(Circulation. 2000;102:III-154.)
© 2000 American Heart Association, Inc.
Surgery for Congenital Heart Disease |
Failure of Stroke Volume Augmentation During Exercise and Dobutamine Stress Is Unrelated to Load-Independent Indexes of Right Ventricular Performance After the Mustard Operation
From the Great Ormond Street Hospital for Children (G.P.D., P.A.W., D.J.P., A.N.R.), Whipps Cross Hospital (I.N.), and Royal Brompton Hospital (A.K., A.B.), London, UK.
Correspondence to Professor Andrew Redington, Paediatric Cardiology Department, Great Ormond Street Hospital for Children, 28 Great Ormond St, London WC1N 3JH, UK. E-mail reding{at}ibm.net
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Abstract |
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Background—Impaired right ventricular function has been implicated as a cause of reduced maximal exercise capacity after the Mustard operation for transposition of the great arteries.
Methods and Results—Fourteen asymptomatic survivors of the Mustard operation were studied. Each underwent conventional cardiac catheterization, and after satisfactory hemodynamics were confirmed, load-independent indexes of ventricular function were derived by conductance catheter during dobutamine infusion (0, 5, and 10 µg · kg-1 · min-1). Seven patients also underwent upright exercise testing on a bicycle ergometer with analysis of respiratory gas exchange by continuous mass spectrometry. Accessible pulmonary blood flow was measured at each workload with an automated acetylene rebreathing technique. All patients exercised to a satisfactory end point (respiratory quotient >1.1). Maximum oxygen consumption during exercise was impaired compared with predicted values (mean, 77%; P<0.02). Both exercise and dobutamine infusion were associated with an increase in cardiac index and heart rate and a reduced stroke volume index response. This was despite significantly improved indexes of myocardial contraction (end-systolic pressure volume relation, P<0.001), preload recruitable stroke work index (P<0.01), VA coupling (P<0.001), and isovolumic relaxation (P<0.001) during dobutamine infusion. There were no changes observed in end-diastolic pressure-volume relations, but there was failure to augment ventricular filling manifest by absence of change in dV/dt (P=NS).
Conclusions—The stroke volume response to exercise stress is reduced in patients after the Mustard operation. A similar failure to augment stroke volume occurs during dobutamine stress despite appropriate responses in load-independent indexes of contraction and relaxation. This is due to failure to augment right ventricular filling rates during tachycardia, presumably as a result of impaired AV transport, consequent to the abnormal intra-atrial pathways.
Key Words: transposition of great vessels • hemodynamics • exercise
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Introduction |
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The development of atrial redirection procedures (the Mustard and Senning operations) revolutionized the care of patients with transposition of the great arteries.1 2 Although these procedures have largely been superseded by the arterial switch operation, there remains a large cohort of young adults who underwent atrial redirection in childhood. There are a number of concerns regarding the long-term outcome in this patient group. Baffle obstruction,3 systemic right ventricular (RV) dysfunction,4 5 exercise intolerance,6 7 8 and increased risk of arrhythmia and sudden death9 have all been reported. Impaired function of the systemic RV has been inferred from the almost-uniform findings of increased RV volumes and decreased ejection fraction in midterm survivors.4 5 10 Our own data have shown that segmental wall motion abnormalities are common in these patients and are related to global RV dysfunction and preoperative damage.11 It has also been suggested that these abnormalities of RV function may underpin the impaired exercise tolerance.7 8 However, although one recent study showed a reduction in stroke volume in response to exercise and concluded that this implied ventricular dysfunction,8 the few available data suggest that measurements of RV volumes and ejection fraction do not predict either functional performance or the likelihood of late deterioration.5 Furthermore, volumetric indexes are flawed by their dependence on preload and afterload conditions. A detailed analysis of load-independent indexes of RV systolic and diastolic performance, the degree of contractile reserve of the systemic RV, and their relationship to exercise performance has yet to be performed.
The objectives of this study were to study the hemodynamic responses to exercise and dobutamine stress in patients after the Mustard operation to assess the amount of contractile reserve of the systemic RV and to investigate the possible relationship between exercise and RV dysfunction.
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Methods |
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The study design was approved by the Institutional Ethics Committee. Informed consent was obtained for 14 late survivors of the Mustard procedure. Demographic data are summarized in the Table
. Original medical records were
unavailable for 2 patients. The intra-atrial baffles were constructed
from glutaraldehyde-treated autologous pericardium,
bovine pericardium, dura mater, or Dacron using the modification of
Brom. Eight patients were recruited during an admission for elective
catheterization as part of the unit policy for
surveillance at late follow-up, and 6 patients were being investigated
because of clinical suspicion of baffle stenosis (n=4) or
because of recent onset of arrhythmia (n=2). All patients were
otherwise well and in sinus rhythm at the time of the study.
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Exercise Testing
A subgroup of 7 patients underwent detailed exercise testing to
ensure that the performance of our study group was
representative of previously published data on exercise
performance. An electromechanically braked exercise bicycle
(SECA 100) was adjusted for the individual size and comfort of each
subject. After a period of rest and familiarization with the equipment,
a resting recording was made. Thereafter, pedaling was begun
while subjects were encouraged to maintain a speed of 50 to 70 rpm.
Workload began at 25 W/m2 and increased by 15
W/m2 every 3 minutes. Basic monitoring included
heart rate (HR) and peripheral transcutaneous oxygen
saturation (Nellcor). Continuous respiratory mass spectrometry (Amis
2000, Innovision) was used for metabolic measurements, with
subjects breathing orally through a mouthpiece into the instrument
while wearing a nose clip. Mean accessible pulmonary blood flow
was measured with the mass spectrometer using an automated acetylene
rebreathing technique during the last 30 seconds of each workload. This
noninvasive technique measures the absorption of 0.3% acetylene from a
closed system and has been validated in our laboratory.12
Exercise testing was performed to maximum volition, confirmed by a
respiratory quotient >1.1.
Invasive Measurements
Cardiac catheterization was performed while
subjects were under a general anesthetic in all cases. Full
conventional diagnostic catheterization and
angiography were performed, followed by balloon dilatation of
significant baffle stenosis (>3 mm Hg mean gradient,
n=6). Patients were included in the subsequent research study if there
were no residual resting hemodynamic abnormalities,
including baffle stenosis or shunts.
Study Preparation
The existing arterial and venous valved introducer
sheaths were used for access to the vasculature. Figure 1 shows a radiograph of the study
preparation.
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A standard 7F balloon-tipped thermodilution catheter (Baxter Healthcare) was advanced into the pulmonary artery for measurement of cardiac output and connected to a dedicated cardiac output processing computer (Com 2, Baxter Edwards). The appropriate manufacturer’s computation constant was entered into the processing unit to allow for predicted changes in injectate temperature from injectate port to catheter exit hole. A latex occlusion balloon (Boston Scientific) was advanced to the junction of the inferior caval vein and the systemic venous atrium and prepared for inflation with carbon dioxide for preload reduction.
A custom-built integrated conductance and Mikro Tip pressure catheter (Millar Instruments) was placed retrograde arterially into the apex of the RV. The conductance electrodes were connected to a signal conditioning and processing unit (Sigma 5DF, Cardiodynamics Corp). The analog volume signal from the Sigma 5DF signal processor, the amplified pressure signal (modified Fylde Isotransducer Amplifier), and the surface ECG signal were all digitized simultaneously by an analog-to-digital converter (Data Translation Ltd) in a customized personal computer running customized software. Digital data were stored for offline analysis.
Protocol
Our protocol for both left
ventricular13 and RV14
pressure-volume relationships using a conductance catheter has been
described in detail elsewhere. Briefly, blood resistivity was measured
from a 5-mL sample of blood drawn from an in-dwelling line for
calibration of the Sigma 5DF signal processing unit.
After steady-state conditions were confirmed, ventilation was stopped at end expiration, and RV pressure and volume were measured during injection of 7 mL of 10% sodium chloride into the pulmonary artery to calculate parallel conductance.15 Ventilation was restarted, and after recovery, with ventilation held at end expiration, hemodynamic recordings were made during preload reduction by inflation of the occlusion balloon.
Cardiac output was measured by a 10-mL cold saline bolus injection into
the injectate port of the thermodilution catheter, and derived cardiac
output was used to compute the gain constant (
=conductance cardiac
output/thermodilution cardiac output). The measurements were repeated
during dobutamine infusion (5 and 10 µg ·
kg-1 ·
min-1). The response to
dobutamine infusion was deemed to be at steady state after
10 minutes or when the HR had reached a new plateau.
Data Analysis
Pressure-volume loops recorded during preload reduction were
analyzed offline to derive 2 load-independent indexes of
contractility, the end-systolic pressure-volume
relation (ESPVR) and preload recruitable stroke work index (PRSW).
Similarly, a load-independent diastolic index was derived
from the linear function of the end-diastolic
pressure-volume relation (EDPVR). An index of VA coupling was
calculated as the ratio between effective arterial
elastance (Ea) and end-systolic elastance (Ees). In addition,
the time constant of isovolumic relaxation (
) was measured from a
monoexponential fit to the pressure decay curve. The
peak diastolic ventricular filling rate was
obtained by the first differential of the volume-time signal averaged
over 5 steady-state cardiac cycles.
Statistical Analysis
Repeated 1-way ANOVA was used to test the effect of
dobutamine infusion on hemodynamic indexes,
with the null hypothesis rejected if P<0.05.
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Results |
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All data presented below are expressed for the entire group. There were no obvious trends toward a relationship between demographics, operative data, previous interventions, and functional results, although clearly a formal subset analysis was not possible.
Exercise
All subjects exercised to a satisfactory end point. This was
defined by arbitrary criteria of maximal aerobic capacity (respiratory
quotient >1.1).16 Median±SD maximum workload was
70±10.4 W/m-2, with only
1 subject falling short of predicted workload. However, maximum oxygen
consumption was impaired (30.5±7.6 mL ·
min-1 ·
kg-1; mean, 77% of
predicted for age and sex17 ; P<0.02).
During exercise, HR increased by 103±12 bpm
(P<0.0001) to a maximum predicted HR of 62.8% to 92%
(mean, 82.7%; P<0.005). Cardiac index increased by
6700±1600 mL/min (P<0.005; Figure 2). After an early rise in stroke volume
index of a mean of 13.8±18 mL ·
min-1 ·
m-2, all patients showed a
progressive fall by 18.5±8.46 mL/m2 as workload
increased.
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Dobutamine Infusion
A similar response was observed during dobutamine
infusion. There was a progressive increase in HR of 47±20 bpm
(P<0.001) and an increase in cardiac index of 920±681
mL · min-1 ·
m-2 (P<0.001).
However, dobutamine infusion was associated with a
progressive fall in stroke volume of 7.4±10.6 mL ·
min-1 ·
m-2 (P<0.05)
as HR increased.
Despite the reduction in stroke volume index during
dobutamine infusion, RV contractility was
augmented. Figure 3 shows typical
examples of the hemodynamic responses. This was
manifest (Figure 4) by increases in ESPVR
of 2.03±0.88 mm Hg/mL (P<0.0001) and PRSW of
64.85±52.3 erg/mL · 103
(P<0.001). Furthermore, the ratio of Ea to Ees was reduced
from 3.47±0.48 to 1.40±0.23 (P<0.0001), suggesting
improved VA coupling. The rate of isovolumic relaxation was enhanced by
dobutamine infusion so that was reduced by 23.28±6.91
s-1
(P<0.0001), and there was no change in the slope of the
EDPVR. However, the ventricular filling rate, dV/dt, failed
to increase.
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There were no differences in dobutamine responses when the subset of 7 patients who underwent exercise testing was compared with the rest of the group; furthermore, no relationships were found between indexes of RV function and exercise performance.
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Discussion |
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The almost universal finding of a dilated RV with reduced ejection fraction has been taken as a manifestation of the inadequacy of the RV to perform as the systemic ventricle after the Mustard operation. Furthermore, this dysfunction has been implicated in the similarly universal finding of reduced exercise capacity in these often asymptomatic patients. There can be no doubt that RV function may be "abnormal," but the impact of the RV dilatation and reduced myocardial shortening on functional performance is far from clear. These features may merely reflect a "normal" response of the systemic RV to its afterload, and it is no surprise that there is little7 or no18 direct relationship between these indexes and exercise performance. In this study, we confirmed a failure to maintain an increased stroke volume as the primary hemodynamic abnormality at peak exercise at a time when it would be expected to be
40% higher than resting
values.19 Although cardiac output rose, the HR response
was disproportionate, leading to a progressive fall in stroke volume
during exercise-induced tachycardia. A similar response was seen during dobutamine infusion. The expected 33% increase in stroke volume during infusion of 10 µg · kg-1 · min-120 was not seen in our patients. Indeed, there was a fall in stroke volume index of 19% at maximum stimulation. Although representing a different cardiovascular stress compared with exercise (when for example increased preload is expected), the similarity in response, with a fall in stroke volume at higher HRs, is compelling.
Our study is unique in measuring load-independent indexes of RV performance and confirms that abnormal myocardial mechanics cannot be invoked as a mechanism for these abnormal stroke volume responses.
Load-independent indexes of systolic contraction (ESPVR, PRSW) showed an appropriate increase with higher dobutamine doses, suggesting that there was an appropriate RV myocardial contractile reserve.
Effective arterial compliance incorporates the principal elements of vascular load, including peripheral resistance, vascular compliance, characteristic impedance, and systolic and diastolic time intervals. The ratio of Ea to Ees describes the efficiency of power transfer during ejection from ventricle to aorta. This ratio, which in optimum conditions would equal unity,21 showed an appropriate fall toward this value, suggesting that dobutamine, in addition to enhancing RV contractile performance, also improved coupling.
Similarly, there is little evidence of abnormalities of
myocardial mechanical performance during diastole.
Isovolumic relaxation was enhanced, as shown by the steep fall in ,
and the magnitude of this change is comparable to previously reported
values at this dobutamine dose.22 Furthermore,
the slope of EDPVR, a load-independent index describing the inherent
elastic and distensible properties of the RV, did not change during the
study period, confirming that there were no changes in compliance of
the ventricle.
The most obvious abnormality, however, was the lack of change in ventricular filling rate, dV/dt. The doses of dobutamine used in this study have been shown to cause a 30% increase in ventricular filling rate22 in normal human hearts. Therefore, it is not surprising that stroke volume falls under the circumstances of reduced diastolic filling time and constant filling rate. The mechanism for failure of augmentation of filling rate must remain speculative, but in the absence of other abnormalities of diastolic function, it is likely that the capacitance and conduit function of the abnormal, often calcified, intra-atrial pathways may be responsible even in our patients proven to have no evidence of stenosis at rest. If correct, then the implications for those with truly stenotic pathways, coexisting left ventricular or RV systolic or diastolic abnormalities, or pathological tachyarrhythmia are clear. Further studies are required to assess the impact of this physiology during, for example, atrial flutter, but it is easy to construct a hypothesis to support the potential malignant effect of inappropriate tachycardia on stroke volume, cardiac output, and ultimately the incidence of sudden death.
Study Limitations
Our data use conductance catheters to derive load-independent
indexes of ventricular function. Although not specifically
validated for use in the systemic RV, the method is relatively
independent of ventricular morphology and geometry and has
been validated and refined by our group and others in a variety of
pathological morphological and physiological
states.13 23 There are few alternative techniques enabling
measurement of load-independent indexes of ventricular
function. Ultrasonic sonomicrometry is inapplicable outside the
operating theater. Quantitative echocardiographic
analyses, including wall stress
analysis,24 involve geometric assumptions that are
suspect in congenital heart disease. The presence of incoordinate
contraction or hypertrophy serves to increase potential
errors of these noninvasive techniques. The conductance catheter
technique overcomes these considerations by measuring chamber volume as
time-varying conductance of the blood pool contained within the
chamber. Measurements were diligently calibrated with measurements of
blood resistivity and parallel conductance. In addition, the
dimensionless gain constant () relating conductance-derived volumes
to a reference method was applied to account for electric field
inhomogeneity resulting from changes in ventricular size
and geometry. Thus, errors in measurement were minimized and internally
constant.
The subjects of this study were all survivors of the Mustard operation. During this operation, pericardial, dural, or Dacron baffles were created within the atrial chamber to redirect venous return. The Senning operation, although introduced earlier than the Mustard operation, was slow to find acceptance in many centers. However, the Senning procedure uses native atrial tissue to create intra-atrial baffles with a minimum of foreign material and is less susceptible to the development of baffle stenosis.25 It is possible that the pathways created in the Senning operation will prove to be less restrictive to a higher demand for blood flow, and this clearly requires further study.
Conclusions
These data suggest that the major factor limiting the increase in
cardiac output and stroke volume in response to exercise and
pharmacological stress late after the Mustard operation is most likely
to be impaired AV transport. This presumably reflects anatomical and
functional abnormalities of the AV pathways, which may be amplified by
coexisting baffle stenosis or ventricular disease.
There may also be implications for the cardiovascular
responses of patients during pathological tachycardia,
because it is likely that ventricular filling is even more
compromised above a critical HR.
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Acknowledgments |
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We would like to thank the British Heart Foundation for their generous research support. Dr Derrick is supported by a British Heart Foundation Project Grant (PG 98176).
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