPC mean,
2.3
L · min-1 · m-2). At 40
W/m2 of exercise (9 minutes of exercise in total), the
increase in effective pulmonary blood flow seen in AP subjects, which
was significantly less than the increase in control subjects
(P=.05), was less than that in the TCPC patients
(P<.01; AP mean, 3.7
L · min-1 · m-2; TCPC mean,
4.8
L · min-1 · m-2) (Fig
1A
). This trend was maintained at 55 W/m2,
but the difference was not significant because of the smaller number of
subjects reaching this workload. Resting heart rate was significantly
higher in both Fontan groups at rest than in control subjects, but the
rise during exercise was less than that in control subjects
(P<.05 for AP, P<.01 for TCPC) (Fig
1B
). At
rest, stroke volume in both Fontan groups was lower than in the control
subjects (P<.0001). The increase in stroke volume during
exercise was slightly greater in the TCPC than in the AP patients, but
the difference just failed to reach significance (P=.057) at
40 W/m2 (Fig 1C
). The difference was approximately 5
mL per
beat per meter squared and was maintained at the next exercise stage.
|
Oxygen Consumption and Arteriovenous Oxygen Difference
Resting oxygen consumption was normal in the AP patients but
significantly lower (approximately 0.01
L · min-1 · m-2) in the TCPC
group
(P<.01) (Fig 2A
). During exercise, oxygen
consumption per unit of work was lower in both Fontan groups compared
with control subjects. This difference was most marked for the AP
patients (P<.01). At rest and throughout exercise, the
arteriovenous oxygen difference was significantly higher in both Fontan
groups compared with controls (P<.001) (Fig 2B
).
Furthermore, the increase in the arteriovenous oxygen difference was
consistently greater in the AP group than in the TCPC group
(P<.01).
|
Ventilation
At rest, both Fontan groups had a minute
ventilation higher
than controls' (P<.01) (Fig 3A
). At low
levels of exercise, minute ventilation in both Fontan groups remained
significantly higher than in the control group, but this difference was
lost at higher workloads. However, the ventilatory pattern was very
different between the two Fontan groups. In the TCPC group, there was a
significant increase in respiratory rate (Fig 3B
) early in
exercise
(P<.03) with a lower tidal volume (Fig 3C
), so that
at 40
W/m2 there was a difference of approximately 10 breaths per
minute. In contrast, the AP patients followed a normal pattern with no
difference in respiratory rate and tidal volume compared with control
subjects.
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The change in respiratory rate in TCPC patients could not be
explained
by increased carbon dioxide production, because both Fontan groups had
the same minute ventilation per unit carbon dioxide production (Fig
3D
). The AP group's anaerobic threshold z score
was
significantly lower than the control group's, but the TCPC group's
was not. In the control group the mean was -0.03 (95% CI, 0.17 to
-0.23); in the AP group it was -0.77 (95% CI, -0.27 to
-1.27;
P<.05); and in the TCPC group it was -0.35 (95% CI, 0.09
to -0.78; NS).
Maximum Exercise Performance
There was no difference in
maximum workload between the two Fontan
groups (Fig 4
); it was subnormal in both compared with
the control group (P<.001). There was no effect of age at
surgery, time from surgery, age at testing, or surgical diagnosis,
although for the Fontan group as a whole, females tended to perform
better than males (P<.07).
|
At maximum exercise, stroke
volume (Fig 5A
) and
effective pulmonary blood flow (Fig 5B
) were both significantly
higher
(P=.05 and P<.001, respectively) in the TCPC
group than in the AP group, but in the TCPC group the arteriovenous
oxygen difference was lower (P<.05) (Fig 5C
). These
differences persisted 6 minutes into recovery. Respiratory rate was
significantly higher in the TCPC group until 3 minutes after exercise
(P<.05) (Fig 5D
).
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| Discussion |
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In the AP group, there was metabolic adaptation even at low workloads. Their cardiac output at rest was lower than in the control subjects, and this difference increased with increasing exercise. Predictably, their anaerobic threshold was lower than in the control subjects, but tissue oxygen extraction was maintained. Consequently, during exercise the AP patients developed a markedly abnormal arteriovenous oxygen difference that was significantly greater than that of TCPC patients or control subjects at all workloads. The mechanism for their relatively high tissue oxygen uptake in the face of reduced oxygen delivery is unclear but is important to their ability to sustain exercise despite a cardiac output significantly lower than TCPC patients'.
The physiological response to exercise in the TCPC group was quite different. These patients had a higher effective pulmonary blood flow with a lower arteriovenous oxygen difference and a respiratory pattern significantly different from that of AP patients. TCPC patients take smaller but more frequent breaths. Although the difference is small (0.01 L · min-1 · m-2), their lower resting oxygen consumption at rest compared with AP patients' is an unexpected finding. Because both Fontan groups had slightly higher heart and respiratory rates at rest compared with controls, a lower resting metabolic rate is an unlikely explanation, although catecholamine levels and thyroid status were not investigated. Methodological bias due to investigator training effects or sequence bias is also unlikely because the children were tested in random order.
We have previously shown that postoperative pulmonary blood flow after
a TCPC procedure is clearly dependent on respiratory
motion.12 Pulmonary blood flow increases during normal
inspiratory effort and is augmented during both the Muller maneuver
(inspiration against a closed glottis)12 and negative
pressure ventilation.26 Although after the AP procedure,
resting pulmonary blood flow is slightly augmented by
respiration,11 the work of breathing appears to be a much
more important energy source for pulmonary blood flow after the TCPC
procedure. The present study indicates that this respiratory
mechanism is also important during exercise. Starting with the onset of
exercise, TCPC patients become relatively tachypneic compared with both
normal subjects and AP patients, and this finding holds at all
workloads. This is not a physiological response to excess carbon
dioxide production (Fig 3D
); it may be an adaptive response to
harness
the energy of the "respiratory pump" to generate pulmonary blood
flow. At maximal workload, the respiratory rates of the Fontan groups
converge, indicating that there may be an optimal respiratory rate
beyond which no further increase in cardiac output is possible.
Experimental studies have indeed shown that the energy efficiency of
the TCPC circulation, by avoiding energy loss due to turbulence, may be
superior to that of the AP connection.3 4
Circulatory adaptation to submaximal workloads is more relevant to ordinary daily life than maximal exercise performance, so even though the two Fontan procedures provide similar maximum performance, the TCPC procedure results in a more efficient circulation, at least in the short term. Nevertheless, this advantage may be lost with even minor pathway obstruction (there was none in our study subjects) because of the lower mechanical reserve in the TCPC group.
If maximal exercise performance is achieved in AP patients by generation of a large arteriovenous oxygen difference, it is difficult for this to be enhanced by exercise training. Exercise performance in some patients who have undergone the TCPC procedure may be limited by an inability to enhance cardiac output by increased respiratory movement. However, they may still be able to increase oxygen extraction and increase their arteriovenous oxygen difference by an exercise training program.
There are unavoidable differences between the study groups. A randomized study comparing the two treatment approaches would be ideal but impractical. Selection criteria and institutional differences lead to an excess of patients with tricuspid atresia in the AP group, whereas the TCPC group includes subjects with more complex intracardiac anatomy. However, a relationship between intracardiac morphology and exercise performance after AP connections6 has not been demonstrated. The interval between Fontan procedure and study participation was slightly greater in the AP group, and there were small differences in length of follow-up between the groups, although length of follow-up was unrelated to performance in this study, confirming the findings of Nir et al.27 The differences in exercise performance are thus likely to be due to the type of surgical connection.
We conclude that, although children who have undergone either the AP or the TCPC Fontan procedure have the same maximum exercise performance, the TCPC procedure, though dependent on respiratory movement, results in a more efficient circulation at exercise levels relevant to ordinary daily life.
| Acknowledgments |
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Effective Pulmonary Blood Flow
The absorption of
acetylene from a closed rebreathing system is
monoexponential and proportional to the pulmonary blood flow perfusing
ventilated
alveoli.17 18 19 20 21
This effective pulmonary flow,
Qeff, in liters per minute, can be calculated with the
equation
![]() |
where
ßAc is the slope of the natural logarithm of
the disappearance of acetylene with time corrected for changes in the
total volume of gas within the lung/rebreathing bag system, which are
calculated from changes in the fractional concentration of a nonsoluble
inert gas (in this study, sulfur hexafluoride).
Fi0 is the volume of the inert gas at the start
of an experiment, and Fieq is the volume of the
gas at equilibrium of the test gas mixture with the subject's lung
gases. VRB is the total volume (in liters) of the test gas
mixture at the start of the experiment; intAc is the
intercept of the disappearance curve of acetylene with time
extrapolated back to time 0 once mixing of the test and native gases
has occurred; PB is ambient atmospheric pressure, measured
in mm Hg; and
b is the solubility constant of acetylene
in blood.
Oxygen Consumption
The absorption of
oxygen from the same closed system is also
monoexponential and can be used in the following equation to calculate
consumption in L/min16 :
![]() |
MixedExpired
Gas Analysis
For helium-dilution mixedexpired gas
analysis,22
a 12-L baffled mixing box is used. The principle is that the addition
of a tracer gas at a known flow rate into the stream of expired gas
from a subject, followed by its remeasurement after perfect mixing,
allows calculation of the flow rate of the expired gas and its
components. The faster the flow of expired gas, the more dilute the
tracer gas becomes. For example, minute ventilation (VE) is
calculated as
![]() |
where VTr is the flow rate of the tracer gas and FTreq is the fractional concentration of tracer gas after complete mixing with the expired gas. The term 1-FTreq is the correction for the addition of tracer gas to the system, and further corrections need to be added to the equation for ambient temperature, pressure, and humidity. In this study, helium was the tracer gas, used at a typical flow rate of 300 mL/min, and the equipment was calibrated for every study with a 3-L syringe (Hans Rudolph Inc). The coefficient of flow variability was always less than 2.5%. In a similar manner, carbon dioxide production can be calculated as well as oxygen consumption.
Received May 2, 1994; accepted August 15, 1994.
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