The Relationship Between Systemic and Whole-Body Hematocrit Is Not Constant during Ultrafiltration on Hemodialysis
Sandip Mitra*,
Paul Chamney,
Roger Greenwood and
Ken Farrington
*Manchester Royal Infirmary, Manchester, United Kingdom; University of Hertfordshire, Hertfordshire, United Kingdom; and Renal Unit, Lister Hospital, Stevenage, United Kingdom
Correspondence to Dr. Sandip Mitra, 35 Wood Road, Sale, Cheshire, UK, M33 3RS. Phone: +44-161-282-2095; Fax: 44-161-276-8022; E-mail rhea2202{at}aol.com
ABSTRACT. The measurement of relative blood volume (RBV) changesduring ultrafiltration assume a constant mass and distributionof circulating blood components such as hematocrit. The authorsexamine the validity of this assumption in 10 subjects undergoingrepeated direct measurements of systemic hematocrit and plasmavolume (PVicg) using indocyanine green dilution at four stagesof dialysis with intermittent ultrafiltration. Ultrasonic RBVchanges were monitored. Absolute blood volumes (ABV) were initiallyderived for each PVicg estimate, and corresponding measuredsystemic hematocrit was adjusted by a factor of 0.86 to correctfor the difference between the systemic and whole-body hematocrit(constant Fcell ratio). PVicg and ABV changes correlated closely(R = 0.98; P <0.001). ABV changes overestimated reductionin PVicg during ultrafiltration (mean difference, -140 ±202 ml). The calculated red cell mass however was variable (P<0.01). Fcell ratio was then adjusted at each blood volumemeasurement (Fcell1, 0.87 ± 0.02; Fcell2, 0.89 ±0.03; Fcell3, 0.94 ± 0.06; Fcell4, 0.94 ± 0.04;P <0.01) to maintain a constant red cell mass (2146 ±460 ml). When ABV was recalculated using PVicg, systemic hematocritand variable Fcell (ABVFvariable), the mean difference betweenPVicg changes and ABVFvariable changes, was negligible (-0.2± 35 ml). During intermittent ultrafiltration, RBV changessystematically underestimated the percentage reduction in ABV(mean difference, 7.7 ± 10.6%). When corrected for variationsin Fcell, ABVFvariable and RBV differences were negligible (meandifference 1.2 ± 2.6%). Varying Fcell ratio probablyreflects microvascular volume change with net fluid shift fromthe microcirculation to macrocirculation (intravascular refill).This may result in underestimation of changes in systemic hematocritand RBV during dialysis such that they were less than thosepredicted by directly measured changes in plasma volume.
Technological advances have allowed the development of devicesthat can continuously and noninvasively monitor biologic constituents(hematocrit [Hct] and plasma protein concentration) during hemodialysis(HD) treatment. Hct and relative blood density changes onlineduring HD have been advocated as tools for assessing blood volume(BV) changes induced by ultrafiltration (UF) (1). The assumptionsthat changes in the measured systemic Hct (Hctsys) result solelyfrom circulating plasma volume (PV) changes induced by UF andthat there is uniform mixing of a constant circulating massof red cells and plasma components in the whole circulationduring UF form the basis of such indirect measurements.
Attempts to quantify volume shifts precisely in the vascularcompartment using relative changes have been difficult as theyoften underestimate directly measured BV changes (2). Apparentrelative BV (RBV) changes therefore cannot be explained by PVdepletion alone. Observational studies to analyze the RBV tracesor determine the critical Hct for hypotension suggest wide degreesof interpatient and intrapatient variability during HD withUF (3). These suggest that other physiologic mechanisms andalterations that affect distribution of the circulatory componentsduring UF may influence these indirect estimates (2).
Accurate measurements of red cell volume by radioactive isotopesshow that the relative volumes of red cells and plasma in thecirculation as a whole (whole-body hematocrit [Hctw]) differfrom those found in the venous blood (Hctsys). The differencebetween the systemic hematocrit in the Hctsys and Hctw is expressedas the Fcell ratio (Hctw/Hctsys). In the steady state, thisis due to a dynamic reduction in microvascular Hct during bloodflow through the capillaries and venules (<200 µm).This is also known as the Fahraeus effect (4) and depends onthe capacity of the microcirculation. Reduction is greater insmaller vessels as a result of anomalous flow properties ofblood (5). The use of changes in Hctsys to reflect BV changesaccurately depends on the constancy of the relationship of Hctwto Hctsys during UF. To our knowledge, the assumption of constancyof Fcell ratio during dialysis with UF has not been investigated.This study examines the validity of this assumption and hypothesizesthat there are significant changes in the microcirculation duringUF that affect Hct redistribution and RBV changes.
Subjects
We studied 10 subjects (eight male) using repeated measurementsof PV and Hct during a single supine HD session with intermittentUF (3 L/hr). Four intermittent UF pulses were used removingsuccessively 40–20–20–20% of total UF volumebetween intervening rest periods. Subjects had received chronicHD for at least 6 mo and had a stable dry weight. The presenceof iodine allergy, eosinophilia, abnormal liver function tests,raised serum IgE levels, or significant access recirculationwithin 1 mo before the study was an exclusion criterion. TheNorth Herts Ethical Review committee approved the study. Allpatients gave informed consent. All were treated with thrice-weeklyhigh-flux bicarbonate HD (Fresenius 4008E) using polyamide membranesand AV fistulae. Blood flow rates were in the range of 350 to450 ml/min, and the mean sessional Kt/V was 1.24 ± 0.16(6).
PV Measurement
PV was measured by dye dilution using indocyanine green (7).Four estimates of PV (i = 1 to 4) were obtained during a singleHD session in each patient. All measurements were made in stablesupine position. UF was commenced after an equilibration periodof 20 min from the connection to the extracorporeal circuit.PV measurements were made before the start and at the end ofthe first and fourth UF pulses (Figure 1) when steady-stateBV conditions were obtained on the RBV monitor (RBV plateauwith variations of <0.5% over at least a 10-min period).
Figure 1. Relative blood volume (RBV) profile during intermittent ultrafiltration (UF) in a subject on hemodialysis (HD). Arrows indicate the timing of the four steady-state hematocrit (Hct) and direct plasma volume (ICG) measurements. M1, measurement before onset of UF; M2, after 40% UF; M3, after 80% UF; M4, after 100% UF removed.
Tracer
The tracer used was Cardiogreen (ICG Green Sterile indocyaninegreen USP Fluka), a tricarbocyanine dye, molecular weight 775,with an absorption peak at 805 nm. The dye is nontoxic, confinedto plasma, not subject to extravascular distribution, and notmetabolized or degraded. After equilibration, the dye decaysfast in an exponential manner. It is exclusively taken up bythe liver and has a plasma half-life of 2 to 3 min (8).
Procedure for Determination of PV
Before each dye injection, blood was withdrawn for Hct and baselineplasma blank in heparinized syringes. ICG (25 mg) was dissolvedin 10 ml of sterile aqueous solvent to produce ICG solutionof 2.5 mg/ml. The dye (10 mg) was then injected as rapidly aspossible into a venous port beyond the bubble trap. All syringeswere weighed on a precision scale before and after the injectionto determine the precise quantity injected. Exactly 3 min afterthe end of the injection, sampling was commenced from the arterialport in heparinized syringes at 1-min intervals for 10 min (eightsamples). Samples were centrifuged at 3000 rpm for 10 min. Theplasma blank sample was used to determine the baseline backgroundabsorption at 805-nm wavelength. The absorption of ICG dye inthe timed plasma samples were then compared against the baselineat the same wavelength (8). A five-point calibration was performedfor each BV measurement using the blank plasma sample just beforedye injection.
Analysis
The natural logarithms of the measured ICG dye concentrationswere plotted against time for each PV measurement, and the best-fitlinear regression was obtained. The logarithm of the dye concentrationat t = 0 was obtained by extrapolation. The antilog of thisyielded the initial dye concentration in plasma at the timeof injection. Plasma volume (PVicg) was calculated accordingto the following equation
Hct Determination
Hctsys was measured using aperture impedance counters (Coulter-STKS)(9). All patients were monitored with relative blood volume(RBVBVM) monitor (1) and oscillometric BP.
Procedure for Determination of Absolute BV and Red Cell Mass
Absolute BV (ABVFconstant) (10) estimates were derived for eachPV estimate and corresponding measured Hctsys adjusted by afactor of 0.86 to correct for the difference between the Hctsysand Hctw (constant Fcell ratio):
Totalred cell mass (RCMFconstant) estimates were then derivedfromeach ABVFconstant estimate and the corresponding Hctw usingthe following relationship:
Subsequently,separate Fcell ratios ([Fcell]i) were calculatedfor each ofthe four plasma volume (PVi) and corresponding Hctsys([Hctsys]I)values obtained during each dialysis session. Thecalculationassumed that (1) RCM remained constant throughoutthe dialysissession and (2) that absolute BV and PV changesduring UF wereeffectively identical.
(ABVFvariable)i was then recalculatedfrom Equation 2 usingthe appropriate PVi and (Hctsys)i measurementsand the corresponding(Fcell)i.
The differences in Fcell ratiobetween the first ([Fcell]1)and subsequent ([Fcell]I) measurementswere used to correctthe RBV reading (corrected reading designatedas RBVc) obtainedfrom the RBV monitor at the second (RBV2),third (RBV3), andfourth (RBV4) measurements:
Statistical Analyses
Statistical methods used were Bland Altman (11) analysis requiredfor comparison of methods, t test for comparison of means (P< 0.05), linear regression, and Pearson correlation tests.Statistical analysis was performed using software package Sigmaplot(version 2.01).
The subjects had a mean age of 61.6 ± 4.8 yr, a meandry body weight of 83 ± 17 kg, and a body surface areaof 2 ± 0.2 m2. The mean UF volume removed was 2298 ±845 ml, and there was a net reduction in PV during dialysisof 1218 ± 474 ml. The mean reduction in weight duringdialysis was 2.48 ± 0.9 kg.
The derived values for ABVFconstant from directly measured plasmavolumes (PVicg) and HCT (Equation 1) are shown in Table 1. PVchanges and BV changes were highly correlated (R = 0.98, P <0.001). When the mean red cell mass (RCMFconstant) was calculatedusing ABVFconstant and the measured HCT, there were significantdifferences between the calculated values obtained at each measuredPVi (P < 0.01; Figure 2a).
Table 1. Absolute blood volumes derived by using measured plasma volume, hematocrit, and constant Fcell ratio (0.86) in 10 subjects during hemodialysis
Figure 2. (a) Box plot showing inconstant total red cell volume (RCMFconstant) in 10 subjects during dialysis using constant Fcell (**P < 0.01) (b) Box plot showing constant red cell volume using variable Fcell ratio (RCMFvariable; NS).
The assumption of a constant circulating RCM during UF is violatedunless there is a progressive increase in Fcell ratio. Hence,the Fcell ratios were corrected for each patient (Fcell1, 0.87± 0.02; Fcell2, 0.89 ± 0.03; Fcell3, 0.94 ±0.06; Fcell4, 0.94 ± 0.04; P < 0.01 Fcell1versusFcell3, P < 0.001 Fcell1versus Fcell4) assuming a constantcirculating RCM (RCMFvariable mean, 2146 ± 460 ml; NS;Figure 2b). The resulting ABV estimations (ABVFvariable) aredepicted in Table 2. The corrected mean absolute BV obtainedat the end of UF was 72.2 ml/kg (Table 2, ABV 4). The changein Fcell ratio (Figure 3) correlated with the UF volume removed(R = 0.32, P < 0.05).
Figure 3. Progressive rise in Fcell ratio obtained in 10 subjects at four steps of intermittent UF (*P < 0.05, **P < 0.01)
ABVFconstant systematically overestimated PVicg with a meandifference of -140 ± 202 ml (Bland Altman analysis; Figure 4a).When corrected for Fcell variation, the mean differenceof PV and BV changes were negligible (-0.2 ± 35.8 ml;Figure 4b).
Figure 4. Bland Altman analysis comparing directly measured plasma volume changes and blood volume changes derived using constant Fcell ratio (ABVFconstant; mean difference, -140 ± 202 ml; a) and variable Fcell ratio (ABVFvariable; negligible mean difference, -0.2 ± 35.8 ml; b). Reference lines indicate mean difference ± 2 SD.
Relative BV changes (RBVbvm%) significantly underestimated thepercentage reduction of absolute BV (ABVFconstant) between thefour measurements (Table 1) with a mean difference (±SD)of 7.7 ± 10.6% (Figure 5a). When corrected for varyingFcell ratio, the mean difference between change in correctedRBV (RBVC; Equation 4) and absolute BV (ABVFvariable; Table 2)was only 1.2 ± 2.6% (Figure 5b).
Figure 5. Bland Altman analysis comparing percentage blood volume changes in 10 HD patients during UF as observed by RBV monitor and absolute blood volume measured by ICG technique (% blood volume reduction during UF between all four measurements; n = 60). Reference lines indicate mean difference ± 2 SD. (a) Comparing observed RBVBVM changes and absolute blood volume changes derived from plasma volume, Hct, and Fcell ratio 0.86 (ABVFconstant). (b) Comparing RBVcBVM changes and absolute blood volume changes (ABVFvariable) both corrected for Fcell variation. RBV changes underestimate ABV reduction with constant Fcell assumption by 7.7 ± 10.6% (a) but by only 1.2 ± 2.6% when corrected for varying Fcell ratio (b).
The assessment of volume shift using systemic Hct or plasmadensity is based on mass conservation. The first assumptionof a constant total circulating RCM during a dialysis sessionis true in the absence of hemolysis or blood leak. This parameteris likely to fluctuate over time only with changes in erythropoietintreatment. Red cell volume may vary with plasma osmolality,but the degree of change is small even across extreme variationsin dialysis fluid sodium concentration (12). A second assumptionis of constant homogeneous distribution of these componentsbetween the macro- and the microcirculation (4) throughout dialysis.The relationship between systemic and whole-body Hct expressedas Fcell ratio is due to microcirculatory effects and remainsconstant in steady state. This study demonstrates that bothof the assumptions cannot be true at the same time during dialysiswith UF. The assumption of a constant circulating RCM duringUF is violated unless there is a progressive increase in Fcellratio during UF.
A model of circulatory changes during UF with or without microvascularchanges can be hypothesized on the basis of these results (Figure 6).In the steady state (Figure 6a), the intravascular volume(Vb) can be divided into two compartments with proportionaldistribution of plasma and red cells: the macrocirculation (Vmac= 60%; Hsys = 0.35) and the microcirculation (Vmic = 40%; Hmic= 0.233). If UF were associated with no change in Fcell ratio,then a proportional volume change would occur in each compartmentand the observed rise in Hctsys would purely reflect the volumeremoved from the macrocirculation (Figure 6b). However, theobserved underestimation of rise in Hctsys suggests that thereare additional physiologic factors in operation. There are twomain possibilities. There could be loss of RCM from the systemiccirculation, which seems unlikely, or there could be intravascularrefill from the micro- to macrocirculation. The latter mechanismresults in a new steady state of the microcirculation and analtered higher Fcell ratio (Figure 6c). It is strongly supportedby the almost complete correction of systemic RBV underestimationby use of a varying Fcell ratio.
Figure 6. Hypothetical blood volume model demonstrating microvascular volume change. (a) Steady-state control shows uniform systemic hematocrit (Hctsys) for the macrocirculation (right compartment Vmac) and the microvascular hematocrit Hctmic for the microcirculation (left compartment Vmic) to represent the total red blood cell content in a blood volume Vb and whole-body hematocrit (Hctw). (b) Post UF considers a state of net volume removed and a static relationship between the contracted macro- (Vmac1) and microcirculation (Vmic1) (constant Fcell). (c) Identical net blood volume depletion with an additional microvascular volume change (Vmic2), resulting in a rise in the Fcell ratio and underestimation of the Hctsys change. It demonstrates a state of redistribution from micro- to macrocirculation (intravascular refill) during UF. (2/3) represents a constant proportional adjustment between the macro- and micro-Hct.
The ratio of the RCM to PV differs in the veins, capillaries,and various organ beds. Any perturbation provokes a proportionalchange in microvascular and systemic Hct, which can be representedby the constant , the value of which is approximately 0.66 basedon studies of different microvascular beds (13, 14). Each microvesselgeneration could constrict in a heterogeneous manner that canbe averaged by using the value . Because is fairly constant,any rise in Fcell ratio entails a reduction in Vmic/Vb (seeAppendix). In the hypothetical example depicted in Figure 6,these relationships predict a reduction in Vmic/Vb from 21%(Figure 6b) to 12% (Figure 6c). Such models have been used todescribe the microvascular circulation under different pathophysiologicconditions (15).
Observations on the hepatic and pulmonary circulation indicatethat changes in microvascular volume lead to transient changesin the Hct or density of blood flowing from these organs (16).If the circulation is subjected to any perturbation, which changesthe microvascular volume, then this contributes partially tothe measured change in the Hctsys. There is no evidence to suggestsignificant alterations in capillary permeability characteristicsduring UF (15, 17). Morphometric data indicate that 40 to 50%of BV resides in the microcirculation. Direct microvascularmeasurements suggest that during hemorrhage, <200-µm-diametervenules form the major reserve capacity of the circulation.Large volumes may be shifted from the micro- to the macrocirculation,reducing the effect of BV loss.
These findings suggest that microvascular change induced byUF is an important factor influencing the Hctsys. This seemsto be accentuated at later stages of UF, when a rise in Hctsysmay not occur, despite hypovolemia. This is likely to be dueto intravascular refill. Studies using tagged red blood cellshave suggested that during hypovolemia caused by UF, mobilizationof blood from the splanchnic region occurs as a compensatorymechanism (18).
This study provides evidence of dissociation between indirectRBV measurements and direct BV changes measured by indocyaninegreen during hemodialysis, most apparent at later stages ofdialysis with ultrafiltration. Lower BV estimates obtained usingradioisotope methods in subjects before the start of dialysisin a previous study (19) are perhaps due to smaller body size,methodologic variations, and differences in hydration statusof the subjects studied.
The absolute mass of protein in the vascular space at the timeof the dye measurement is not relevant for the PV and BV determination.The dye simply binds instantaneously to the available circulatingprotein mass. This study assumes that during blood volume steadystate with no UF and a relative small sampling period, thereis dynamic equilibrium and negligible net flux of protein acrosscapillary membrane. RBV measurements are also based on the sameassumption allowing comparison between two methods. Changingvascular refill rates despite apparent steady-state conditionsin the RBV profile seem unlikely to account for this, giventhe degree of underestimation. Although the ultrasonic RBV monitorhas a very low noise–signal ratio, momentary fluctuationsmay introduce potential errors. However, the dissociation isalmost eliminated when the variation in Fcell ratio is considered,suggesting that intravascular refill and regional blood flowredistribution during UF significantly affect RBV measurements.These observations and others, such as the RBV changes observedduring maximal exercise on dialysis (20), support the notionthat RBV measurements can be significantly affected by proceduresthat induce changes in the recruitment of the microcirculation.
Microcirculatory changes lead to volume shifts from the micro-to the macrocirculation with adjustment of the macrovascularHctsys during UF. A compliant microcirculation acts as a bloodreservoir allowing volume compensation during UF. Such redistributionleads to a progressive rise in the Fcell ratio during UF inthe presence of a constant RCM. Hence, the assumption of a constantand homogeneous Hct distribution during UF is invalid, and theuse of Hctsys change as the sole determinant of PV change couldbe erroneous. Both the blood density and the Hct based equationsused to determine changes in RBV ignore volume redistributionbetween the macro- and microcirculation. This study can serveas the basis to design experiments to characterize the mechanismsthat produce microvascular change during UF.
where H is hematocrit, V is volumes, b is whole blood, w iswhole-body hematocrit, mic is microcirculation, sys is macrocirculation,and rbc is red cell mass (14).
Acknowledgments
The study was supported by grants from Fresenius Medical Care,Germany. We thank D. Murray for technical assistance.
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Received for publication April 9, 2003.
Accepted for publication October 31, 2003.
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Abstract
Introduction
, the value of which is approximately 0.66 based on studies of different microvascular beds (13, 14). Each microvessel generation could constrict in a heterogeneous manner that can be averaged by using the value 
