Continuous, on-line determination of the plasma refill rate during combined hemodialysis and ultrafiltration

Determining the correct dry weight and reaching a situation of true euvolemia
in patients who are treated with hemodialyse is very difficult. A too high
estimation of dry weight leads to chronic overvulling and hypertension, with an
increase risk of cardiovascular events on the longer term. A too low estimation
of dry weight not only leads to hypotension during the hemodialysis treatment
itself, but also during the interdialytic interval. The accompanying symptoms
and signs limit the quality of life.

There is no gold standard for determination of dry weight. The most used and
accepted methods are bioimpedance analysis, ultrasonography of the vena cava
and natriuretic peptides such as BNP. These methods are time-consuming and not
very practical because of the need for specialized personnel.

Determination of the plasma refill rate (PRR) during dialysis is not possible
without the use of radioactively labelled substances. We have developed a
method that allows on-line determination of the PRR non-invasively and
continuously. During pilot research with hypotension prone patients, in which
we investigated whether the PRR could be improved by means of two
interventions, we saw that the refill during the second half of dialysis
stopped in most of these hypotension prone patients. This led to the following
hypothesis:

Hypothesis: the disappearing of refill indicates euvolemia of the interstitium.

Methodology (part A):

(1) What is the intra-individual variation in refill?

(2) Is the magnitude of the ultrafiltration rate of influence on refill?

(3) Is the amount of the initial intended blood volume decline of influence on
refill?

Implementation (part B):

(4) Is the moment that refill declines a good indication of reaching euvolemia
of the interstitium?

Question 1: What is the intra-individual variation in refill?
Rationale: It is necessary to know the intraindividual variations in refill
before refill changes can be used as a new method to determine dry weight.
-Protocol:
Dialysis 1: determination of lowest achievable blood volume (BV) change
(=lowest achievable value during dialysis without hypotension or the value at
which hypotension occurs) during dialysis with linear ultrafiltration (UF).
Dialysis 2: repeat dialysis 1.
Dialysis 3: With the same UF need as dialysis 1, UF is started at 3x linear UF
rate until the BV target range is reached. This range is defined as the lowest
achievable BV change, as found during dialysis 1, +2.5%. Start refill
measurement: the UF rate is continuously adjusted by a software feedback
algorithm to keep BV within the target range. I this situation UF rate equals
refill.
Dialysis 4: repeat dialysis 3.

Question 2: Is the magnitude of the ultrafiltration rate of influence on refill?
-Rationale: it is possible that the speed at which the refill inducing factor
(= BV reduction) is presented, is of influence on refill. A lower UF rate
implies that the same reduction in BV will be achieved later, in other words
the refill inducing factor is presented slower.

-Protocol:
Dialysis 5: repeat dialysis 3, but with an initial speed of 2x instead of 3x
linear UF rate.
Dialysis 6: repeat dialysis 6.

Question 3: Is the amount of the initial intended blood volume decline of
influence on refill?
- Rationale: it is possible that the initial amount of BV decline is of
influence on activating refill. This is investigated by setting the target BV
range at a higher level with an unchanged initial UF rate. The refill mechanism
is induced less in this way.

- Protocol:
Dialysis 7: repeat dialysis 3, but with BV target range set +2.5% higer than in
dialkysis 2.
Dialysis 8: repeat dialysis 7.

Question 4: Is the moment that refill declines a good indication of reaching
euvolemia of the interstitium?
- Rationale: Zie *Relevant Literature*.
- Protocol:
(A). Dry weight is determined by the usual clinical methods. Determine
hydration status: BNP before and after dialysis, pattern of relative blood
volume change, blood pressure and heart rate changes during dialysis,
extracellular volume using bio-impedance analysis and vena cava ultrasonography
one houd after dialysis, chest X-ray, 24 hour blood pressure measurement 1 day
after dialysis.

Dialysis 1: determination of lowest achievable blood volume (BV) change
(=lowest achievable value during dialysis without hypotension or the value at
which hypotension occurs) during dialysis with linear ultrafiltration (UF).
Dialysis 2: With the same UF need as dialysis 1, UF is started at 3x linear UF
rate until the BV target range is reached. This range is defined as the lowest
achievable BV change, as found during dialysis 1, +2.5%. Start refill
measurement: the UF rate is continuously adjusted by a software feedback
algorithm to keep BV within the target range. I this situation UF rate equals
refill.
When refill declines to 0, UF is stopped (=moment of *refill-euvolemia*). When
this is before the target UF volume is reached, the target dry weight is
increased by the amount that was not removed. When this is after target UF
weight is reached, target dry weight is decreased by the extra amount that was
removed. After this regular dialysis sessions are continued with the new target
dry weight.

(B) After 2 weeks dialysis with the new target dry weight, the measurements
under (A) are repeated to determing the hydration status.
-Analysis: changes in parameters that determine volume status before and after
changing target dry weight on the basis of *refill-euvolemia*.
- Power analysis: (a) adjusting target dry weight increases mean 24 hour blood
pressure by 20 mmHg (SD 25 mmHg) in overhydrated patients and decreases it by
20 mmHg in underhydrated patients. Power 0.8, p <0.05: sample size 15 patients;
(b) adjusting target dry weight changes BNP by 500 pg/ml (SD 400 pg/ml). Power
0.8, p <0.05: sample size 16 patients.

Taking into account loss to follow-up, a sample size of 20 patients is needed.

The patients are compared under different ultrafiltration conditions (part A).
Next, the target dry weight is determined (using primary study parameters), and
the patients are ultrafiltrated according to the protocol. Then the volume
status is determined again using primary study parameters and the hypothesis is
tested (part B).

- Natriuretic peptides (BNP) befor and after dialysis: 2 extra blood samples
taken from the arterial port of the dialysis tubing
- Non-invasive measurement of the extracellular volume using bioimpedance +
ultrasonopgraphy of the vena cava one hour after dialysis: total time one hour
- Chest x-ray: 0.1 mSv
- 24-hour blood pressure measurement 1 day after dialysis: limits the patient
in his freedom of movement
- Complete Quality of life-index form.

Risk:
- The risk of hypotension during hemodialysis is always present. We do not
expect this risk to be higher when our intervention is applied.
- Chaning the dry weight on the basis of changes in refill patterns carries the
risk of putting the patients in an overhydrated state.