1Division of Cardiology and 2Division of Nephrology, Department of Internal Medicine, Taipei Veterans General Hospital, and the Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan
Correspondence and offprint requests to: Chen-Huan Chen, MD, 201 Shih-Pai Road, Sec. 2, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. Email: chench{at}vghtpe.gov.tw
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Abstract |
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Methods. Three study groups were enrolled: 40 healthy volunteers (NTNR), 40 HD patients who were normotensive without receiving antihypertensive agents (NTHD) and 38 HD patients who had remained hypertensive (HTHD) despite antihypertensive treatment. Measurements of Doppler echocardiographic parameters from pulmonary vein (PV) and mitral inflow (Mi) were performed on a non-dialysis day. Extracellular water as a percentage of body weight (ECW%) and pre-dialysis mean blood pressure (BDMBP) were references for fluid status. The best Doppler parameter for fluid status assessment identified from the study groups was then tested in another validation groups (38 NTHD and 38 HTHD).
Results. Among all of the PV and Mi parameters, the S/D ratio (peak systolic velocity divided by peak diastolic velocity) was correlated with fluid status parameters best (with ECW%, r = 0.49, P<0.001; with BDMBP, r = 0.51, P<0.001). The correlations were independent of age, sex and Mi parameters. The receiver operating characteristics curve analysis demonstrated that an S/D ratio >1.33 had a sensitivity of 90% and a specificity of 77% in identifying NTHD patients. When the same criterion was applied to the validation groups, the positive predictive value was 64% and the negative predictive value was 86%.
Conclusion. The Doppler-derived S/D ratio is a potentially useful marker for the assessment of fluid status in HD patients.
Keywords: dry weight; echocardiography; fluid status; haemodialysis
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Introduction |
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The evaluation of fluid status is generally approached from clinical observation of body weight change, congestion, oedema, blood pressure and chest X-ray. However, evaluation on clinical grounds alone is not accurate enough in HD patients. For this reason, more objective methods, such as biochemical markers, bioimpedance analysis (BIA) and inferior vena cava (IVC) diameters have been developed for the assessment of fluid status. However, no single method has emerged as a gold standard, and the combination of these methods is generally needed to complement their respective limitations.
The mitral inflow Doppler spectrum reflects the left ventricle (LV) filling dynamics, and the pulmonary vein Doppler spectrum reflects the left atrium (LA) filling dynamics, respectively. Both of them have been shown to be very load dependent in subjects with various cardiac diseases [1]. In addition, these parameters reflect the left heart filling physiology, and are theoretically less influenced by abnormalities of right heart haemodynamics. In consequence, the mitral inflow and pulmonary vein Doppler spectra may have the potential to complement the present methods of fluid status assessment. To our knowledge, the load-dependent nature of these Doppler echocardiographic parameters has not been carefully investigated and applied in HD patients, who have distinct cardiovascular characteristics, such as high cardiac output, impaired LV relaxation and arterial stiffening [2].
Accordingly, the purposes of the present study were (i) to investigate the relationships between various Doppler echocardiographic and other fluid status parameters; (ii) to examine the role of the Doppler echocardiographic parameters in the assessment of fluid status in these patients; and (iii) to identify and validate the usefulness of the best Doppler echocardiographic parameter.
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Subjects and methods |
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In the 78 eligible HD patients, 40 had attained clinical dry weight and were normotensive without receiving antihypertensive agents for at least 6 months (NTHD). Dry weight was not attained in the other 38 patients who had remained hypertensive (HTHD) under antihypertensive treatment. In this study, dry weight was defined as the body weight at the end of dialysis at which the patient can remain normotensive until the next dialysis session without antihypertensive medication despite fluid accumulation [4]. Another 40 normotensive volunteers with normal renal function and without history of cardiovascular disease were enrolled as normal control (NTNR). The characteristics of these three study groups are displayed in Table 1.
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Validation population
To validate the best Doppler parameter identified from the study groups, another 100 HD patients were selected consecutively from the same database, following the first 110 patients for the study groups. By the same criteria as for the study groups, 24 patients (24%) were excluded due to congestive heart failure (20 patients, four also had evidence of coronary artery disease), moderate mitral regurgitation (two patients) and technically inadequate Doppler echocardiographic recordings (two patients). Among the 76 eligible patients, 38 were NTHD and 38 were HTHD.
Anthropometrical and blood pressure measurement
Body weight and height of barefoot patients in underclothes were measured with a beam scale and under identical conditions on successive records. Body surface area (BSA) was calculated from weight and height. Blood pressure measurement was taken 30 min after the end of the dialysis session (value considered as the post-dialysis blood pressure), and before the start of the subsequent dialysis (pre-dialysis blood pressure). Mean blood pressure (MBP) was calculated as diastolic blood pressure plus one-third of pulse pressure. Presented blood pressure values were averages from 25 consecutive dialysis sessions after the echocardiographic study.
Haemodialysis procedures
The HD patients received a 4 h dialysis session thrice weekly using 1.6 m2 surface area dialysers with bicarbonate-based dialysate (Na+ 140 mEq/l, 39 mEq/l, K+ 2.0 mEq/l, Ca2+ 3.0 mEq/l, Mg2+ 1.0 mEq/l). The ideal dry weight was assessed via meticulous bedside evaluation, which comprises physical examinations, cardiac-thoracic ratio estimated by chest X-ray, and echocardiography, if necessary. If symptoms and signs of fluid overload were noted, the excess volume was ultrafiltrated during the dialysis session or via additional sessions. All patients were treated with subcutaneous rHu-EPO® at a mean dosage of 20 000 U per month with the aim of keeping their haematocrit levels up to 30%, according to the recommendation from our National Health Insurance Bureau.
Echocardiography
Echocardiographic examination was performed with a Hewlett Parker Echo system (model 5500) incorporating a 2.02.5 MHz phase-array transducer. Recordings were made with the patients in a slight left lateral position and during quiet respiration with the transducer placed at the cardiac apex. The Doppler spectrum of the mitral inflow was recorded between the tips of mitral leaflets in the four-chamber view. The pulmonary vein Doppler spectrum was obtained by placing the Doppler sample volume 0.51.0 cm into the right upper pulmonary vein. The vein was visualized by a slightly cephalic elevation of the interrogation plane from a standard four-chamber view. The position of the sample volume was confirmed by obtaining a characteristic pulmonary vein Doppler pattern. The IVC diameter was measured in the supine position at the level just below the diaphragm in the hepatic segment. An M-mode echocardiogram was recorded with simultaneous ECG monitoring. All echo images of still frames and loops were stored in the optic discs for off-line analysis.
Echo Doppler spectra were analysed with the use of the measuring software incorporated in the echo system. From the mitral inflow velocity tracings, peak velocity (E) and deceleration time (DT) of the early inflow wave, peak velocity (A) of the late inflow wave at atrial contraction, and isovolumic relaxation time (IVRT) were measured (Figure 1, upper). The parameters evaluated for the pulmonary vein spectrum included the peak velocity of the systolic forward spectrum (S) and diastolic forward spectrum (D) (Figure 1, lower). In cases of a biphasic systolic pulmonary vein spectrum, the peak velocity was measured on the taller of the two peaks. The S/D ratio of the pulmonary vein spectrum was defined as the peak systolic velocity divided by the peak diastolic velocity; the E/A ratio of the mitral inflow spectrum was defined as the peak velocity of the early inflow wave divided by that of the late inflow wave. The IVC diameters were measured on M-mode echocardiograms before the P-wave of the ECG during expiration, and indexed by BSA (IVCI) in cm/m2 [5]. All measurements were averaged from four consecutive beats.
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Statistical analysis
Data were expressed as the mean ± SD for continuous variables and as proportions for categorical variables. Comparisons among NTNR, NTHD and HTHD groups were made by one-way analysis of variance with Bonferroni post hoc test for continuous variables and by 2 test for categorical variables. Pearson's correlation coefficients between clinical, echocardiographic and fluid status parameters [ECW% and pre-dialysis MBP (BDMBP)] were calculated. Partial correlation coefficients accounting for age and sex were also provided. Only parameters with significant correlation with fluid status parameters were included in the subsequent multiple regression models. Stepwise multiple linear regression analyses were performed to identify the independent determinants of ECW% and BDMBP, respectively. The receiver operating characteristics (ROC) curve was used to determine the cut-off point for the S/D ratio that yielded the highest combined sensitivity and specificity for identifying NTHD (dry weight attained). Comparisons in the validation groups with a high and low S/D ratio were performed by using Student's t-test for continuous variables and
2 test for categorical variables. All statistical tests were two-tailed, with a P-value <0.05 indicating statistical significance.
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Results |
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HTHD patients and NTNR subjects had comparable mean age and sex proportion. With regard to the pulmonary vein Doppler parameters, no significant differences between the two groups were observed. For the mitral inflow parameters, HTHD patients had a higher A (P<0.05) and a lower E/A ratio (P<0.05) than NTNR subjects. While both groups had comparable IVCI, HTHD patients had a significantly higher ECW% (P<0.05) than NTNR subjects.
Comparison between NTHD and HTHD groups (Table 1)
The HTHD group was significantly younger (P<0.001) and had more male patients (P<0.05). HTHD patients had significantly higher pre- and post-dialysis blood pressures (both P<0.001) than NTHD patients, while both groups had similar pre- and post-dialysis body weight. As regards the pulmonary vein Doppler parameters, HTHD patients had significantly higher D (P<0.001) and a lower S/D ratio (P<0.001) than NTHD patients. For the mitral inflow Doppler parameters, the HTHD group had significantly lower A (P<0.05) and a higher E/A ratio (P<0.05) than NTHD patients. While both groups had a comparable IVCI, HTHD patients had a significantly higher ECW% (P<0.05) than NTHD patients.
Relationships between echocardiographic and fluid status parameters
Among the three pulmonary vein Doppler parameters, the S/D ratio was correlated best with fluid status parameters (Table 2). The S/D ratio was significantly correlated with ECW% (r = 0.49, P<0.001) and BDMBP (r = 0.51, P<0.001) (Figure 2). The S and D were correlated variably with ECW% and/or BDMBP (Table 2).
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In contrast, the IVCI was not significantly correlated with fluid status parameters (Table 2).
Partial correlation coefficients accounting for age and sex are provided in Table 3. When age and sex were accounted for, D, S/D ratio, E, A, E/A ratio and DT remained significantly correlated with ECW%, and only S and the S/D ratio remained significantly correlated with BDMBP.
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Discussion |
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Currently, every methodology for fluid status assessment in HD patients has its own limitations. For example, the biochemical markers, such as atrial natriuretic peptide and cGMP, are sensitive for detecting overhydrated patients, but are neither specific nor sensitive for detecting underhydrated patients [7]. Therefore, there is no gold standard for volume status and no uniform criteria for dry weight definition. In the present study, we combined BIA and BDMBP for surrogate standards for volume status and defined dry weight by BDMBP alone. BIA is a simple and convenient non-invasive technique for determining the volume of body fluid compartments, including both ECW and intracellular water. Because technical variability in measuring intracellular water is 4:1 greater than that for ECW, the assessment of ECW by BIA is more reliable than intracellular water and has been used successfully in adjusting dry weight for HD patients [8]. However, BIA does not differentiate interstitial from intravascular fluid [9].
Fluid status is increasingly believed to be an important determinant of blood pressure in HD patients [10]. Volume expansion is significantly correlated to casual BDMBP and 24-h arterial pressure, and the normalization of the patient hydration status is followed by a reduction in pressure values [10]. Although blood pressure is not the only factor, it remains acceptable to use BDMBP as a surrogate criterion for defining dry weight [4]. We did observe a significant difference in hydration status (ECW%) between NTHD and HTHD patients, justifying the use of blood pressure as the reference for fluid status.
In the present study, we demonstrated that, among all of the Doppler echocardiographic parameters, the S/D ratio from the pulmonary vein spectrum was best correlated to fluid status estimated by BIA-derived ECW% and BDMBP. The S/D ratio differed significantly between NTHD (dry weight attained) and HTHD (dry weight not attained) patients, and yielded a sensitivity of 90% and specificity of 77% for the identification of HD patients who had attained dry weight in the study groups. The high sensitivity (92%) of an S/D ratio >1.33 was reconfirmed in the validation groups. The low specificity combined with the high sensitivity implies that an S/D ratio >1.33 is most useful in identifying patients who have not attained dry weight (good negative predictive value). Most, if not all, of our NTHD patients should have had attained their dry weight, since their blood pressure could be controlled by HD alone. On the other hand, it was possible that not all HTHD patients had volume overload, since factors other than volume might dominate the blood pressure regulation in these patients. Thus, the apparent low specificity for an S/D ratio >1.33 might have resulted from the less than ideal definition for dry weight in this study.
The pulmonary vein Doppler spectrum reflects the phasic change of LA filling and is highly load dependent [11]. Several recent studies have found close correlations between the S/D ratio of the pulmonary vein Doppler spectrum and LV filling pressure (r from 0.47 to 0.88) in the peri-operative setting or during cardiac catheterization [12,13]. In the present study, the S/D ratio was significantly correlated to fluid status parameters assessed by the BIA method and BDMBP, indicating the pre-load dependency of the S/D ratio in HD patients. Nevertheless, some confounding factors reside in the correlation between fluid status and pulmonary vein Doppler parameters, such as age, sex, BSA and, particularly, LV diastolic function [14]. Patients with impaired LV diastolic function tolerate HD less well, which might be a reason for the fact that dry weight was more difficult to attain in these patients [15]. In spite of this, the S/D ratio depends more on the fluid status than on the LV diastolic function, as shown in our previous invasive catheterization study [16]. In addition, multivariate analysis in the present study demonstrated that the correlations between S/D ratio and fluid status parameters were independent of age, sex and LV diastolic function parameters (E/A ratio, DT and IVRT).
The clinical application of the load dependency feature of the pulmonary vein Doppler spectrum is probably limited by other well-documented factors, such as LV systolic dysfunction, significant mitral regurgitation and atrial fibrillation [11]. The S wave depends on both fluid status and LV contraction [11,16]. In patients with preserved LV systolic function, the S/D ratio is largely dependent on the LV filling pressure [11]. However, in the presence of significant LV systolic dysfunction, the S/D ratio would decrease secondarily to a reduced S wave. In fact, when the data of the 17 patients with significant LV dysfunction were included for analysis, the usefulness of the S/D ratio was less satisfactory: the sensitivity of an S/D ratio >1.33 to identify HD patients who had attained dry weight (NTHD) was 87%, the specificity was 67%, the positive predictive value was 73% and the negative predictive values was 84%. Although various degrees of LV systolic dysfunction are present in many ESRD patients, a large proportion of HD patients have preserved LV systolic function (LV ejection fraction 55% in 85% of our study population and 76% of our validation population) and the S/D ratio may be useful in these patients.
IVC diameters have been validated against the right atrial pressure and total blood volume in ESRD patients, and the post-dialysis IVC diameters reliably predicted haemodynamic changes during HD [17,18]. However, the correlation between IVC diameters and the BIA method varied widely (correlation coefficients from 0.42 to 0.78) among different studies [18,19]. In addition, in patients with cardiac failure or right-sided heart diseases, the feasibility of IVC diameters has not been validated. Furthermore, IVC diameters may overestimate underhydrated status due to the time lag of refilling from interstitial fluid [20]. In our study, IVC diameters were not significantly correlated with fluid status assessed by the BIA method or pre-dialysis blood pressure. The disparity from previous studies may be due to different hydration status in our patients (IVCI 1.15 cm/m2 [5] in only five of 78 patients), the potential impact from significant tricuspid regurgitation and the intrinsic difference between intravascular (IVCI) and interstitial (ECW%) volume.
Some limitations of the present study should be addressed. First, the echocardiographic and BIA evaluations were performed on the non-dialysis day. Some variations in the achievement of equilibrium between intravascular and interstitial fluid between patients might have been present. Secondly, patients with significant mitral regurgitation, LV systolic dysfunction and atrial fibrillation were excluded because these are well-documented factors affecting the S/D ratio. Therefore, our results may not be applicable to these patients. Thirdly, the study was a retrospective study with a post hoc group definition. However, the cases were selected consecutively from the database and were excluded only for pre-defined criteria. The selection bias and other limitations inherent to the retrospective design might be reduced further with the addition of another validation population.
In summary, our study investigated several pre-load-dependent Doppler echocardiographic parameters that have not been used in the fluid status assessment for HD patients. The results showed that the S/D ratio from the pulmonary vein Doppler spectrum is a potentially useful marker for the fluid status in HD patients.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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