**5.1 Hemocontrol® system**

30 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

While monitoring may help to understand how BV is regulated during UF in an individual patient, the HD prescription often remains empirical. The hemodynamic stability during the previous HD sessions dictates the delivered parameters of the next HD treatments. Dialytic parameters such as UF rate and dialysate sodium concentration are usually set at the start of the HD session, and remain fixed throughout the treatment, with the assumption that they continue to be adequate for the whole treatment duration. However, this is not taking into account that patients may undergo physiologic variations during HD, and that fixed parameters, creating labile gradients, may not always be appropriate and may promote IDH. In fact, the standard HD prescription lacks a rapid retroactive response in case of variation of the monitored parameter, as the action to bring it back towards the desired value are taken manually (by the operator, a nurse or physician) or semi-automatically (authorized by the operator) (Locatelli et al., 2005), thus implying a certain lag of time that

The method used to traditionally prescribe HD parameters is far from how the kidneys really behave to maintain internal homeostasis, keeping biologic variables in very tight ranges through instantaneous adjustments in response to precise negative or positive feedback loops. To try to get closer to what would be called « physiological dialysis », technological advances of the last decades have conducted to the development of sophisticated softwares that allow automated biofeedback. The concept of biofeedback is based on repetitive on-line measurements of the patient's biochemical parameters with biosensors, which are then constantly analysed by an automatic controller as being within the target values pre-set by the operator, or not. If the measured parameter is within the desired values considered safe, the treatment continues unchanged. If not, an action to bring it back towards the aimed values is immediately and automatically undertaken through the

The theoretical advantage of such devices is that they not only rapidly detect physiological abnormalities which may predict hemodynamic instability (blood volume reduction for example), but they automatically adjust one or more dialytic parameters to correct the situation. This obviates the need to perform manual changes by the operator and, at the same time, avoids the time lag before the action is undertaken. By modulating on-line some of the delivered dialysis parameter, these devices also address the physiological variations occurring during HD (and the variability of the patient's parameters from session to session), and thus

At the present time, biofeedback systems are available for different parameters: relative blood volume, thermal energy balance, plasmatic conductivity, to which arterial pressure feedback using fuzzy logic control can be added. These devices are described here, with

Currently, only two commercially blood volume biofeedback devices are available: the Hemocontrol® (Gambro) and the BVM® (Fresenius) systems. Although both monitor change in relative blood volume during HD, they use different technologies and different

effectors, in a closed-loop that insures the stability of the monitored parameter.

provide more physiological dialysis, which may be more suited to prevent IDH.

**4. Biofeedback system**

may be deleterious if IDH is to be prevented.

emphasis on blood volume biofeedback.

integration systems. They are reviewed here.

**5. Blood volume biofeedback**

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 updates on the latter).

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

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

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

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

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

Automated Blood Volume Regulation During Hemodialysis 33

Because of safety concerns, limits (or tolerance range) concerning maximum UF rate and sodium/conductivity range are also pre-specified (figure 2). Of note, there is no specific probe for plasmatic sodium with Hemocontrol®, as it is the case for Diacontrol® (see below). The dialysate conductivity is modulated toward a mean final value, but not in an

Overall, the goal of the Hemocontrol® system is to reach the same sodium and water balance as would a traditional approach, while the hemodynamic tolerability is enhanced by the profiling of the UF rate and the dialysate conductivity. Indeed, when the blood volume approaches the lower acceptable value for a given patient, UF is diminished or ceased while the dialysate conductivity is raised. Conversely, UF rate can be increased and/or dialysate conductivity decreased when blood volume is higher than expected on the pre-defined BV

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) »

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

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

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

Actual UF rate = initial UF rate x factor (1)

Initial UF rate = 2 x (remaining UF/remaining time) (2)

automatic feedback response to patient's plasmatic sodium.

concept instead of tracking an optimal curve to reach a final BV.

calculated from the changes in sound transmission velocity.

trajectory.

**5.2 BVM® Fresenius**

reaching the cRBV:

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

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 actual curve parallel to the optimal trajectory.

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


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 session.

Because of safety concerns, limits (or tolerance range) concerning maximum UF rate and sodium/conductivity range are also pre-specified (figure 2). Of note, there is no specific probe for plasmatic sodium with Hemocontrol®, as it is the case for Diacontrol® (see below). The dialysate conductivity is modulated toward a mean final value, but not in an automatic feedback response to patient's plasmatic sodium.

Overall, the goal of the Hemocontrol® system is to reach the same sodium and water balance as would a traditional approach, while the hemodynamic tolerability is enhanced by the profiling of the UF rate and the dialysate conductivity. Indeed, when the blood volume approaches the lower acceptable value for a given patient, UF is diminished or ceased while the dialysate conductivity is raised. Conversely, UF rate can be increased and/or dialysate conductivity decreased when blood volume is higher than expected on the pre-defined BV trajectory.
