**3. Blood volume regulation**

### **3.1 Concept of plasma refilling**

Blood volume is dependent on two main factors: plasma refilling capacity and UF rate. During HD, fluid is removed directly from the intravascular compartment. Total body water (TBW), which is about 60% of body weight (BW), is distributed in part in the intracellular (40% BW) and in part in the extracellular (20% BW) compartments. The latter is further subdivided in the interstitial (15% BW) and the intravascular (5% BW) spaces. Thus, only 8% of the TBW is readily available for UF. Therefore, in order to remove a substantial amount of fluid during a short period of time, the vascular compartment needs to be continuously refilled from the interstitial space.

Plasma refill is mostly driven by hydrostatic and oncotic forces. During the first part of a HD session, the vascular oncotic pressure raises and the hydrostatic pressure lessens as a result of progressive UF. Pressure gradients thus created drive the water back into the vascular space until a new equilibrium is reached. As UF and water withdrawal from the intravascular space continue, the new disequilibrium thereby generated has to be once again balanced, and so on until the end of the session (Santoro et al., 1996). Several factors can influence rate of plasma refilling by acting on these forces: hydration status, plasma osmolality, and plasma protein concentration. Patient's proper refilling capacity, which is not measurable as a parameter, also has an effect on the rate at which water moves back in the blood vessels. Overall, IDH is generated when the imbalance between UF rate and plasma refilling capacity cannot be surpassed by cardio-vascular compensatory reflexes.

### **3.2 Relative blood volume measurement**

Cardio-vascular reactivity and plasma refilling capacity of each patient, albeit central in the pathogenesis of IDH development, are difficult to assess and therefore are not convenient as monitoring tools. Direct measurement of blood volume is feasible, classically using dilution of radioactively labelled blood elements (such as 131I albumin or 51Cr red blood cells), but it implies serial blood tests and radiation, and so is clearly impractical for the repetitive assessment of blood volume. One way to circumvent this problem is to measure blood volume change during HD which, as a surrogate marker of vascular refilling, can be estimated using bedside devices.

medication, etc. On the other hand, factors associated with the dialysis prescription itself can also contribute to hemodynamic instability: short HD sessions, high ultrafiltration rate, high dialysate temperature, low dialysate sodium concentration, inflammation caused by membrane activation, etc. As a consequence, various interventions aimed at modulating these parameters have been proposed to ameliorate the vascular tolerance to ultrafiltration

On a physiological basis, IDH can be viewed as the inability of the cardio-vascular system to respond adequately to the reduction of blood volume. Cardio-vascular reactivity involves reflex activation of the sympathetic system, with appropriate tachycardia and arterial and venous vasoconstriction in response to cardiac underfilling and hypovolemia. These compensatory mechanisms are altered in some patients, which put them at risk of developing IDH. However, these are difficult to assess and to modify. Comprehensive study of blood volume regulation during HD can help understand IDH susceptibility of

Blood volume is dependent on two main factors: plasma refilling capacity and UF rate. During HD, fluid is removed directly from the intravascular compartment. Total body water (TBW), which is about 60% of body weight (BW), is distributed in part in the intracellular (40% BW) and in part in the extracellular (20% BW) compartments. The latter is further subdivided in the interstitial (15% BW) and the intravascular (5% BW) spaces. Thus, only 8% of the TBW is readily available for UF. Therefore, in order to remove a substantial amount of fluid during a short period of time, the vascular compartment needs to be continuously

Plasma refill is mostly driven by hydrostatic and oncotic forces. During the first part of a HD session, the vascular oncotic pressure raises and the hydrostatic pressure lessens as a result of progressive UF. Pressure gradients thus created drive the water back into the vascular space until a new equilibrium is reached. As UF and water withdrawal from the intravascular space continue, the new disequilibrium thereby generated has to be once again balanced, and so on until the end of the session (Santoro et al., 1996). Several factors can influence rate of plasma refilling by acting on these forces: hydration status, plasma osmolality, and plasma protein concentration. Patient's proper refilling capacity, which is not measurable as a parameter, also has an effect on the rate at which water moves back in the blood vessels. Overall, IDH is generated when the imbalance between UF rate and plasma refilling capacity cannot be surpassed by cardio-vascular compensatory reflexes.

Cardio-vascular reactivity and plasma refilling capacity of each patient, albeit central in the pathogenesis of IDH development, are difficult to assess and therefore are not convenient as monitoring tools. Direct measurement of blood volume is feasible, classically using dilution of radioactively labelled blood elements (such as 131I albumin or 51Cr red blood cells), but it implies serial blood tests and radiation, and so is clearly impractical for the repetitive assessment of blood volume. One way to circumvent this problem is to measure blood volume change during HD which, as a surrogate marker of vascular refilling, can be

(UF), but with variable efficacy and limited benefits.

individual patients.

**3. Blood volume regulation 3.1 Concept of plasma refilling** 

refilled from the interstitial space.

**3.2 Relative blood volume measurement**

estimated using bedside devices.

Relative blood volume (RBV) is the term used to describe « the blood volume at any time as a percentage of the blood volume at the commencement of treatment » (Nesrallah et al., 2008). Most of the non-invasive devices extrapolate the RBV change from the variation of the hemoconcentration of a blood element. The basic premise of this calculation is that if the blood component remains constant throughout the HD session (i.e., the numerator), the variation of its concentration is necessarily due to the change in the blood volume (i.e., the denominator). The various devices available vary in the blood element they measure (i.e., red blood cells, hematocrit, total protein concentration) and in the method used to measure it (i.e., optical absorbance, ultrasound, etc.).

One caveat of these techniques is that they are based on the assumption that uniform mixing of the measured blood element and plasma occurs throughout the whole circulation (Dasselaar et al., 2007a). Venous (or systemic) hematocrit (Hctsys) is usually higher than whole-body hematocrit (Hctw), due to the dynamic reduction of hematocrit in the microcirculation during blood flow through capillaries and venules. This is expressed as the F-cell ratio, Hctw/Hctsys. However, during UF, it was shown that the F-cell ratio rises as a result of the compliance of the microcirculation and fluid transfer to the macrocirculation. Therefore, the equations on which the inference of the blood volume change during HD is based may not be always valid (Mitra et al., 2004).

In a study from Dasselaar et al. (2007a), the blood volume reduction estimated by three commonly used devices (Crit-line®, Hemoscan® and BVM®, see below) was compared to a standard laboratory-derived Hb relative blood volume measurement during two HD sessions. It was shown that all three devices systematically overestimate the RBV reduction at modest RBV change, and underestimate the real fall in blood volume at higher RBV decline.

In addition, RBV monitoring also assumes that red blood cell mass or plasma protein density remains constant throughout the length of the session, which may not be true if hemolysis or blood leak happens, or when a blood transfusion is given.

### **3.3 Relation between relative blood volume and intradialytic hypotension**

While hypovolemia is clearly a major determinant in the pathogenesis of IDH, the link between blood volume reduction and appearance of arterial hypotension is still a matter of debate. Recent studies have been unable to find a linear relationship between RBV and blood pressure, and a specific threshold to which hypotension will certainly occur does not seem to exist, even in an individual patient. This is probably because of variations, for each treatment, in the patient's ability to activate cardio-vascular compensatory mechanisms, in order to offset BP reductions induced by a wide range of hypovolemic states.

In fact, in many trials where blood volume (BV) biofeedback was effective in reducing the occurrence of IDH, there was no difference in the final RBV reached by either the standard treatment or the BV-controlled treatment. According to some authors, it is possible that RBV reduction *per se* is not the main risk factor for development of IDH. Rather, the excessive fluctuations of BV and the form of the RBV slope during HD may contribute more to hemodynamic instability (Andrulli et al., 2002). Indeed, the slope of the RBV curve with BV regulation device is different from that produced by standard HD (Franssen et al, 2006). The initial phase is usually steeper (meaning higher UF rate), which is rendered possible and tolerable because of higher initial interstitial pressures and better plasma refilling rate. The second phase is characterized by a reduced UF rate, which in turn make the RBV more stable and the patient less prone to IDH in this vulnerable period.

Automated Blood Volume Regulation During Hemodialysis 31

The Hemocontrol® blood volume management system was first designed by Santoro and colleagues (Santoro et al., 1994) and afterwards modified in collaboration with the Hospal-Gambro research group. It is available on the Integra® and Artis® machines (with a few

This biofeedback system is based on an automatic multi-input multi-output controller (MIMO) capable of integrating a multitude of signals and to modulate controlled variables to force the blood volume reduction along a pre-defined trajectory towards a pre-defined target of blood volume reduction (Locatelli et al., 2005). This results in a smoother and more gradual decline of relative blood volume, limiting the irregularity of BV variation that was

Basically, the monitored parameters are the actual UF (or weight loss), the actual dialysate sodium (or conductivity) and the actual blood volume change. The differences between the target values of the same three parameters (that is: desired UF, desired dialysate sodium (or equivalent conductivity) and desired final blood volume change) and the actual parameters serve as inputs to the MIMO controller. At any moment, the actual BV curve is plotted against the pre-determined BV trajectory and, should it deviate the least, automatic modulation of the UF rate and dialysate sodium (or conductivity) allows smooth redirection

The blood volume change during dialysis is monitored using an optical sensor located in the arterial line that measures on-line hemoglobin (Hb) concentration by optical absorbance, according to Lambert-Beer law. The law states that Hb is a function of monochromatic light absorbance. Provided that the amount of Hb does not change, the blood volume variation

The three targets prescribed by the physician (total UF, final dialysate sodium, and final BV reduction) are computed in the Hemocontrol® software and are compared to the actual same parameters (UF, dialysate sodium, and RBV) on a continuous basis during HD. The controller can modulate the UF rate and dialysate sodium in order to bring the actual

from the start of the session can be inferred from the change in Hb concentration.

**5.1 Hemocontrol® system**

shown to be predictive of IDH (Andrulli et al., 2002).

Fig. 1. Hemocontrol® biofeedback system (from Gambro).

parameters back on the pre-determined trajectory of the RBV curve.

to the « ideal » curve (figures 1 and 2).

updates on the latter).
