bioimpedance-based volume overload at clinical...

Bioimpedance-based volume overload at clinical target

weight is negative in hemodialysis patients with a high

body mass index

Werner Ribitsch1, Jakob Stockinger2, and Daniel Schneditz2

1Division of Nephrology, Department of Internal Medicine,

and

2Institute of Physiology, Medical University of Graz, Austria

Address correspondence to:

Daniel Schneditz, Ph.D.

Institute of Physiology

Center for Physiologic Medicine

Medical University of Graz

Harrachgasse 21/5

8010 Graz, Austria

phone: +43 (316) 380 4269

fax: +43 (316) 380 9630

e-mail: [email protected]

Short running title: Bioimpedance-based volume in hemodialysis patients

Character count (whole document, including spaces): 29325

Bioimpedance-based volume in hemodialysis patients

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Abstract

Objective: To compare volume overload in stable hemodialysis (HD) patients

assessed by standard clinical judgment with data obtained from bioimpedance

analysis.

Methods: Ultrafiltration volume (VU) was delivered as prescribed by standard

clinical practice. Independently, a measure for volume overload was assessed by

a clinical score (SW). The Body Composition Monitor (BCM, Fresenius Medical

Care, Bad Homburg, Germany) was used to derive values for extracellular

volume (VE) and volume overload (VO) before HD. Arterial pressures (P0, P1) and

serum levels of NT-pro-BNP (B0, B1) were evaluated before and after HD.

Results: In 28 patients (11 women, age: 51.3±13.3 y, body mass index, BMI:

18.5 to 40.9 kg/m²; VE 17.91±3.45 L) delivered VU was 2.41±1.03 L and not

different from VO of 2.08±1.49 L derived from bioimpedance analysis. There was

no correlation between VO and VU (r=-0.15, p=0.46) but a negative correlation

between the difference VO-VU (i.e. the volume overload at treatment end) and

BMI (r=-0.49, p<0.01). Positive correlations were observed between B0 and the

relative volume overload (=VO/VE) (r=0.58, p<0.001).

Conclusion: The well recognized relationship between cardiac natriuretic

peptides and volume expansion was confirmed. The volume overload at

treatment end (VO-VU) was negligible for the whole group of patients but more

negative with increasing BMI. It therefore appears that in comparison to

bioimpedance-based evaluation the clinical judgment overestimates volume

overload in obese patients which leads to the delivery of high ultrafiltration

volumes and to volume contraction at the end of a dialysis session in this group

of patients. (250 words)

Keywords: bioimpedance – body mass index – natriuretic peptide – ultrafiltration


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Introduction

Volume overload and hypertension are known to importantly contribute to

high cardiovascular morbidity and mortality seen in dialysis patients [1, 2]. The

correct assessment of volume status is especially demanding as only a small

increase in extracellular volume over prolonged periods of time is assumed to

lead to considerable cardiac strain and, as a consequence, to left ventricular

hypertrophy [3, 4]. In clinical practice volume overload is most often judged by

clinical signs such as edema, dyspnea, hypertension, or coughing. It is obvious

that such an assessment is subject to many limitations because these symptoms

are not specific for volume status. To overcome these limitations, alternative and

more objective methods have been suggested. For example, the diameter and

collapsibility of the vena cava measured by ultrasonography is assumed to

provide information on intravascular volume [5, 6, 7]. Pulmonary congestion

seen in the chest X-ray offers another possibility to detect fluid overload [3, 8].

And the N-terminal fragment of B-type natriuretic peptide (NT-pro-BNP) has

been proposed as a serologic biomarker of volume overload. But these methods

have their own limitations, they are time consuming and/or they are not readily

available at the bedside. As of today bioimpedance analysis appears to be the

most promising technique for a simple, user-friendly, standardized, and

objective assessment of patient volume status to be used with every treatment

[9, 10, 11, 12, 13]. With this technique it is not only possible to estimate the

patient’s fluid status with sufficient accuracy but to obtain information on body

composition and nutritional aspects as well [9, 10, 14]. Recent studies have

shown that information derived from bioimpedance analysis is useful to improve

the fluid management in dialysis patients, to save antihypertensive medication,

and to reduce the frequency of intradialytic adverse events [15]. In spite of

these promising results there is an ongoing discussion regarding the reliability

and the clinical value of bioimpedance analysis in clinical practice. Volume

assessment is especially difficult in obese subjects where the distribution of

adipose tissue affects bioelectric measurements and where increased skin turgor

conceals volume depletion assessed by clinical judgment.

The aim of this study therefore was to compare the clinical assessment to the

volume status measured by a new bioimpedance device in everyday practice in a


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group of patients with a wide range of body mass indices. Additionally, the

relationships between clinical, bioelectrical, and serological measures of volume

overload were assessed.


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Material and Methods

Subjects

Twenty-eight prevalent stable hemodialysis patients from the dialysis unit of

the University Medical Center Graz provided written informed consent to

participate in this study. The study protocol was approved by the local Ethics

Committee of the Medical University Graz. Subjects with pacemakers and

patients with major amputations of extremities were excluded.

Bioimpedance

Fluid status was assessed using the Body Composition Monitor (BCM,

Fresenius Medical Care, Bad Homburg, Germany) measuring so-called whole

body bioimpedance at 50 frequencies within the range of 5 kHz to 1 MHz.

Measurements were done in supine body position after a 5 min of rest as

specified by the manufacturer. Current injection and voltage sensing electrodes

were placed on the wrist and the ankle of the contra-lateral access side of the

body. Measurements were performed immediately before a midweek dialysis

session. Total body water (VT), extracellular (VE) and intracellular water volumes

(VI) were derived from bioimpedance data and the volume overload (VO) was

then calculated by the BCM device, using the proprietary body composition

model as described elsewhere [14, 16, 17].

Parameters

In all patients the body mass index (BMI) was recorded before treatment.

Weight, arterial blood pressures (P0, and P1, respectively), and serum levels of

NT-pro-BNP were determined before and after hemodialysis (B0, and B1,

respectively). NT-pro-BNP was measured by immunoassay (ECLIA Roche

Diagnostics GmbH, Mannheim, Germany).

In all patients the volume status was assessed according to the clinical

volume score (SW) developed by Wizemann and Schilling [18]. In a

questionnaire clinical signs of volume expansion (i.e. different stages of pretibial

edema formation, dyspnea, chronic coughing, rising blood pressure during

ultrafiltration) as well as signs of volume depletion (i.e. presence of thirst,

varying degrees of symptomatic hypotension, muscle cramps, dizziness and

fatigue between dialysis sessions) are recorded and scored. A positive sum of


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the scored symptoms indicates volume expansion while a negative sum indicates

volume depletion.

Treatment settings such as blood flows and dialysate compositions as well as

the removal of excess volume by ultrafiltration were delivered as prescribed

without adjustment. Delivered ultrafiltration volumes (VU) were recorded.

Statistical analysis

Pearson´s correlation coefficients were determined for variables B0, B1, VO, VU,

VO/VE and SW. χ2- and two-sided t-tests were used to assess differences among

groups. For all tests, the significance level was set at 5%. Statistical calculations

were done with SPSS, Version 17.0 for Windows (SPSS Inc., Chicago, IL, USA).


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Results

Twenty-eight patients (11 women, 51.3±13.3 years) were studied (Tab. 1).

The mean arterial pressure before dialysis (P0) was 102.6±15.5 mmHg and

significantly correlated with the clinical volume score (WS) (r=0.44, p<0.05).

Mean arterial pressure after dialysis (P1) significantly fell to 93.1±17.9 mmHg

(p<0.01).

The ultrafiltration volume effectively removed (VU) determined from the

difference between pre- and post-dialysis body mass was 2.4±1.0 L and

0.45±0.16 L larger than the ultrafiltration volume prescribed according to the

patient’s target body mass. This small difference was most likely due to a

systematic overestimation of fluid ingested during dialysis and/or the amount of

fluid required to rinse the blood from the extracorporeal circulation. However,

both volumes where highly correlated (r=0.99, p<0.001) and the ultrafiltration

volume effectively removed (VU) was used for further analysis. This volume was

not different from the mean volume overload (VO) of 2.08±1.49 L obtained from

bioimpedance analysis (p=n.s., t-test). Bland-Altman analysis showed a small

bias of -0.33 L for the difference (VO-VU), albeit with considerable limits of

agreement (-4.2 to 3.5 L) (Fig. 1). In spite of this small bias determined for the

whole group there was no correlation between VU and VO in individual studies

(r=-0.13, p=0.51). There was a positive correlation between VU and BMI

(r=0.47, p<0.01) and a negative correlation between VO and BMI (r=-0.31,

p=0.12). Thus, the difference (VO-VU) was also significantly correlated to BMI

(r=0.49, p<0.01) (Fig. 2). BMI was significantly correlated to body mass

(r=0.91, p<0.001) so that high BMI was due to high mass and not to small

stature.

Post-dialysis blood pressures (P1) as well as the drop in arterial pressures (P0-

P1) were negatively correlated to ultrafiltration volume VU (P1: r=-0.43, p<0.05;

P0-P1: r=-0.59, p<0.001) and positively correlated to post-dialysis volume

overload VO-VU (P1: r=0.44, p<0.05; P0-P1: r=0.41, p<0.05). Post-dialysis

pressure P1 was negatively correlated with body mass Mb (P1: r=-0.41, p<0.05)

and BMI (P1: r=-0.52, p<0.01).

Predialytic NT-pro-BNP levels (B0) were negatively correlated with body mass

(r=-0.31, p<0.05) and positively correlated with relative volume overload


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(VO/VE) (r=0.58, p=0.001, Fig. 3). Last, but not least, NT-pro-BNP levels

significantly dropped during dialysis (p<0.05).


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Discussion

The main observations of this study are: a) There was a close correspondence

between estimated volume overload obtained from bioimpedance analysis VO

and ultrafiltration volume VU for the whole group of patients, albeit with wide

limits of agreement; b) at the same time, there was no correlation between VO

and VU in individual patients; and c) there was a negative correlation between

this discrepancy quantified as VO-VU with body mass index.

The negligible bias between estimated volume overload and ultrafiltration

volume is in support of the null-hypothesis that for the whole group of patients

volume overload was adequately removed as prescribed by routine clinical

practice. This result therefore appears to be in support of bioimpedance

measurements and model calculations provided by the BCM. The limits of

agreement, however, were wide, presumably because of the large range in body

mass and BMI of the study population (Tab. 1). Thus, the comparison of VO and

VU requires a more careful analysis.

In individual studies, there was no relationship between VO and VU, and the

reason for this discrepancy can be attributed to errors in the prescription of VU

according to clinical routine and/or to errors in the estimation of VO by

bioimpedance analysis. Indeed, the BCM has been validated for subjects with a

BMI between 18 and 32 kg/m², and volume estimates in patients with a BMI

outside that range are therefore uncertain. On the other hand, there was only a

slight trend for VO to decrease as BMI increased in this study. It therefore

appears as if BCM predictions could be extended into the higher BMI range.

Others have observed that volumes derived from so-called whole-body

bioimpedance measurements are more variable in obese subjects and the

question therefore arises whether segmental measurements should be preferred

in this setting [19, 20, 21]. Part of the variability in obese subjects is most likely

due to the different contribution of adipose tissue on whole-body bioimpedance

depending on its distribution between the trunk (visceral, central fat) and the

limbs (peripheral fat). This effect is comparable to the different contribution of

extracellular fluid on whole-body bioimpedance whether it is located in the trunk

or in the limbs [22]. It has been shown that the redistribution of fluid between

the trunk and the limbs affects the measurement and the interpretation of so-


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called whole bioimpedance data [23, 24, 25] and for this reason an immediate

measurement before dialysis treatment is recommended by the manufacturer of

the BCM. The fluid shifts between body segments probably also explain the

differences in post-dialysis bioimpedance seen after long 8 h treatments where

fluid is allowed to equilibrate across the body compared to regular 4 h

treatments where such equilibration is more likely incomplete [26].

VU was observed to increase with BMI which is plausible, as larger patients

tend to accumulate more volume. Therefore, the difference VO-VU significantly

decreased with increasing BMI. The difference VO-VU refers to the volume

overload at the end of dialysis, a positive value representing a (positive) volume

overload, and a negative value representing a volume deficit, respectively. A

(positive) volume overload at the end of dialysis is not so surprising because of

the well known difficulties to remove excess fluid volume from the patient during

hemodialysis for hemodynamic reasons [27]. More surprising, however, is the

negative correlation of volume overload with increasing BMI. In fact, at very

high BMI the difference VO-VU was always negative in our study. Especially in

obese patients the clinical assessment seems to overestimate patient volume

status thus leading to high ultrafiltration and consequently to volume depletion

at the end of a dialysis session. One can argue that the standard clinical

assessment of volume to be removed by ultrafiltration was inaccurate because of

limitations mentioned above. This assumption is confirmed by the poor

correlation found between bioimpedance measures and the clinical score in this

cross-sectional analysis. The negative correlation between post-dialysis blood

pressure P1 with body mass Mb and BMI also indicates that more volume was

removed in large patients than that required to reach the same blood pressure

in the whole study group.

Part of the overestimation, however, is inherently linked to body size. It is

clear that - everything else being equal - the large patient is less susceptible to a

given volume overload or volume contraction compared to the small patient,

essentially because the capacity to buffer the same volume perturbation

increases with body size. Therefore, if volume removal is for example prescribed

to attain the same blood pressure, more volume is automatically removed in the

large patient. As current clinical practice attempts to remove as much volume as


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possible, the large patient is more likely to be volume contracted compared to

the BCM estimate. This approach, however, is in debate [28, 29].

Consistent with the well-known fact that elevated cardiac natriuretic peptides

reflect volume expansion [30, 31, 32, 33] we found a positive relationship

between predialytic NT-pro-BNP levels and the estimated pre-dialysis volume

overload VO. NT-pro-BNP levels significantly decreased during dialysis and

ultrafiltration. This decrease cannot exclusively be tied to the improved volume

situation because NT-pro-BNP is also cleared with high-flux dialysis. As NT-pro-

BNP is affected by other factors beyond volume expansion, it fails to be a

reliable tool for assessing patient dry mass. For example, it was recently shown

that elevated NT-pro-BNP concentration was also related to malnutrition [34]. In

our study, NT-pro-BNP concentration in obese patients was inversely related to

body mass, supporting the existence of such a relationship and the hypothesis of

inverse epidemiology regarding obesity in dialysis patients. This observation is

also consistent with our finding that at the end of dialysis obese patients

appeared to be volume contracted compared to the BCM estimate.

A limitation of the present study is of course the small number of patients and

the lack in statistical power. On the other hand, bioimpedance analysis was

tested in a standard clinical setting thus providing practical information for

everyday routine.

In conclusion, the well recognized relationship between cardiac natriuretic

peptides and volume expansion was confirmed. In addition, there was no

significant difference between clinically-based and bioimpedance-based volume

assessment in the whole group of patients. However, there was a large

discrepancy between clinically- and bioimpedance-based estimates in individual

patients depending on BMI. At the end of dialysis obese patients appeared to be

volume contracted compared to the BCM estimate. The clinical implications of

this observation remain to be elucidated in future and larger studies.


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Conflict of interest

None to declare.


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Disclosure

This work originated from a diploma thesis [35] and part of it has been

presented and published in abstract form at the Annual Meeting of the Austrian

Society of Nephrology, Oct. 2-3, in Graz, Austria [36], and at the XVII ERA-EDTA

Congress – II DGfN Congress, June 25–28, 2010, in Munich, Germany [37].


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Acknowledgement

We thank Dr. C. Weber from Fresenius Medical Care Austria GmbH for

providing the Body Composition Monitor. Dr. W. Ribitsch was supported by a

research grant from Baxter Healthcare Austria. This work was partly supported

by the Austrian Research Promotion Agency (FFG).


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Fig. 1

Volume overload and ultrafiltration volume

Bland-Altman analysis for volume overload VO and ultrafiltration volume VU

comparing the difference (VO-VU) to the average of both measures. The mean

difference is indicated by the full line, the limits of agreement (± 2 SD) are given

by the broken lines (n=28).


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Fig. 2

Volume overload and body mass index

Difference between volume overload and ultrafiltration volume (VO-VU) (i.e.,

the volume overload at the end of dialysis) plotted vs. body mass index BMI.

The broken line shows the linear regression given as y=3.90-0.16x; r2=0.24,

p<0.01 (n=28).


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Fig. 3

NT-pro-BNP and volume overload

Correlation between predialytic levels of NT-pro-BNP and the relative

predialytic volume overload (VO/VE): r2=0.58; p≤0.001; line of linear regression

(dotted line).


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Tab. 1

Patient and treatment characteristics in presented in the order of increasing

BMI (n=28)

M0 BMI P0 P1 VE VO VU VO-VU VO/VE B0 B1 SW

kg kg/m² mmHg mmHg L L L L % pg/mL pg/mL

45.2 18.5 130.3 119.0 13.7 4.0 1.9 2.2 29.2 30137 11704 1

49.7 19.6 116.7 98.3 13.3 1.9 2.7 -0.8 14.3 10690 14044 -3

65.5 20.5 112.3 87.3 16.6 1.1 3.9 -2.8 6.6 3795 1747 0

66.7 21.1 89.0 104.7 18.1 1.9 1.5 0.4 10.5 2144 1431 0

55.5 21.3 96.7 106.3 14.3 1.1 0.0 1.1 7.7 2436 2477 0

53.4 21.3 107.3 108.0 11.7 0.0 1.4 -1.4 0.0 5157 5545 0

68.3 21.7 109.7 115.0 18.9 1.7 3.7 -2.0 9.0 4639 3135 0

77.3 22.2 112.7 98.7 20.8 3.0 1.7 1.3 14.4 5413 3055 2

67.7 22.9 83.0 77.7 19.3 4.9 2.0 2.9 25.4 17145 20088 2

68.1 23.7 90.7 71.3 15.5 0.5 2.1 -1.6 3.2 566 372 0

71.0 24.0 122.3 101.0 16.8 2.2 1.5 0.7 13.1 35000 35000 8

68.4 24.2 121.0 105.3 15.0 1.4 3.3 -1.9 9.3 4138 2895 5

76.5 24.5 110.3 106.7 19.8 3.2 2.3 0.9 16.2 3884 1848 -2

69.9 24.9 112.7 91.0 18.7 3.4 2.5 0.9 18.2 14328 5704 0

60.7 25.0 83.3 71.3 14.8 3.3 2.5 0.8 22.3 17407 9268 -4

67.2 25.3 88.0 126.7 14.3 2.7 1.3 1.4 18.9 35000 25798 -1

74.5 26.1 112.0 116.3 20.5 5.0 1.7 3.3 24.4 7060 8342 0

86.1 28.8 84.3 93.3 17.9 0.5 1.6 -1.1 2.8 1288 1663 -4

95.1 29.1 116.7 101.7 22.7 4.9 2.2 2.7 21.6 3064 2357 2

87.0 29.7 117.0 99.3 20.0 1.8 2.4 -0.6 9.0 17605 11311 0

74.0 30.2 101.7 69.3 14.7 1.4 3.0 -1.6 9.5 14606 5911 0

76.0 31.0 60.3 51.3 16.8 2.3 2.9 -0.6 13.7 8333 5443 -3

87.5 31.6 91.7 88.0 15.5 0.0 1.1 -1.1 0.0 571 642 -3

88.0 32.2 101.3 89.0 21.8 2.7 3.3 -0.6 12.4 7230 4909 1

105.8 36.4 117.7 96.3 20.7 1.9 3.4 -1.5 9.2 7601 9379 -4

119.2 36.4 86.7 65.0 23.7 0.8 3.5 -2.7 3.4 258 165 0

122.0 38.2 100.0 74.7 26.0 1.2 4.8 -3.6 4.6 965 619 -3

107.6 40.8 97.3 75.0 19.6 -0.5 3.3 -3.8 -2.6 833 1019 0

x 76.9 26.8 102.6 93.1* 17.9 2.1 2.4 -0.3 11.7 9332 6995* 0

SD 19.3 5.9 15.5 17.9 3.4 1.5 1 1.9 8.1 9887 8093 2.6

Abbreviations: number of subjects, n; predialytic body mass, M0; body mass index, BMI; pre- and post-dialytic mean arterial pressures, P0, P1; extracellular volume, VE; volume overload VO; relative volume overload, VO/VEC; delivered ultrafiltration volume, VU; pre- and post-dialytic NT-pro-BNP, B0, B1; clinical


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score according to Wizemann et al., SW; *p<0.05 (post- compared to pre-dialytic values)


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