Accuracy and safety of online clearance monitoring based on conductivity variation

Uwe Kuhlmann1, Rainer Goldau2, Nader Samadi1, Thomas Graf2, Malte Gross2, Giancarlo Orlandini2 and Harald Lange1,

1 Centre of Internal Medicine, Clinic of Nephrology, University of Marburg, Marburg, Germany 2 Fresenius Medical Care, Schweinfurt, Germany

Abstract

Background. Haemodialysis dose has been shown to have a distinct impact upon the morbidity and mortality rate in patients on regular dialysis therapy. Accordingly, the adequacy of dialysis treatment should be guaranteed.

Methods. In 200 dialysis sessions two or three ±10% dialysate conductivity variations were applied to test patient compliance and the accuracy of an electrolyte based online clearance measurement (OCM) reflecting the total clearance of urea.

Results. Using a step profile the electrolytic clearance showed highly significant correlation with the reference data in the blood side (n=118, r=0.867, P<0.001) and dialysate side (n=118, r=0.820, P<0.001) if only reference values were taken into account for which the error in mass balance did not exceed 5%. Kt/V according to the single pool model (n=35, r=0.940, P<0.001), the equilibrated single pool variable volume kinetic model (n=36, r=0.982, P<0.001), Daugirdas formula (n=34, r=0.951, P<0.001) and direct quantification of dialysance via spent dialysate (n=26, r=0.900, P<0.001) showed outstanding correlations with electrolyte-based Kt/V at mass balance error below 5%. No adverse clinical effect of OCM was reported. Serum sodium, body weight, heart rate and breathing rate at rest, arterial pO2 and pCO2 and blood pressure before haemodialysis remained unaffected in OCM measurements in comparison with baseline parameters. A small influx of sodium (1.53±7.62 mmol) into the patient was seen following the impulse, but no signs associated with fluid overload were observed during the study period of 10 consecutive dialysis sessions.

Conclusions. The OCM option of the haemodialysis machine provides a safe and accurate tool for continuous online monitoring of total urea clearance.

Keywords: adequacy of dialysis; conductivity based clearance; haemodialysis; Kt/V; online clearance

Introduction

The morbidity and mortality rates of patients on renal dialysis therapy (RDT) are influenced by a number of factors such as age, underlying disease, malignancies as well as the quality of the haemodialysis treatment. The National Cooperative Dialysis Study (NCDS) gave evidence of a positive correlation between morbidity and mortality rate of patients on RDT and the assessment of the delivered dialysis dose [ 1]. The Kt/V index [ 2]—calculated by estimating the urea clearance (K), the urea distribution volume of the patient (V) and the time of treatment—is commonly accepted for quantification of the dialysis dose. Different approaches are recommended to assess Kt/V. The kinetic models such as e.g. the eSPVV-KM (equilibrated single pool variable volume kinetic modelling) require several blood samples drawn at the beginning and at the end of the dialysis session or 30–60 min post-dialysis in order to take the urea rebound into consideration [ 3, 4]. Direct quantification demands complete or representative dialysate sampling [ 5]. These disadvantages prevent the dialysis dose from being assessed routinely at each dialysis.

Kt/V is affected by various factors such as the surface and type of membrane, blood and dialysate flow, fistula and cardiopulmonary recirculation. Because of dialysis-related problems like arterial hypotension with subsequent reduction of blood flow or dialysis time, microclotting of the dialyser, and vascular access problems, the delivered dose may vary from session to session. Therefore, an ideal approach should measure continuously the administered dialysis dose at each single treatment.

The diffusion coefficients of urea and electrolytes are almost equal and the electrolyte-dialysance therefore corresponds well with the clearance of urea. Conductivity-based clearance reflects the clearance of electrolytes and thus of urea [ 7]. The measurement of conductivity dialysance by change in dialysate conductivity was inaugurated in 1982 by Polaschegg [ 6]. In the present study a double probe conductivity-based online clearance measurement (OCM) (Figure 1Go) was evaluated for the accuracy of Kt/V with respect to established standard calculations of urea clearance, the urea kinetic modelling and direct quantification.



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Fig. 1. The original shape of conductivity variation. The conductivity difference between dialysate inlet and outlet of the dialyser is measured for two different dialysate inlet concentrations. This allows the calculation of the electrolyte dialysance, which is expected to be equal to the effective urea clearance. Because of the safety limits of dialysate sodium concentrations (128–157 mmol/l) the impulse is not fully balanced (baseline: 140.2 mmol/l, upper level 155 mmol/l, lower lever 132,5 mmol/l). The duration of the impulse (144 balance chamber cycles here 3.33 s/cycle) depends on the dialysate flow (here 540 ml/min). From the difference of the shaded areas the positive and negative sodium shift was calculated.

 

Methods

Patients and haemodialysis parameters
A total of 20 informed patients (14 male and six female, age 59.4±16.0 years, body weight 74.18±12.12 kg, height 1.73±0.09 m) with ESRD treated by standard haemodialysis (dialysate: Na 140 mmol/l, K 3.0 mmol/l, Ca 1.5 mmol/l, Mg 0.5 mmol/l, bicarbonate 28.0 mmol/l, glucose 2 g/l, constant ultrafiltration rate) at 9.13±14.99 months were enrolled in the study. Underlying diseases were chronic glomerulonephritis (11 patients), diabetic nephropathy (five patients), obstructive nephropathy (one patient), APCKD (two patients) and plasmocytoma (one patient). The remaining kidney function corresponded to interdialytical residual Kt/V fraction of 0.45. All patients were dialysed thrice weekly by 216±28 min plus 30 min ultrafiltration at the end of haemodialysis with the dialysis machine 4008 (Fresenius Medical Care) and the hollow fibre polysulfone membrane (F8 HPS, 1.8 m2, Fresenius Medical Care). Blood flow ranged between 200 and 250 ml/min. Dialysate flow was maintained at 540 ml/min. The ultrafiltration was 1.99±0.6 l/ dialysis. Drug therapy was not varied during the study period. Each patient was subjected to OCM during 10 sequential haemodialysis treatments.

OCM
The details of electrolytic clearance measurements, based on two conductivity probes, have been described in detail by Polaschegg [ 8]. The dialysis machine was modified by providing a second standard conductivity cell downstream of the dialyser in addition to the conventional upstream cell. No other hardware modification was done. An impulse of a delta ±10% dialysate conductivity (DC) variation of about 10 min above and 10 min below standard conductivity was applied 2–3 times per session of dialysis (Figure 1 Go). The data of DC pre- and post-dialyser and blood/dialysate/ultrafiltration flow were collected online by an additional personal computer. In order to minimize the error of clearance assessment in patients with a great intradialytic weight loss the conductivity-based clearance was calculated according to Petitclerc [ 7] by the formula, which respects the convective clearance. Eight minutes after termination of the automatic clearance measurement, blood and dialysate samples were drawn from the arterial and venous blood lines as well as from the inlet and outlet dialysate lines. The samples were submitted to the laboratory for urea tests (Hitachi 747 Automatic Analyzer) [ 9] immediately after dialysis. Additionally, a 2% computer-controlled dialysate sample was taken from the dialysate drain with a dedicated valve. To exclude phases of inactive dialysis, all bypass and alarm times were automatically recorded and considered by the software in calculating Kt/V. The dialyser clearance was corrected for recirculation three times per session by the thermodilution device [ 10] of the blood temperature monitor (BTM, Fresenius Medical Care) in order to obtain the effective clearance for determination of Kt/V by the OCM.

Using the conductivity-based clearance the correlation of total instantaneous (diffusive and convective) clearance with the reference of instantaneous blood side urea clearance and dialysate side urea clearance was determined. In order to consider the mass balance error (MBE), only those blood and dialysate side urea clearances taken simultaneously were used as reference, which varied by less than 5%. Kt/V based on the single pool kinetic model, on the equilibrated single pool variable volume-kinetic model (eSPVV-KM) or derived either from the Daugirdas equation [ 11] or obtained by direct quantification was compared with electrolyte based Kt/V of the OCM. Those OCM in which the MBE of the two reference clearances was in excess of 5% were not considered for comparison. Urea generation during dialysis treatment and the patients’ residual urea clearance were neglected. All mathematical expressions are given in the Appendix.

Clinical outcome
To assess subjective feelings every patient was interviewed by a skilled physician concerning thirst, muscle cramps, headache, nausea and vomiting after every study session. Serum sodium at start of each haemodialysis and serum sodium prior to and 8 min after the impulse were measured to detect sodium imbalance. Electrolytic balance—calculated by the area under the curve and dialysate flow—was calculated as a parameter of ionic shift balance. Fluid homeostasis was monitored by body weight, breathing and heart rate at rest and arterial pO2 and pCO2 at the start as well as by the blood pressure at the start and the end of haemodialysis. All parameters of fluid homeostasis were compared with the baseline level of the last 10 haemodialysis sessions before the study.

Statistical analysis
Descriptive statistics include the arithmetic mean, standard deviation (SD) and mean error in per cent. The Wilcoxon test was used to compare paired data. The correlation obtained from normal distributed data was analysed by the product-moment correlation test. Significance was accepted as P-value <=0.05.

The study was approved by the Ethical Committee of the University of Marburg and performed in accordance with the guidelines of the Declaration of Helsinki and fulfilled the requirements of good clinical practice.

Results

Total instantaneous electrolytic clearance (KeCN), instantaneous blood side (KeUB) and dialysate side (KeUD) clearance and recirculation
In 118 OCM (MBE<5%) KeCN was 150.0±11.85 ml/min, KeUB 152.95±10.89 ml/min and KeUD 152.6±11.04 ml/min. SD of the mass balance was 2.8%. KeUB correlated with KeUD (r=0.92, P<0.001), KeCN with KeUB (r=0.867, P<0.001) and KeCN with KeUD (r=0.820, P<0.001) significantly. Recirculation determined by thermodilution was 7.03±5.17%. Further data are given in Table 1 Go and Figure 2a Go and b Go.


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Table 1. Statistical data of 118 OCM corresponding to KeUB and KeUD paired data with MBE<5% as well as the comparison according electrolytic based Kt/V to kinetic modelling and direct quantification

 


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Fig. 2. The figure shows the individual correlation of KeUB (a) and KeUD (b) versus KeCN for mass balance <5%. Each single value of KeCN as calculated by the machine by means of dialysate side conductivity measurements has been compared to its associated reference as derived from blood/dialysate samples with respect to recirculation.

 

Electrolytic Kt/V versus single pool, eSPVV-KM and Daugirdas Kt/V
Kt/V based on OCM correlated significantly with data of the single pool model (n=35, r=0.940, P=0.001), eSPVV-KM (n=36, r=0.982, P=0.001) as well as with Kt/V calculated by Daugirdas (n=34, r=0.951, P=0.001). Detailed data are given in Table 1 Go. The mean deviations of Kt/V calculated by KeCN in respect to Kt/V of the single-pool/eSPVV-KM/Daugirdas were: -4.52±6.14%/1.13±3.63%/9.90±6.65%.

Electrolytic Kt/V versus direct quantification
The conductivity-based Kt/V of OCM correlated significantly (n=26, r=0.900, P=0.001) with Kt/V from direct quantification. Detailed data are given in Table 1 Go. The deviation of Kt/V calculated by KeCN in respect to Kt/V of direct quantification was -3.82±6.28%.

Clinical outcome
No patient reported of a change in thirst, muscle cramps, headache, nausea and vomiting in comparison with the baseline values (data not shown). Serum sodium, body weight, breathing and heart rate at rest, arterial pO2 and pCO2 at start as well as arterial blood pressure at the start and end of the dialysis remained unaffected in comparison with the baseline values. A slight increase of the average serum sodium concentration (0.2±1.5 mmol/l, P<0.002) was obtained, which might be in accordance with a calculated sodium shift into the patient of 1.53±7.62 mmol/OCM impulse (Table 2 Go).


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Table 2. Clinical data of sodium and water balance

 

Discussion

Haemodialysis dosage (Kt/V) has been shown to have a distinct impact on the morbidity and mortality rate in patients on RDT [ 2]. Therefore the adequacy of each dialysis should be guaranteed. Different methods for quantification of Kt/V have been suggested. Some authors expected for non-scientific purposes a single pool model to be sufficient for calculating dialysis dosage, while others suggested the two-pool model, which takes the urea rebound into account. However, the practicability of the two-pool model is limited because the final measurement of serum urea has to be done with a 30-min delay to equilibrate the second pool. Therefore, Daugirdas suggested an empirical formula to estimate equilibrated Kt/V without waiting for the rebound, which is still a matter of debate. Direct quantification by a urea monitor is claimed to be the ‘gold standard’ [ 12] but it necessitates a special device and is up to now limited to special, e.g. scientific, studies. Hence, disadvantages like the inconvenience for the patient and the indispensable sampling of blood and dialysate prevent the regular assessment of Kt/V at each dialysis.

Conductivity cells are ideal sensors for the continuous measurement of the conductivity of the dialysate. The insertion of these cells into the dialysers in- and outlet line allows a simple and safe continuous measurement of the actual electrolytic clearance. As sodium and urea diffusion coefficients are almost equal, electrolyte clearance monitoring should give exact figures for the effective total urea clearance. Furthermore, conductivity-based clearance measurements could be performed several times monitoring repeatedly the efficiency of each haemodialysis with consideration of real blood and dialysate flow, dialysis time, recirculation and ultrafiltration without additional burden to the patient and the dialysis staff.

This study was designed to evaluate the accuracy and patient safety of conductivity-based dialysate side online clearance in comparison with established reference methods of clearance and Kt/V calculations. Sodium imbalance was assessed by clinical parameters such as change in body weight, heart and breathing rate and arterial blood gas analysis as well as by the balance of ionic shift of the OCM impulse.

In order to improve the quality of the urea reference values (maximum tolerance of laboratory chemistry 8%) [ 14], the data set was limited to an error in mass balance of corresponding blood and dialysate sides urea amounts of less than 5%. This restriction cut down the data set to less than half (119/260 OCM). The corresponding OCM values of restricted data set has been proven to be highly correlated to the measurement of dialysers urea clearance corrected for recirculation (blood side: r=0.87, dialysate side: r=0.82, P<0.001). In spite of MBE <5% screen the references (KeUB/KeUD) were correlated by r=0.92 and not by r=1.0 as you would expect from a perfect reference. The remaining ‘error’ of conductivity-based clearance measurement is assumed to be strongly-related to the residual error of the reference and not only to the conductivity measurement itself. The correlation between blood or dialysate clearance of urea and conductivity dialysance confirmed the results obtained with a single conductivity probe operating alternately at the dialysate inlet and outlet line [ 1316]. Dead space, sample mixture effects and the need of temperature compensation, however, raise problems when switching from high to low and from low to high conductivity within one probe. The apprehension of a marked drift between the two conductivity probes generated by the presence of urea and other waste products [ 16] seems obviously to be spurious. The use of two probes instead of one results in a reliable approach producing simultaneous information of the dialysate inlet and outlet conductivity without switching from the inlet to the outlet line.

The conductivity-based Kt/V showed good correlation (r=0.94/0.98/0.94/0.90) as well as a reliable coincidence of 0.5±4.6% (weighted mean±SD) with the one-pool modelling/eSPVV-KM/Daugirdas/direct quantification. The urea generation rate of about 3 g/4 h dialysis time was not considered by the one pool model, eSPVV-KM and direct quantification. Hence, urea concentration at the end and 30 min after haemodialysis treatment appeared to be higher with than without urea generation and therefore urea clearances calculated by these formulas have been underestimated. The determination of an electrolyte based clearance (K) is independent of urea generation. Therefore, it could be speculated that the remaining SD of the conductivity-based Kt/V was mainly related to this source of error and not to the principle of the conductivity measurement itself.

No subjective alterations in the patient, such as an increase in thirst or blood pressure, were reported. Blood pressure as well as other clinical parameters of sodium and fluid overload remained unaffected in comparison with the pre-study baseline values (Table 2 Go). In this study the mean sodium baseline of the dialysate (14.2 ms/cm) was asymmetric with regard to implemented safety limits of conductivity variation (12.8–15.7 ms/cm) (Figure 1 Go). The resulting diminutive ‘cut off’ of the negative phase of the impulse could account for a small influx of sodium into the patient. Although not taking into account the concentration of other electrolytes the ratio of 1:10 for conductivity (ms/cm) over concentration of sodium (mmol/l) in general is accepted. Based on this simplification a net sodium transfer of 1.53 mmol per measurement was assumed to occur, which could be blamed for the slight increase in serum sodium (Table 2 Go). Therefore, the ultrafiltration rate had to be intensified theoretically by 11±55 ml/impulse (S-Na 138 mmol/l) to eliminate the presumed additional sodium uptake. Nevertheless, no significant signs of sodium and fluid overload were observed during the study period of 10 sequential OCM haemodialysis sessions without adjusting ultrafiltration. Presumably an increased sodium efflux by diffusive and convective transmembrane transport had completely counterbalanced the small net sodium influx caused by the sodium impulses by OCM application.

In conclusion, the conductivity-based OCM provides a safe and accurate tool to monitor the ‘dose’ of each haemodialysis session. The OCM device includes the continuous online control of recirculation, fistula access problems and fibre clotting of the dialyser and appears to be the most appropriate control of dialysis effectiveness.

Appendix

Error in mass balance:


Clearance:






Kinetic models:










Direct quantification:






Abbreviation and equations:

cdii Conductivity of inlet dialysate
   at time i
cdoj Conductivity of outlet
   dialysate at time j
DQ Refers to direct quanitfication
   of urea by dialysate sampling
eSPVV Refers to equilibrated Single Pool
   Variable Volume urea kinetic model
K Clearance in general
KeUBti Bloodside effective urea clearance
   at time i
MBE Mass balance error
MUrea Total mass of urea in drain dialysate
Qd Dialysate flow rate
Qe Effective bloodflow rate
Qf Ultrafiltration rate
R Recirculation
SP Refers to Single Pool urea  kinetic model
t0 Time at start of dialysis
t30 Time 30 min after termination
   of dialysis
t, tDial, tBypass Time in general, time of dialysis
   duration, time of alarms or filter
   in bypass
tEnd Time at the end of dialysis
ti Refers to a particular time i
UDO,ti Urea concentration of filter outlet  dialysate
UPWA,ti Plasma water urea concentration at  arterial inlet of dialyzer at time i
UPW,t0, Urea concentration of plasma water
UPW,tEnd,    at begin /at end /30 min after
UPW,t30    termination of dialysis
UPWV,ti Plasma water urea concentration at
   venous outlet of dialyzer at time i
V Urea distribution volume

Notes

Correspondence and offprint requests to: Prof. Dr H. Lange, Centre of Internal Medicine, Clinic of Nephrology, Philipps-University of Marburg, Baldingerstr, D-35033 Marburg, Germany. Back

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Received for publication: 14. 2.00
Revision received 21.11.00.