1 Department of Medicine, 2 Department of Biomedical Engineering and 3 Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
Correspondence and offprint requests to: Eric H. Y. Ie, MD, PhD, Department of Medicine, Erasmus MC, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. Email: e.ie{at}erasmusmc.nl
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Abstract |
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Methods. Routine measurement of ejection fraction (EF) was done before dialysis in 15 patients without significant valvular disease or symptoms of coronary heart disease. Continuous arterial pressure was measured by Finapres, with systolic blood pressure (SBP) as surrogate for LV end-systolic pressure. Simultaneously, LV area was measured using automated border detection. SBP and LV area data were combined online to create pressurearea loops in real time following intravenous NTG bolus. Ees was determined offline by beat-to-beat analysis of consecutive pressurearea loops.
Results. SBP, at baseline 168 mmHg (128188 mmHg), decreased to 127 mmHg (79161 mmHg). End-systolic LV area, at baseline 6 cm2 (112 cm2), decreased to 4 cm2 (110 cm2). Ees in the HP group (11 mmHg cm2; 722 mmHg cm2) was not different from Ees in the HR group (9 mmHg cm2; 416 mmHg cm2). EF was 61% (4573%). There was no correlation between Ees and EF.
Conclusions. In this population of dialysis patients without clinically manifest heart disease, the HP and HR groups had a similar Ees. Therefore, these two types of dialysis patients were not distinguished by a difference in myocardial contractility. The results of this study argue against a role for reduced myocardial contractility in the genesis of intradialytic hypotension.
Keywords: automated border detection; dialysis hypotension; echocardiography; end-systolic elastance; load dependence; myocardial contractility
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Introduction |
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Unfortunately, this question cannot be answered easily, as accurate measurement of LV function in dialysis patients is hampered by the load dependence of commonly used parameters. Although changing loading conditions clearly affect routine LV function parameters, the relative contributions of these changes to the outcome of LV function measurements is difficult to determine. Newer Doppler echocardiography applications, such as mitral annulus velocity by Doppler tissue imaging, have been advocated as less load-dependent measures of LV systolic and diastolic function. However, these were recently shown to be load-dependent as well [4,5].
A more accurate assessment of LV systolic function can be obtained with simultaneous information on LV pressure and LV volume. This can be used to establish the LV pressurevolume relationship, or elastance E (P/
V), throughout the cardiac cycle to measure the changes in myocardial contractility. The end-systolic pressurevolume relationship represents the mechanical properties of a fully contracted ventricle. End-systolic elastance (Ees) is an inherent characteristic of a given LV, and a systolic function parameter that is almost insensitive to changes in preload and afterload [6]. During acute changes in load, the pressurevolume loops representing consecutive cardiac cycles show the end-systolic pressurevolume relationship to be linear. The slope of this line represents Ees (Figure 1). A decreasing Ees value within the same patient over time, therefore, indicates deterioration of LV systolic function.
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Subjects and methods |
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A patient was considered HP if intradialytic hypotension, combined with symptoms of hypotension such as dizziness and nausea, occurred in at least one-third of dialysis sessions during the 3 months prior to the measurements. Hypotension was defined as a drop in systolic blood pressure (SBP) of 25% or <100 mmHg. The other dialysis patients, who did not meet these criteria, were considered HR. Using these definitions, the study population consisted of seven HP and eight HR patients. Renal insufficiency was due to diabetes mellitus (five patients), hypertension (four patients), reflux nephropathy (two patients), ischaemic nephropathy after aortic surgery (one patient), Wegener's disease (one patient), membranoproliferative glomerulonephritis (one patient) and polycystic kidney disease (one patient). For patient characteristics, please also refer to Table 1.
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Measurements
All patients were tested shortly before the start of the dialysis procedure. The patients were in supine position, and were connected to the dialysis machine with only blood flow but no haemodialysis or UF taking place. Transthoracic echocardiograms were obtained using a Hewlett-Packard Sonos 5500 machine equipped with a 3.5 MHz transducer (Hewlett Packard, Andover, MA). An experienced echocardiographer performed all measurements. LV mass was measured from Penn Convention measurements according to Devereux and Reichek [7]. LV mass is reported as LV mass index (LVMI) by height according to the Framingham Study [8]. Stroke volume (SV) and ejection fraction (EF) were measured from the apical four-chamber view using the Method of Discs single plane volume calculation (modified Simpson's rule). Automated border detection was used to measure the changes in LV cavity area. Cross-sectional images were recorded from the midventricular short-axis view, with the midpapillary muscle level as an anatomic landmark, and with the transducer positioned to obtain the image with the most circular area with uniform wall thickness. Echocardiographic gain settings were adjusted using visual assessment of the automated border. A region of interest was manually drawn beyond the LV endocardial border to exclude the right ventricular cavity. The area of pixels within this region identified as blood density was calculated from each frame and displayed as a waveform in real time. After adjusting the ordinate from the default volume setting (in ml) to area setting (in cm2), the changes in end-systolic LV cavity area were recorded. Continuous finger arterial blood pressure was recorded by Finapres (Ohmeda 2300 FinapresTM Blood Pressure Monitor; Ohmeda, Louisville, CO). SBP was used as a surrogate for end-systolic LV pressure.
The analogue echo and Finapres data were recorded simultaneously using an analogue to digital conversion system (ACODAS, DATAQ Instruments Inc, USA), which combined continuous SBP and LV area data online to create pressurearea loops in real time. Sampling and storage rate were 300 Hz. The area signal was calibrated on both the echo machine and the computer workstation before the start of the measurements. Data were subsequently stored on a standard personal computer.
Nitroglycerine administration
To induce acute unloading, a bolus of NTG was administered intravenously. Venous access was obtained by using the efferent (venous) line of the dialysis machine. NTG was administered through a three-way multiple infusion manifold placed immediately before the dialysis needle. Blood flow was set at 300 ml/min. The dosage of the initial bolus was in the range of 0.1 to 0.5 mg. If tolerated well, a second bolus was given after 5 min. The dosage of the second bolus depended on the initial SBP decrease. If the initial decrease was <20 mmHg, the dose was doubled. If SBP decrease was 20 mmHg and the patient agreed, the experiment was repeated using the same dose.
Data analysis
Ees was determined offline by beat-to-beat analysis of consecutive pressurearea loops using a customized program written in in-house developed software (Matlab, The Mathworks Inc, USA), which was validated previously [9]. As a result of baroreflex activation, acute unloading induces a change in myocardial contractile state after a brief time lag. To determine Ees, it is therefore a prerequisite that only data measured before the onset of adrenergic activation be used. This analysis focused on the first series of pressurearea loops during SBP decline following the NTG bolus until the SBP nadir was reached or the heart rate increased by 10%, as a result of baroreflex activity.
The end-systolic pressurearea relation was determined by an iterative search algorithm intended to maximize the pressurearea ratio per beat. Subsequently, a linear regression was performed, and the slope of the regression line determined an initial Ees and area-axis intercept. The above-mentioned analysis was repeated, now including an estimate of the area-axis intercept. This iterative process continued until convergence was reached for the area-axis intercept as described previously [10]. The slope of the last regression line was used for the determination of Ees.
Statistical analysis
Echocardiographic parameters, UF volume and Ees in HP and HR patients were compared by the MannWhitney U-test. In patients with a second Ees measurement, the reproducibility was analysed by the Wilcoxon matched pairs test. The correlation of Ees with EF was tested using the Spearman rank correlation coefficient. Data are reported as median values and range.
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Results |
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SBP decline was >20 mmHg after the initial NTG bolus in 10 patients (Figure 2). Seven of these 10 patients agreed to repeat the experiment and a second bolus with the same dose was given. There was an adequate decline in all other patients after a subsequent NTG bolus with a doubled dose. SBP, at baseline 168 mmHg (128188 mmHg), decreased to 127 mmHg (79161 mmHg). Diastolic BP, at baseline, 87 mmHg (69108 mmHg), decreased to 71 mmHg (53104 mmHg). End-systolic LV area, at baseline 6 cm2 (112 cm2), decreased to 4 cm2 (110 cm2). End-diastolic LV area, at baseline 11 cm2 (718 cm2), decreased to 10 cm2 (616 cm2).
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Discussion |
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During hypovolaemia, the role of myocardial contractility as a cardiac compensatory mechanism is open to question [3]. Studies in animals and humans have shown that in hypovolaemia, cardiac compensation mechanisms, i.e. increased contractility and heart rate resulting from sympathetic activation, play a limited role. Blood pressure response was not altered under pharmacological ß-adrenergic blockade or by cardiac denervation [11,12]. The results of these studies show that optimizing pump function has hardly any effect if cardiac filling is decreased to the point that SV is too low for an adequate CO [3]. Consequently, if LV systolic function does not determine CO during decreased cardiac filling, when the heart is insufficiently preloaded, it seems doubtful whether a reduction in myocardial contractility predisposes to dialysis hypotension. This is confirmed by our finding that Ees in HP dialysis patients was not different from Ees in HR patients.
While Ees measurement has been developed in animals, and has been applied clinically in several patient populations, it has never been applied in dialysis patients. Ees from pressurearea loops has been validated against Ees from pressurevolume loops in animals and humans, with the use of automated border detection to record the changes in LV cavity area resulting from load variation [10,13]. Cross-sectional images of LV cavity changes recorded from the midventricular short-axis view, with the midpapillary muscle level as an anatomic landmark, have been shown to closely correlate with changes in LV volume [10,13]. In these studies, automated border detection was used with transoesophageal echocardiography in unconscious patients in the operation room. Transthoracic echocardiography is a non-invasive alternative in a conscious dialysis patient in a dialysis room, which yields good quality LV cross-sectional images in the midventricular short-axis plane in selected patients.
Ees from pressurearea loops was previously measured in patients before and after coronary bypass surgery (CABG) [1315]. Ees was decreased immediately following CABG, indicating a systolic stunning possibly due to hypothermia, ischaemia and reperfusion, whereas load-dependent measures of LV systolic function, such as SV and CO, remained unchanged. In two of these studies, the methodology was comparable to our study, combining LV cavity area measurements with peripheral arterial pressure recordings. Ees in our study population was in the same range as post-CABG values in one, and pre-CABG values in the other study [13,15]. Myocardial contractility in these asymptomatic dialysis patients, therefore, does not appear to compare favourably with patients who were non-uraemic but did have coronary artery disease. However, it is difficult to compare Ees in these different populations. Nevertheless, LV dysfunction can be expected to be a common problem in dialysis patients, in view of the high prevalence of LV hypertrophy and myocardial fibrosis. While myocardial fibrosis is difficult to diagnose, almost all our patients had LV hypertrophy. Myocardial fibrosis and LV hypertrophy may also lead to diastolic dysfunction. Diastolic LV dysfunction is likely to be an important cause of dialysis hypotension, although its load-independent measurement is another complicated issue, and was not part of our study design.
There was no correlation between Ees and EF. Measurement of LV EF is widely used and generally accepted as a parameter of LV systolic function, even though it does not accurately predict SV and CO without consideration of the coexisting LV volumes (hence preload) and afterload [16]. EF is a LV performance index, and reflects not only myocardial contractility but also cardiac filling and peripheral resistance. It therefore describes the entire cardiovascular system rather than the intrinsic properties of the myocardium. The success of EF as a measure of LV systolic function in non-uraemic patients is probably derived from the observation that, when myocardial contractility is reduced, SV is maintained at an increased preload, leading to a reduced EF. In haemodialysis patients, however, the cyclic changes in volume status, resulting from progressive volume overload before dialysis and volume withdrawal during dialysis, are associated with substantial changes in preload and afterload. In our study population, EF values appeared to indicate good systolic function. This may be explained by the timing of the measurements shortly before dialysis with UF. Volume loading has repeatedly been shown to increase EF, primarily due to a decrease in total peripheral resistance with a concomitant decrease in end-systolic volume [17]. Although none of the patients had symptoms of overt hypervolaemia, they were in a state of relative fluid overload. EF and UF volume were similar in the two groups. Although it is conceivable that a higher UF volume is related to a higher incidence of dialysis hypotension, this was not the case in our study.
The need for load alteration, which in these previous studies was achieved by inferior vena cava occlusion, has been a limitation to the clinical application of Ees measurements. An intravenous NTG bolus is a simple method to induce acute unloading in a dialysis patient connected to a dialysis machine. As a result of the large blood flow in an arteriovenous shunt, the effect of a NTG bolus is quick in onset and short in duration. It was generally tolerated well, as patients were relatively protected from an excessive decline in blood pressure by their hypervolaemic state before dialysis. Although it would be interesting to repeat these Ees measurements after dialysis to test the effect of the dialysis procedure on myocardial contractility, administration of NTG at the end of dialysis carries an increased risk of inducing symptomatic hypotension.
To circumvent the need for load alteration, an alternative approach is to estimate Ees on a single-beat basis [18]. However, these methods rely on several assumptions and result in more variation in Ees estimates than with the method based on load-varied beat-to-beat analysis [19]. This is partly due to the use of additional information from other time-points in the single pressurevolume loop, which reintroduces load-dependent elements.
Although clinically feasible and well tolerated, a non-invasive approach means the use of surrogate markers, which is an inherent limitation to our study. To measure arterial pressure continuously and non-invasively, Finapres SBP was used as a surrogate for LV end-systolic pressure. Finger pressure measurement by Finapres is an accepted method to measure blood pressure continuously, and Finapres SBP readings agree well with intra-arterial SBP measurements [20]. A possible limitation of this technique is the distance travelled by the pressure wave. Dialysis patients may have arteriosclerosis, leading to an increased pressure gradient. This may interfere with the Finapres measurements, although in the present study all patients had excellent arterial wave recordings. However, for the calculation of Ees, we were not interested in the absolute pressure values, but only in pressure changes. Changes in peripheral peak pressure, measured invasively in the femoral and brachial artery or as SBP by sphygmomanometry, have been shown to correlate with changes in LV end-systolic pressure, provided that there is no significant aortic stenosis or any other LV outflow tract obstruction present [14].
We conclude that, as the HP and HR groups in this study had a similar Ees, these two types of dialysis patients were not distinguished by a difference in myocardial contractility. The results of this study argue against a role for reduced myocardial contractility in the genesis of intradialytic hypotension.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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