**5.2 BVM® Fresenius**

32 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Fig. 2. Optimal trajectory of Relative blood volume (RBV) reduction during HD with

The Hemocontrol® software designs the ideal RBV reduction curve, for each patient at each session, based on both initial and target parameters. Upper and lower tolerance limits are set to ensure safety. UF rate and dialysate sodium vary continuously during HD to keep the

In practical terms, several parameters need to be set. Before the first use, data on the patient's sex, age, height and weight are needed to calculate total body water with any of the proposed formula. Treatment duration is also determined before the beginning of the

1. Total body weight loss or total UF (for water balance), based on clinical evaluation of

2. Final sodium or equivalent dialysate conductivity. Conductivity refers to the electrical conducting property of the dialysis solution given by the dissociation of inorganic salts into charged ions. Since sodium is the principal ion in solution, conductivity is used as a surrogate for sodium concentration. For simplification purpose, conductivity was replaced by sodium concentration in the recent devices. Equivalent conductivity represents the dialysate conductivity that produces the same sodium balance at the end of a BV regulated

session as a HD session with constant dialysate conductivity (Franssen et al., 2005); 3. Relative BV change to be reached at the end of HD which is individually determined for each patient on the basis of anterior sessions. A short observation period (approximately two weeks) is usually required to analyse each patient's BV curve morphology and to determine their respective BV/UF ratio. This ratio represents the %BV per each kilogram of UF fluid, and indirectly reflects the individual patient refilling plasma capacity. Depending on this ratio, and on the total UF prescribed for

Of note, these three targets may sometimes be in conflict with each other, for example when large UF is prescribed for a patient with low plasma refilling rate (i.e. a high BV/UF ratio). The closed feedback loop system has then to reach the best compromise between the various targets and produce the most appropriate BV curve for this patient during that specific

Hemocontrol® (from Gambro).

dry weight;

session.

actual curve parallel to the optimal trajectory.

treatment. Then, the three main targets need to be specified:

each dialysis, the final %BV can be adjusted.

The Blood Volume Management (BVM®) module designed by Fresenius is available on the 4008 and 5008 HD machines. This system also has relative blood volume as the core feature of the feedback loop, but rather deals with the « critical relative blood volume (cRBV) » concept instead of tracking an optimal curve to reach a final BV.

The BV monitor is based on the measurement of total protein concentration (which includes plasma protein and Hb) by on-line ultrasound technology. Initially described by Schneditz (Schneditz et al., 1990), this method uses a probe in the arterial line that continuously measures the speed at which the ultrasounds travel through a specially designed cuvette. Since the sound speed is positively correlated to blood density, and, once again, assuming that the total content of blood does not change during UF, blood volume variations can be calculated from the changes in sound transmission velocity.

The critical relative blood volume (cRBV) is individually determined for each patient. It is the threshold at which a particular patient would be at risk of IDH, based on the anterior sessions. The monitored parameter is the blood volume reduction, and a defined algorithm modulates the UF rate according to the relation of the actual BV to the cRBV. The algorithm is designed to allow the maximal UF rate at the beginning of the session, where the plasma refilling capacity is generally at its best, with a gradual decrease afterwards to avoid reaching the cRBV:

$$\text{Actual UF rate} = \text{initial UF rate} \times \text{factor} \tag{1}$$

$$\text{Initial UF rate} = \text{2} \times \text{(remaining UF/remaining time)}\tag{2}$$

The actual UF rate is the delivered UF rate and the initial UF rate is two times the ratio between the remaining UF and the remaining time (remaining UF/remaining time). The factor is a coefficient between 0 and 1 determined according to the current RBV. When the cRBV is reached, the factor is 0 and so the UF is transitorily suspended until the RBV rises again. When the relative blood volume is more than halfway the distance between the cRBV and 100%, the factor is 1 and maximal UF is allowed. Finally, when the RBV is more than halfway towards the cRBV, the factor is between 0 and 1 and decreases in a linear fashion (figure 3). This automatic feedback loop thus constantly adjust the UF rate to ensure, on one hand, that RBV stays over the predefined threshold and, on the other hand, that the UF rate is maximal at the beginning of the session and minimal at the end, where hypovolemia is

Automated Blood Volume Regulation During Hemodialysis 35

more likely to happen (figure 4). Of note, the dialysate conductivity is not an effector in this

The two biofeedback systems described above are designed differently but share the same goal: stabilizing blood volume reduction to avoid IDH and, ideally, its related complications. Many studies have been published on the ability of these devices to reduce vascular instability, mostly with the Hemocontrol® system, but few studies assessed other outcomes. Table 1 summarizes published trials that evaluated the impact of blood volume

Definition of IDH in the literature is not standardized and so differs between studies. Some authors use a strict definition based on an absolute or relative reduction of arterial pressure, while others report IDH as a drop in BP accompanied by symptoms and/or requiring nursing intervention (such as stopping or slowing UF, saline infusion or Trendelenburg's position). Regardless of the definition used, the great majority of published trials, conclude that blood volume biofeedback systems are valuable in reducing IDH compared to standard hemodialysis (cf. table 1). Reduction of the proportion of HD sessions with at least one IDH episode ranges from 10 to 60%. However, it must be emphasized that most of these studies recruited patients who were already prone to hemodynamic instability, at varying degrees. As a general rule, the more severe and/or frequent the hemodynamic instability, the greater

The largest randomized controlled trial assessing the impact of biofeedback regulation on IDH occurrence was published by Santoro in 2002. Thirty-two hypotension-prone patients recruited in ten Italian nephrology centers were analysed in a cross-over, parallel group study of 4 months duration, comparing conventional HD to automatic BV-controlled HD. Although UF rate, pre and post-dialysis BP, and end-dialysis BV were the same with both treatments, a 30% reduction in dialysis sessions complicated by acute hypotension (systolic blood pressure ≤ 90 mm Hg or a ≥ 25 mm Hg decrease with symptoms) was observed with the use of automatic biofeedback. An additional aim of this trial was to identify which patient's parameters influence individual response to biofeedback. Clinical characteristics, dialysis prescriptions and plasma sodium values did not differ between the two treatment arms. However, two parameters appeared to be linked to responsiveness to BV-regulated feedback. First, good responders had higher final BV reduction and higher BV/UF ratio, suggesting a certain plasma refilling impairment. Second, poor responders had lower mean arterial pressure at the start of the HD sessions, and smaller increase in heart rate when standing from the lying position. Overall, these results indicate that IDH secondary to decreased plasma refilling capacity responds better to BV regulation than IDH due to impaired cardio-vascular reactivity. Of note, most studies that reported beneficial effects of biofeedback systems found similar results with regard to RBV changes during HD suggesting that reduction of IDH might not be exclusively explained by RBV preservation. As postulated by several authors, it is possible that treatment with BV automatic feedback exerts its favourable hemodynamic effect by preventing

To evaluate whether BP stabilisation obtained per-dialysis with Hemocontrol® in IDHprone patients was also sustained in the post-HD period, Franssen et al. (2005) used 24h BP

system and, unless a specific sodium profile is prescribed, remains unchanged.

**5.3.1 Reduction of intradialytic hypotension and nursing interventions**

**5.3 Impact of blood volume biofeedback systems**

the benefits are from the automatic volume regulation.

rapid RBV fluctuations (Santoro et al., 1994).

biofeedback systems.

This figure illustrates an example where the cRBV is set at 85%. When the actual RBV is 85% or less (white area), factor is 0 and UF stops. When RBV is greater than halfway between cRBV and 100% (here, halfway between 85% and 100% is 92,5%), the factor is 1,0 and UF is maximal (shaded area). In between (gray area), factor is between 0 and 1, and UF is not maximal.

Fig. 4. UF rate in relation to RBV with the use of BVM® algorithm (from Fresenius). This figure illustrates the changes in UF rate (UFR) and RBV during HD given a cRBV set at 85% (same as Figure 3). The UFR is initially higher and progressively declines following reduction of RBV.

This figure illustrates an example where the cRBV is set at 85%. When the actual RBV is 85% or less (white area), factor is 0 and UF stops. When RBV is greater than halfway between cRBV and 100% (here, halfway between 85% and 100% is 92,5%), the factor is 1,0 and UF is maximal (shaded area). In between (gray area), factor is between 0 and 1, and UF is not maximal.

Fig. 4. UF rate in relation to RBV with the use of BVM® algorithm (from Fresenius). This figure illustrates the changes in UF rate (UFR) and RBV during HD given a cRBV set at 85% (same as Figure 3). The UFR is initially higher and progressively declines

Fig. 3. BVM® algorithm (from Fresenius).

following reduction of RBV.

more likely to happen (figure 4). Of note, the dialysate conductivity is not an effector in this system and, unless a specific sodium profile is prescribed, remains unchanged.

### **5.3 Impact of blood volume biofeedback systems**

The two biofeedback systems described above are designed differently but share the same goal: stabilizing blood volume reduction to avoid IDH and, ideally, its related complications. Many studies have been published on the ability of these devices to reduce vascular instability, mostly with the Hemocontrol® system, but few studies assessed other outcomes. Table 1 summarizes published trials that evaluated the impact of blood volume biofeedback systems.

### **5.3.1 Reduction of intradialytic hypotension and nursing interventions**

Definition of IDH in the literature is not standardized and so differs between studies. Some authors use a strict definition based on an absolute or relative reduction of arterial pressure, while others report IDH as a drop in BP accompanied by symptoms and/or requiring nursing intervention (such as stopping or slowing UF, saline infusion or Trendelenburg's position). Regardless of the definition used, the great majority of published trials, conclude that blood volume biofeedback systems are valuable in reducing IDH compared to standard hemodialysis (cf. table 1). Reduction of the proportion of HD sessions with at least one IDH episode ranges from 10 to 60%. However, it must be emphasized that most of these studies recruited patients who were already prone to hemodynamic instability, at varying degrees. As a general rule, the more severe and/or frequent the hemodynamic instability, the greater the benefits are from the automatic volume regulation.

The largest randomized controlled trial assessing the impact of biofeedback regulation on IDH occurrence was published by Santoro in 2002. Thirty-two hypotension-prone patients recruited in ten Italian nephrology centers were analysed in a cross-over, parallel group study of 4 months duration, comparing conventional HD to automatic BV-controlled HD. Although UF rate, pre and post-dialysis BP, and end-dialysis BV were the same with both treatments, a 30% reduction in dialysis sessions complicated by acute hypotension (systolic blood pressure ≤ 90 mm Hg or a ≥ 25 mm Hg decrease with symptoms) was observed with the use of automatic biofeedback. An additional aim of this trial was to identify which patient's parameters influence individual response to biofeedback. Clinical characteristics, dialysis prescriptions and plasma sodium values did not differ between the two treatment arms. However, two parameters appeared to be linked to responsiveness to BV-regulated feedback. First, good responders had higher final BV reduction and higher BV/UF ratio, suggesting a certain plasma refilling impairment. Second, poor responders had lower mean arterial pressure at the start of the HD sessions, and smaller increase in heart rate when standing from the lying position. Overall, these results indicate that IDH secondary to decreased plasma refilling capacity responds better to BV regulation than IDH due to impaired cardio-vascular reactivity. Of note, most studies that reported beneficial effects of biofeedback systems found similar results with regard to RBV changes during HD suggesting that reduction of IDH might not be exclusively explained by RBV preservation. As postulated by several authors, it is possible that treatment with BV automatic feedback exerts its favourable hemodynamic effect by preventing rapid RBV fluctuations (Santoro et al., 1994).

To evaluate whether BP stabilisation obtained per-dialysis with Hemocontrol® in IDHprone patients was also sustained in the post-HD period, Franssen et al. (2005) used 24h BP

Automated Blood Volume Regulation During Hemodialysis 37

6 months Home SBP

16 weeks Pre-HD weight

6 weeks Sessions with

6 months Change in

12 weeks Sessions with

change (mm Hg)

Nursing interventions (% change)

Kidney burden score (change in score)

Pre-HD SBP reduction (mm Hg)

Pre-HD DBP reduction (mm Hg)

IME requiring intervention (%)

Subgroup of high IDH incidence

Frequency of IDH

IME requiring intervention (%)

Mean no. of IME/session

Equilibrated Kt/V

% of IDH

% of severe IDH

142 to 135 vs. 148 to 140

reduction (kg) 0,2 vs. 0,1 NS





43 vs. 46 NS

57 vs. 65 p=0,016

0,19 p<0,01

32 vs. 40 p=0,02

0,53 p=0,04

1,12 NS

NS

p<0,01

ECFV (%) 1,8 vs. 0,87 NS

0,11 vs.

0,42 vs.

1,17 vs.

26 vs. 44 (A1) and 27(A2)

3 vs. 27 (A1) vs. 17(A2)

NS between groups

Std HD+HC vs. Std HD

Std HD+HC vs. Std HD

Std HD+BVM vs. Std HD

Std HD+BVM vs. Std HD

Std HD+BVM vs. Std HD

Std HD + HC vs. Std HD

3 months

**Randomized trials**

RCT 57 patients

RCT 28 patients

with hypertensi on and volume overload

56 patients IDH-prone

with volume overload

26 patients IDH-prone

> 8 patients IDHprone

RCT 60 patients

Unselected

**Déziel (2007)**

**Dasselaar (2007)**

**Garzoni (2007)**

**Nesrallah (2008)**

**Gabrielli (2009)**

**Santoro (1998)**

RCT Cross-over Multi-center

RCT Cross-over Multi-center

> Prospective Cross-over

**Non-randomized trials**

monitoring in a small prospective study. Following Hemocontrol®-driven HD, systolic blood pressure was significantly higher in the first 16 hours following HD, but this difference disappeared on the next morning. There was no difference in diastolic blood pressure. The authors concluded that the higher post HD systolic BP may explain the improvement of inter-HD symptoms observed in other studies (see below), although their study did not specifically evaluate interdialytic symptoms.

Only one randomized controlled trial did not restrict patient selection on the basis of previous hemodynamic instability or fluid overload (Déziel et al. 2007). This study included 57 patients (55% of them hypotension-prone) who were randomized to either standard HD or Hemocontrol®-driven HD. At 6 months, there was a 43% reduction in the number of sessions that required nursing interventions for IDH in the Hemocontrol® group (35% to 19%), compared with a 36% increase in nursing interventions in the control group (23% to 32%, p=0,04 for changes between groups). These results are in accordance with those reported by Ronco et al. (2000), who also demonstrated a significant decrease in the number of nursing interventions in a population prone to IDH when treated with BV biofeedback.

Finally, two non-randomized, short-term prospective studies specifically assessed the value of BV-regulated HD among non hypotensive-prone patients (Wolkotte et al., 2002 and McIntyre et al., 2003). Both found a statistically significant improvement in dialysis tolerance in terms of reduction of IDH.


monitoring in a small prospective study. Following Hemocontrol®-driven HD, systolic blood pressure was significantly higher in the first 16 hours following HD, but this difference disappeared on the next morning. There was no difference in diastolic blood pressure. The authors concluded that the higher post HD systolic BP may explain the improvement of inter-HD symptoms observed in other studies (see below), although their

Only one randomized controlled trial did not restrict patient selection on the basis of previous hemodynamic instability or fluid overload (Déziel et al. 2007). This study included 57 patients (55% of them hypotension-prone) who were randomized to either standard HD or Hemocontrol®-driven HD. At 6 months, there was a 43% reduction in the number of sessions that required nursing interventions for IDH in the Hemocontrol® group (35% to 19%), compared with a 36% increase in nursing interventions in the control group (23% to 32%, p=0,04 for changes between groups). These results are in accordance with those reported by Ronco et al. (2000), who also demonstrated a significant decrease in the number of nursing interventions in a population prone to IDH when treated with BV biofeedback. Finally, two non-randomized, short-term prospective studies specifically assessed the value of BV-regulated HD among non hypotensive-prone patients (Wolkotte et al., 2002 and McIntyre et al., 2003). Both found a statistically significant improvement in dialysis tolerance

study did not specifically evaluate interdialytic symptoms.

**Patients Intervention**

12 patients IDH-prone

32 patients IDH-prone

10 patients IDH-prone

8 patients IDH-prone LVH

**(control)**

AFB + HC

Std HD+HC

Std HD+HC

Std HD+HC

vs. Std HD 4 months

vs. Std HD 4 weeks

**Duration Main** 

vs. AFB 4 weeks Sessions with

vs. Std HD 4 months Sessions with

**endpoint(s)**

Equilibrated Kt/V

Mean no. of interdialytic

> Post-HD plasm. conduct.

Ionic mass removal (mmol)

No. of regional wall motion abnormalities

No. of IDH 12 vs. 24

**Results (treatment vs. control)**

1,03 p<0,001

IDH (%) 33 vs. 82 p<0,001

IDH (%) 24 vs. 34 p=0,004

symptoms 2,7 vs. 3,1 p<0,001

IDH (%) 16 vs. 8 NS

23 vs. 42

14,11 vs. 14,11 NS

432 vs. 383 NS

OR 1,8; 95%CI, 1,1-3,0

OR 2,0; 95%CI, 1,0-4,4

1,13 vs.

in terms of reduction of IDH.

**design**

RCT Cross-over

RCT Cross-over Multicenter

RCT Cross-over

RCT Cross-over

**Randomized trials**

**Author Study** 

**Ronco (2000)**

**Santoro (2002)**

> **Moret (2006)**

**Selby (2006)**


Automated Blood Volume Regulation During Hemodialysis 39

**5.3.2 Reduction of intra- and inter- dialytic symptoms and improvement in quality of** 

(notably, thirst) was not significantly different between the two treatment arms.

symptoms following treatment with BV-controlled HD.

**5.3.3 Hypertension and volume control**

interdialytic weight gain.

Regarding improvement of patient's symptoms during HD, some data are available in the literature but they are mostly based on secondary outcome analysis and show only limited evidence of benefit. Basile et al. (2001) prospectively followed patients for up to 36 months with BV-regulated HD during which period nurses and patients had to fill a symptoms questionnaire for each HD session. A reduction of muscle cramps during HD and an improvement in the post-HD asthenia score were found to be significantly associated with biofeedback system. However, self-evaluation of other intra- and inter- HD symptoms

Ronco et al. (2000) found a significant reduction of the proportion of sessions with selfreported intradialytic symptoms following treatment with BV-controlled UF (21% vs. 76%, p<0,001). In addition, Santoro et al. (2002) also showed a 10% decrease of interdialytic

In a study by Déziel et al. (2007), the Kidney Disease and Quality of Life questionnaire (KDQOL) was used to evaluate quality of life at baseline and after 6 months of treatment with either Hemocontrol® or standard HD. Among the 20 items related to physical and mental health, only one parameter, burden of kidney disease, was significantly improved in the Hemocontrol® group versus the control group. Finally, in a randomized controlled trial of 60 patients, Nesrallah et al. (2008) did not find any significant difference with regard to dialysis-related symptoms and quality of life between the two treatment groups (Hemocontrol® versus standard HD) despite the fact that a reduction of IDH could be

Three RCT specifically assessed the utility of BV regulation devices in improving fluid status and/or BP control in chronic hemodialysis patients. First, Dasselaar et al. (2007b) studied 12 hypertensive and mild volume-overloaded patients managed with either standard HD or BV tracking, where dry weight reduction was gradually undertaken by nephrologists according to clinical judgement. At 12 weeks, patients treated with BV regulation had a significantly lower pre- and post- HD systolic and diastolic blood pressure. Patients achieved larger UF volume without any change in RBV and showed reduction in extracellular water (determined by bioimpedance analysis). Despite these improvements in surrogate markers of volume status, no difference in mean weight from baseline could be observed. Authors concluded that this observation could result from increase in lean body

Second, in a trial published by Nesrallah et al. in 2008, volume-overloaded patients were included if bioimpedance displayed an extracellular fluid volume (ECFV) of at least 45%. In the treatment group, dry weight was adjusted by an algorithm guided by the Hemocontrol® biofeedback software based on plasma-refilling characteristics. At 6 months, there was no statistically significant difference between the two groups in the primary endpoint (change in ECFV) nor were there any significant differences in systolic blood pressure, total UF and

Finally, in a trial by Déziel et al. (2007), change in home blood pressure was evaluated following treatment with BV device versus standard HD. Patients were not selected on the basis of prior hypertension or volume overload history. While the use of Hemocontrol® effectively reduced home systolic BP, the clinical-based decision algorithm to manage BP in

mass; however, other specific nutritional parameters were not measured.

**life**

observed.


Trials are subdivided in randomized or non-randomized studies and listed by year of publication. AFB: acetate-free biofiltration, BVM: blood volume monitor (Fresenius), DBP: diastolic blood pressure, ECVF: extracellular fluid volume, IDH: intradialytic, hypotension, IME: intradialytic morbid events, HC: Hemocontrol® (Gambro), HD: hemodialysis, LVH: left ventricular hypertrophy, NS: nonsignificant, RCT: randomized controlled trial, SBP: systolic blood pressure, Std HD: standard bicarbonate-based hemodialysis

Table 1. Trials on the use of blood volume biofeedback control system in chronic hemodialysis

20 – 36 months

9 weeks

8 weeks

Std HD + HC 12 weeks % sessions

vs. Std HD Post-HD SBP o

% sessions with IDH Post-HD asthenia score

(sessions without intervention for IDH)

% of IDH % of minor symptoms

% sessions

24h recording (mm Hg)

Dry weight

session Dry weight reduction (kg)

> % Cardiac ejection fraction

48 weeks No. of IDH per

12 weeks % of event-free

21 vs. 32 6,2 vs. 4,3

sessions 51 vs. 29 p<0,01

6 vs. 16 11 vs. 18

with IDH 3,5 vs. 7 p<0,001

with IDH 28 vs. 64 p<0,01

reduction (kg) 2,1 vs. 2,0 NS

Same at

1 vs. 9 -1,7 vs. 0

53 vs. 43 NS

24h NS

p<0,01 NS

p<0,0001 p<0,0001

> p<0,05 p<0,05

Std HD + HC vs. Std HD

Std HD + HC vs. Std HD

Std HD + HC vs. Std HD

Std HD + HC vs. Std HD

Std HD + HC vs. baseline

Trials are subdivided in randomized or non-randomized studies and listed by year of publication. AFB: acetate-free biofiltration, BVM: blood volume monitor (Fresenius), DBP: diastolic blood

Table 1. Trials on the use of blood volume biofeedback control system in chronic

pressure, ECVF: extracellular fluid volume, IDH: intradialytic, hypotension, IME: intradialytic morbid events, HC: Hemocontrol® (Gambro), HD: hemodialysis, LVH: left ventricular hypertrophy, NS: nonsignificant, RCT: randomized controlled trial, SBP: systolic blood pressure, Std HD: standard

**Non-randomized trials**

Prospective Cross-over

Prospective Cross-over

Prospective Cross-over

Prospective Cross-over

Observational Cohort

bicarbonate-based hemodialysis

Prospective 12

19 patients IDHprone

7 patients IDHprone

16 patients Non IDHprone

15 patients Non IDHprone

patients

IDHprone

18 patients IDHprone with diabetes

**Basile (2001)**

**Bégin (2002)**

**Wolkotte (2002)**

**McIntyre (2003)**

**Franssen (2005)**

**Winkler (2008)**

hemodialysis

### **5.3.2 Reduction of intra- and inter- dialytic symptoms and improvement in quality of life**

Regarding improvement of patient's symptoms during HD, some data are available in the literature but they are mostly based on secondary outcome analysis and show only limited evidence of benefit. Basile et al. (2001) prospectively followed patients for up to 36 months with BV-regulated HD during which period nurses and patients had to fill a symptoms questionnaire for each HD session. A reduction of muscle cramps during HD and an improvement in the post-HD asthenia score were found to be significantly associated with biofeedback system. However, self-evaluation of other intra- and inter- HD symptoms (notably, thirst) was not significantly different between the two treatment arms.

Ronco et al. (2000) found a significant reduction of the proportion of sessions with selfreported intradialytic symptoms following treatment with BV-controlled UF (21% vs. 76%, p<0,001). In addition, Santoro et al. (2002) also showed a 10% decrease of interdialytic symptoms following treatment with BV-controlled HD.

In a study by Déziel et al. (2007), the Kidney Disease and Quality of Life questionnaire (KDQOL) was used to evaluate quality of life at baseline and after 6 months of treatment with either Hemocontrol® or standard HD. Among the 20 items related to physical and mental health, only one parameter, burden of kidney disease, was significantly improved in the Hemocontrol® group versus the control group. Finally, in a randomized controlled trial of 60 patients, Nesrallah et al. (2008) did not find any significant difference with regard to dialysis-related symptoms and quality of life between the two treatment groups (Hemocontrol® versus standard HD) despite the fact that a reduction of IDH could be observed.

### **5.3.3 Hypertension and volume control**

Three RCT specifically assessed the utility of BV regulation devices in improving fluid status and/or BP control in chronic hemodialysis patients. First, Dasselaar et al. (2007b) studied 12 hypertensive and mild volume-overloaded patients managed with either standard HD or BV tracking, where dry weight reduction was gradually undertaken by nephrologists according to clinical judgement. At 12 weeks, patients treated with BV regulation had a significantly lower pre- and post- HD systolic and diastolic blood pressure. Patients achieved larger UF volume without any change in RBV and showed reduction in extracellular water (determined by bioimpedance analysis). Despite these improvements in surrogate markers of volume status, no difference in mean weight from baseline could be observed. Authors concluded that this observation could result from increase in lean body mass; however, other specific nutritional parameters were not measured.

Second, in a trial published by Nesrallah et al. in 2008, volume-overloaded patients were included if bioimpedance displayed an extracellular fluid volume (ECFV) of at least 45%. In the treatment group, dry weight was adjusted by an algorithm guided by the Hemocontrol® biofeedback software based on plasma-refilling characteristics. At 6 months, there was no statistically significant difference between the two groups in the primary endpoint (change in ECFV) nor were there any significant differences in systolic blood pressure, total UF and interdialytic weight gain.

Finally, in a trial by Déziel et al. (2007), change in home blood pressure was evaluated following treatment with BV device versus standard HD. Patients were not selected on the basis of prior hypertension or volume overload history. While the use of Hemocontrol® effectively reduced home systolic BP, the clinical-based decision algorithm to manage BP in

Automated Blood Volume Regulation During Hemodialysis 41

multi-centered, randomized, controlled trial of 443 chronic HD patients followed for 6 months during which ultrafiltration was either managed according to Crit-Line® values of RBV reduction, or by usual clinical strategies. Patients were not selected on a basis of prior IDH history, and the algorithm of the treatment group was only proposed and not mandatory. During the follow-up period, there were no statistically significant differences between the two groups regarding the number of IDH, the occurrence of intradialytic symptoms and the control of BP. Surprisingly, the risk ratios for both non-access and accessrelated hospitalizations were higher in the Crit-Line® group (adjusted RR 1,61 and 1,52; pvalue 0,01 and 0.04, respectively). Mortality was 8.7% in the treatment group and 3.3% in the control group (p=0.021). The authors concluded that the availability of Crit-Line® may alter clinicians' behaviour and may cause a risk for patients, although these results have to be interpreted cautiously since the control group had an atypically low hospitalization and

One of the potential risks of automated BV regulation using sodium (Na) or conductivity modulation is alteration in sodium removal, with consequent Na overload and increased thirst, which can theoretically lead to increased interdialytic weight gain and worsening hypertension. Most of the studies described above did not find a significant change in pre and post HD sodium concentration (Santoro et al., 2002; Wolkotte et al., 2002; Dasselaar et

Moret et al. (2006) assessed the effect of such devices on sodium transfer during hemodialysis. In a cross-over randomized trial of 10 patients with frequent hypotension, plasma conductivity (PC) and ionic mass balance (IMB) were compared in four different HD modalities: standard HD with fixed Na concentration (140 mmol/L), linear Na profiling (150 to 140 mmol/L), BV-controlled feedback with Hemocontrol® (mean dialysate conductivity (DC) 14,0 mS/cm) and plasma-conductivity (PC)-controlled feedback with Diacontrol® (see below) (post-dialytic PC target of 14,0 mS/cm). Mean pre- and post-dialytic PC were statistically higher during Na-profiled HD, and post-dialytic PC was lower in PC-controlled feedback, compared to the other three modalities. The effects of BV-regulated HD on PC and IMB did not differ from those of standard HD, and thus it seems that BV-regulated HD can

Three other biofeedback systems were designed to reduce the occurrence of hypotensive episodes during HD. Rather than focusing on BV changes during HD, these devices use other targets (e.g. arterial BP) or other means of action (e.g. thermal balance, plasma

Arterial pressure biofeedback aimed at stabilizing BP during HD uses repetitive measurement of arterial blood pressure as the monitored parameter and a fuzzy-logic system as the controller of fluid removal. Created by B. Braun and implemented on the Dialog Advanced machines, the APBS® (Automatic Blood Pressure Stabilization system) puts blood pressure itself as the main input to the automatic fuzzy controller rather than a surrogate marker (e.g. blood volume). Fuzzy logic is a problem-solving system, rather than

al., 2007b, etc.), although plasma Na is a poor surrogate of real sodium balance.

be prescribed without any safety concern regarding sodium loading.

**6. Other biofeedback systems**

**6.1 Arterial pressure biofeedback**

conductivity). They are reviewed here briefly.

mortality rate.

**5.4 Blood volume biofeedback and sodium overload** 

the standard group was as effective, and the overall difference between the groups was not significant.

In summary, no randomized trial has clearly demonstrated that the use of biofeedback devices is superior to standard HD and clinical judgement in reducing dry weight in volume expanded patients. Biofeedback devices may be of value in reducing blood pressure in hypertensive patients, although a systematic and clinical treatment algorithm may be as useful.

### **5.3.4 Reduction of left ventricular dysfunction**

Cardiovascular morbidity and mortality are extremely high among chronic HD patients. Aside from the conventional risk factors for atherosclerosis, it was proposed that recurrent subclinical myocardial ischemia occurring during HD, as a result of silent decrease in myocardial perfusion, may contribute to the excessive cardio-vascular burden. In support of this hypothesis, Selby et al. (2006) demonstrated that reversible regional wall motion abnormalities which develop in a majority of hypotension-prone patients during HD, were substantially reduced with biofeedback dialysis. However, the observation period in this study was only 4 weeks, and it is unknown at the present time whether biofeedback HD provides any benefit on long-term cardiac dysfunction.
