Two patients had a central venous access where mixed venous blood entered the extracorporeal circulation and passed the arterial measuring site. In this case, the initial phase of the dilution curve was systematically different from that obtained with a peripheral arteriovenous access where arterial concentrations were sampled (Figure 4).
The decline in dialysate volume after the injection was identified from exponential curve fits. The rate constant (k) was significantly different from zero (p < 0.0001, One-Sample Sign test) and negative in 58 studies (Table 2). The half-life t1/2 of indicator volume identified from rate constants was 17.2 ± 29.7 min. Indicator concentrations estimated at the time of indicator maximum (t), corresponding distribution volumes (Vt), and distribution volumes corrected for the relative change in blood volume between measuring time points are given in Table 2. Volumes estimated at t and at the beginning of dialysis were larger than anthropometric blood volumes (p < 0.0001, Friedman test). A comparison of distribution volumes and specific blood volumes obtained in individual patients and within single treatments is shown in Figure 5.
This study shows that dialysate infused as a bolus during on-line HDF produces a distinct dilution and volume expansion with an appreciable half-life and is feasible to identify cardiovascular parameters such as blood volume and volume residence time.
Saline has been used to measure cardiac output and central blood volume in experimental applications and during hemodialysis before.23–25 Dialysate is comparable to saline in its physical characteristics with the important advantage that it is available at the proper temperature and osmotic concentration and that it can be delivered under ultra-pure conditions with on-line HDF. One important difference to classic indicator dilution is the duration of the infusion. Unlike other techniques, the infusion is not instantaneous, but indicator volume is infused over a short albeit definite period of time. As a consequence, the infusion overlaps with the transit of indicator recirculating through the body and returning to the measuring site. Thus, the first transit of indicator passing through the heart and lungs and measured in arterial blood cannot be separated from subsequent transits, and the slow injection cannot be used to identify cardiac output using the classic Hamilton approach.26 However, the concentration of indicator after the injection can be used to identify the distribution volume and the elimination from the vascular space. The decrease in volume indicator observed in almost all dilutions indicates a slow loss of infused dialysate from the intravascular compartment. A plausible explanation for this loss is the reduction in plasma colloid osmotic pressure induced by the dilution thereby changing the microvascular filtration equilibrium so that outward filtration outweighs inward microvascular refilling.27 From the rate constant, the half-life of dialysate was estimated in the range of 10 to 15 min, which is somewhat longer than what has been reported for crystalloid solutions.28
The distribution volumes determined within the same treatment or within the same patient (on the occasion of subsequent treatments) were quite reproducible. The smallest volume was obtained in a patient with bilateral leg amputation (patient FR, V0 = 3.6 ± 0.6 L, Va = 3.5 L, Figure 5). In the other patients, the volumes were consistently larger than those expected from anthropometrically derived estimates. This difference was not seen in in vitro studies were the experimental distribution volume was exactly known and where the bias of absolute volume estimations was only 1.3 ± 2.1%.29 The blood volume excess observed in dialysis patients is plausible as significant deviations from anthropometric estimates can be expected for the beginning of dialysis, before excess body fluid is removed from the patient by ultrafiltration. Mitra et al.30 for example observed that blood volumes derived from indocynanine-green (ICG) dilution were 20% larger than those estimated from four different anthropometric methods. Such discrepancies where not observed in a companion ICG study where blood volumes measured late during dialysis were not different from anthropometric estimates.31 Another explanation for increased blood volumes is the expansion of the circulation by the extracorporeal blood circuit by up to 300 ml. Part of the priming volume contained in the extracorporeal circulation is usually infused when the patient is connected to the extracorporeal circulation. Because of these effects in the magnitude of 0.5 L, we think that the measured distribution volume is a good estimate of total circulating blood volume. A comparison of initial distribution volumes to established reference volumes was not possible at that point. This is a limitation of this study.
Could the measured indicator concentrations have been too low and thus distribution volumes be overestimated? Access recirculation produces an early peak, is easily recognized, and will increase rather than decrease the arterial concentration of an indicator injected into the venous bloodline.32 Is indicator lost from the circulation during the first cardiopulmonary transit? Others have injected 50 ml of saline to measure cardiac output and have not reported such loss during pulmonary transit.25 One explanation for a possible underestimation of saline or dialysate is the preferred sequestration of cell-free volume indicator in the compliant venules and vessels of the microcirculation so that the increase in volume concentration measured in large vessels is blunted.33 Such an effect can be expected with the addition of volume described here as well as with the removal of volume by ultrafiltration described previously.34
Indicator concentration in arterial blood reaches a pronounced peak and declines more rapidly during the first few minutes after infusion, whereas the later phase appears to be adequately described by a mono-exponential decline with a reduced rate constant (Figure 4, left panel). The arterial overshoot can be explained by the superposition of cardiopulmonary indicator transits with mixed venous concentrations and is akin to the effects of so-called cardiopulmonary recirculation in hemodialysis.35 Consequently, such an overshoot was not observed when dilutions were done with central-venous accesses measuring mixed venous blood (Figure 4, right panel).
The approach described here is not limited to the ultrasonic measurement of blood water but can also be applied to on-line hemoglobin and hematocrit measurements available with almost all on-line HDF machines. It is, however, important that the extracorporeal sampling site is located upstream of the infusion site to record arterial or mixed venous patient concentrations, depending on the type of vascular access. Automatic volume infusions provided by the machine are very helpful. This bypasses the requirement of manual infusion and avoids all risks associated with such manipulation. The test should also be possible with different forms of hemofiltration used in acute treatments. The technique has the potential for complete automation with appropriate changes in system software only. Changes in hardware are not required.
Infusion of saline appears to defeat the purpose of volume removal during hemodialysis and other forms of renal replacement therapy. However, in complicated treatments, on-line infusion of dialysate will help to improve hemodynamic stability because of intravascular volume expansion and at the same time provide information whether stability is related to a reduced intravascular volume or to impaired vascular tone. In acute therapy, fluid requirements are assessed using various measures of fluid responsiveness.36 Interestingly, little information is available on the efficiency of infusions to expand the intravascular space in acute treatments.28,37 This test may therefore help to assess to which degree infusion volume remains within the circulation and to establish a measure for intravascular volume efficiency. Infusion volume leaking into the tissue has lost its hemodynamic effect while impairing tissue oxygenation because it aggravates peripheral edema.
In conclusion, on-line dilution of dialysate is easily done and produces a reproducible and distinct dilution curve to estimate the distribution volume of isotonic dialysate as well as the escape rate of fluid into peripheral fluid compartments. Given the factors that tend to increase the blood volume of dialysis patients, the initial distribution volume is consistent with blood volume determined from anthropometric measurements. Such information could be of interest for volume management in hemodialysis patients and more importantly for the management of fluid therapy in intensive care patients undergoing extracorporeal blood treatment. We call upon manufacturers to consider implementing this measuring technique into machines for treatment of chronic and acute renal failure.
Therefore, the mass of a solution after mixing (index m) is given as the sum of the mass before mixing and the mass of added indicator (index ind) as
Accordingly, mass balance for water before and after addition of a volume indicator is given as
The water content of the indicator is known; the water content before and after dilution can be measured with available technology.21,38 Fluid density at a given water content W and temperature T (in °C) can be determined from the following relationship39:
In case of isotonic dilution, the indicator concentration can also be derived from the relative blood volume (RBV, in vol/vol) measured before and after (index m) addition of volume indicator as
The authors thank A. Wüpper, Fresenius Medical Care, Bad Homburg vor der Höhe, Germany, for financial support and J. Gross for excellent technical help with the studies.
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ultra-pure dialysate; indicator dilution; volume kinetics; blood volume; half-life