**4. Intradialytic haemodynamic stability**

Based on the European Best Practice Guidelines (EBPG) for hemodynamic instability (Kooman et al., 2007) the average incidence of hypotensive episodes during dialysis therapy is 20%. In some cohort studies, hypotensive events were observed in up to 33% of cases during dialysis therapy. Hypotensive episodes during the course of dialysis therapy are closely correlated with morbidity and mortality and play a fundamental role in the development of myocardial and cerebral ischemia. Frequent occurrences of hypotension lead to chronic over-hydration and have a negative impact on the clearance of dissolved substances due to water retention.

The first study on HBS was run by Santoro in 1994 which was addressed to check the feasibility of the system. They included a small sample of five patients in a HD-HBS-HD experimental set-up. The occurrence of dialysis complicated by severe hypotension was 8 in HD, 1 in HBS and 5 in the second HD period.

Subsequently, they did another clinical investigation on 8 hypotension-prone patients in a prospective crossover study including 8 hypotension-prone haemodialysis patients (Santoro et al, 1994). They compared conventional haemodialysis (HD) to the HBS, following a protocol with an HD1-HBS-HD2 sequence, with each treatment period lasting one month. Changes in predialysis to postdialysis systolic arterial pressure were lower in the HBS

Blood Volume Regulation 243

phase over 3 weeks. There was a reduction in symptomatic episodes (per patient over 3 weeks) from 3 during HD to 0.13 with HBS (*P*<0.001). The number of treatments affected by a reduction of > 40% in systolic blood pressure decreased from 1.4 to 0.46 and episodes during which relative blood volume fell by > 10% were reduced from 6.3 to 1.13 per patient and treatment period (*P*<0.001). The treatment of 28 hypertensive patients with either standard HD or HBS in a randomised manner showed significantly fewer hypotensive episodes, lower brain natriuretic peptide levels (not significant) and a significant reduction

Since, most of the studies, addressed the intradialytic hypotension, we summarized the data about the cardiovascular instability (intradialytic hypotension and weight loss) in the following pooled analysis. We included all the studies of any type (random cross-over, random not cross over and not random), which reported available data in form of percentage of dialysis complicated by hypotensions or average frequency of hypotension

Fig. 4. Pooled analysis of intradialytic hypotensions. The figure shows the hypotension

We did not include in the analysis those studies for which confounding factors like hemodiafiltration and/or acetate free biofiltration, cold dialysate temperature if not present both in the intervention and control treatments could interfere with data interpretation. For each study we extracted the total number of treatments performed both with standard and HBS hemodialysis and the total events (dialysis complicated by hypotensions or major hypotension events) for each one, or the meanSD hypotension events as reported in the

events expressed as mean ± SD over the total number of dialysis.

paper.

in predialysis blood pressure in the HBS group (Neshrallah et al., 2008).

**5. Pooled analysis about intradialytic cardiovascular stability** 

events, disregarding this was or was not the primary response variable.

period (-12.4%) compared to both HD periods (-20% in HD1 and -17.5% in HD2; *P*<0.05), despite comparable total ultrafiltration rates and mean treatment times. A significant reduction in the number of severe hypotensive episodes (HBS: 3, HD1: 26, HD2: 16; *P*<0.05) and fewer intradialytic events, such as cramps and nausea, were observed. This resulted in a reduced need for therapeutic isotonic saline in each session (HBS: 60 mL, HD1: 160 mL, HD2: 95 mL; *P*<0.05).

The first randomised, controlled trial on HBS was published by Ronco (Ronco et al, 2000), who treated 12 hypotension-prone patients with either 2 weeks of HD followed by 2 weeks of HBS or *vice versa* (6 session per patient and 72 in total)*.* They also observed fewer hypotensive episodes with HBS (24/72 vs 59/72 in HD; *P*<0.001). Saline infusion was required in 15 cases during HBS in comparison to 57 cases during HD (*P*<0.001).

Medium-term treatment with HBS was evaluated in a prospective study published by Basile (Basile et al., 2001). They investigated the efficacy and safety of HBS vs conventional HD in 19 hypotension-prone uraemic patients. After a period of 6 months on HD, patients switched to HBS for 14 to 30 months. A wash-out phase of 4 weeks was followed by a shortterm treatment period of 3 weeks, first with HD and then after wash-out with HBS. The overall occurrence of symptomatic hypotension and muscle cramps was significantly reduced, with a decrease of 34% and 40% respectively (*P*-values: <0.002 and <0.02 respectively). In the short-term part of the study, the vascular refilling (residual BV%/ECV% ratio) was significantly higher during the HBS treatment.

Several other groups have been shown improvement in haemodialysis-induced hypotension in hypotension-prone patients [Santoro et al., 2002; Franssen et al., 2005; Selby et al., 2006; Moret et al., 2006; Dasselaar et al., 2007; Neshrallah et al; Winkler et al., 2008).

Ambulatory blood-pressure measurement in one prospective trial revealed that during the first 16 hours post-HD, systolic blood pressure was significantly higher with HBS in comparison to conventional HD (Franssen et al., 2005). Other trials showed a significant overall decrease in systolic blood pressure in both groups during the study period (*P*=0.005 vs the baseline) (Deziel et al., 2007). However, the difference between the HD and HBS arms was not significant.

Attempts to correct extracellular fluid volume (ECFV) with aggressive ultrafiltration often leads to intradialytic hypotension. Therefore, it was of interest to see whether HBS treatment could safely reduce ECFV in extracellular fluid-expanded patients (Neshrallah et al., 2008). However, the results of this randomised trial revealed no change with HBS, even after multivariate adjustment.

Bégin et al. investigated whether improvement in hypotension-related events can be explained by changes in dry weight (Begìn et al., 2002). In their prospective trial in 7 hypotension-prone patients, they observed the greatest improvement in event-free sessions (i.e. sessions not requiring therapeutic intervention for hypotension-related signs and symptoms) in patients who had the smallest changes in dry weight. This is supported by other studies, which revealed that HBS was not effective in reducing post-HD dry weight (Fransesen et al, 2005, Dasselaar et al., 2007). A randomised, controlled trial demonstrated that the best responders to HBS treatment were those with higher predialysis systolic bloodpressure values compared to poor responders (*P*=0.04) (Santoro et al., 2002).

While most data on HBS were obtained from the study of hypotension-prone patients, one trial was especially designed to look at the effects in non-hypotension-prone uraemic patients (McIntyre et al., 2003). During this prospective study, 15 patients received conventional HD over 3 weeks followed by a 2-week wash-out phase and an HBS-treatment

period (-12.4%) compared to both HD periods (-20% in HD1 and -17.5% in HD2; *P*<0.05), despite comparable total ultrafiltration rates and mean treatment times. A significant reduction in the number of severe hypotensive episodes (HBS: 3, HD1: 26, HD2: 16; *P*<0.05) and fewer intradialytic events, such as cramps and nausea, were observed. This resulted in a reduced need for therapeutic isotonic saline in each session (HBS: 60 mL, HD1: 160 mL,

The first randomised, controlled trial on HBS was published by Ronco (Ronco et al, 2000), who treated 12 hypotension-prone patients with either 2 weeks of HD followed by 2 weeks of HBS or *vice versa* (6 session per patient and 72 in total)*.* They also observed fewer hypotensive episodes with HBS (24/72 vs 59/72 in HD; *P*<0.001). Saline infusion was

Medium-term treatment with HBS was evaluated in a prospective study published by Basile (Basile et al., 2001). They investigated the efficacy and safety of HBS vs conventional HD in 19 hypotension-prone uraemic patients. After a period of 6 months on HD, patients switched to HBS for 14 to 30 months. A wash-out phase of 4 weeks was followed by a shortterm treatment period of 3 weeks, first with HD and then after wash-out with HBS. The overall occurrence of symptomatic hypotension and muscle cramps was significantly reduced, with a decrease of 34% and 40% respectively (*P*-values: <0.002 and <0.02 respectively). In the short-term part of the study, the vascular refilling (residual

Several other groups have been shown improvement in haemodialysis-induced hypotension in hypotension-prone patients [Santoro et al., 2002; Franssen et al., 2005; Selby et al., 2006;

Ambulatory blood-pressure measurement in one prospective trial revealed that during the first 16 hours post-HD, systolic blood pressure was significantly higher with HBS in comparison to conventional HD (Franssen et al., 2005). Other trials showed a significant overall decrease in systolic blood pressure in both groups during the study period (*P*=0.005 vs the baseline) (Deziel et al., 2007). However, the difference between the HD and HBS arms

Attempts to correct extracellular fluid volume (ECFV) with aggressive ultrafiltration often leads to intradialytic hypotension. Therefore, it was of interest to see whether HBS treatment could safely reduce ECFV in extracellular fluid-expanded patients (Neshrallah et al., 2008). However, the results of this randomised trial revealed no change with HBS, even after

Bégin et al. investigated whether improvement in hypotension-related events can be explained by changes in dry weight (Begìn et al., 2002). In their prospective trial in 7 hypotension-prone patients, they observed the greatest improvement in event-free sessions (i.e. sessions not requiring therapeutic intervention for hypotension-related signs and symptoms) in patients who had the smallest changes in dry weight. This is supported by other studies, which revealed that HBS was not effective in reducing post-HD dry weight (Fransesen et al, 2005, Dasselaar et al., 2007). A randomised, controlled trial demonstrated that the best responders to HBS treatment were those with higher predialysis systolic blood-

While most data on HBS were obtained from the study of hypotension-prone patients, one trial was especially designed to look at the effects in non-hypotension-prone uraemic patients (McIntyre et al., 2003). During this prospective study, 15 patients received conventional HD over 3 weeks followed by a 2-week wash-out phase and an HBS-treatment

required in 15 cases during HBS in comparison to 57 cases during HD (*P*<0.001).

BV%/ECV% ratio) was significantly higher during the HBS treatment.

Moret et al., 2006; Dasselaar et al., 2007; Neshrallah et al; Winkler et al., 2008).

pressure values compared to poor responders (*P*=0.04) (Santoro et al., 2002).

HD2: 95 mL; *P*<0.05).

was not significant.

multivariate adjustment.

phase over 3 weeks. There was a reduction in symptomatic episodes (per patient over 3 weeks) from 3 during HD to 0.13 with HBS (*P*<0.001). The number of treatments affected by a reduction of > 40% in systolic blood pressure decreased from 1.4 to 0.46 and episodes during which relative blood volume fell by > 10% were reduced from 6.3 to 1.13 per patient and treatment period (*P*<0.001). The treatment of 28 hypertensive patients with either standard HD or HBS in a randomised manner showed significantly fewer hypotensive episodes, lower brain natriuretic peptide levels (not significant) and a significant reduction in predialysis blood pressure in the HBS group (Neshrallah et al., 2008).
