Magn Reson Mater Phy (2012) 25:215–222DOI 10.1007/s10334-011-0282-7

RESEARCH ARTICLE

Contrast agent derived determination of the total circulatingblood volume using magnetic resonance

Kerstin Pannek · Florian Fidler · Ralf Kartäusch ·Peter M. Jakob · Karl-Heinz Hiller

Received: 4 April 2011 / Revised: 31 August 2011 / Accepted: 31 August 2011 / Published online: 18 September 2011© ESMRMB 2011

AbstractObject Knowledge of the total circulating blood volume(TCBV) is essential for the treatment of a variety of medicalconditions and blood disorders. To date, blood volume anal-ysis is rarely carried out due to the disadvantages of availablemethods. Our aim was to develop a widely available, simple,fast, yet accurate method for the determination of the totalcirculating blood volume.Materials and methods Magnetic resonance (MR) is awell-established, non-invasive technique. In this article, wepresent a method that uses MR contrast agents for the deter-mination of the blood volume. The dependence of MR relaxa-tion times on the concentration of MR contrast agents allowsthe calculation of the volume the contrast agent has beendiluted in.Results In phantom and in vivo experiments we could dem-onstrate that TCBV can be determined with high accuracyand precision.Conclusion This work introduces a novel method for thedetermination of the total circulating blood volume usingmagnetic resonance contrast agents as tracers.

Keywords Total circulating blood volume · Magneticresonance · Contrast agent

K. Pannek · F. Fidler · R. Kartäusch · P. M. Jakob ·K.-H. Hiller (B)Research Center Magnetic-Resonance-Bavaria, Am Hubland,97074 Wuerzburg, Germanye-mail: hiller@mr-bavaria.de

P. M. JakobDepartment of Experimental Physics 5, University of Wuerzburg,Wuerzburg, Germany

Introduction

Accurate knowledge of the total circulation blood volume(TCBV) is essential in clinical medicine, particularly in oper-ative surgery and monitoring. The TCBV is one of the mostimportant determinants in understanding circulating physiol-ogy for the evaluation of disorders. However, it can often onlybe estimated by indirect parameters such as blood pressure,hematocrit or hemoglobin concentration. These estimationscan lead to severe misjudgment, endangering the health ofthe patient [1]. Hypo- or hypervolemia, if severe, can lead topotentially fatal complications [2,3].

More precise methods for the determination of the TCBVemploy the so-called indicator dilution technique. This tech-nique refers to the addition of a tracer with known volumeVBol and concentration cBol to an unknown volume V ofliquid. After complete mixing, a sample is taken from theunknown volume and the concentration c of the tracer isdetermined in this sample. Then the unknown volume V canbe calculated using the relation

V · c = VBol · cBol (1)

This relation is commonly known as conservation of amountof substance. Dilutional techniques for the measurement ofTCBV can be classified into (i) methods that use a radioiso-tope tagged to a blood product (either red blood cells [4] oralbumin [5,6]) and (ii) methods that use a dye (Evans blue[7] or indocyanine green [8]).

Nuclear medicine techniques are the gold standard forTCBV measurement and are highly accurate, but very expen-sive, time-consuming and patients are exposed to unwelcomeionizing radiation. Therefore these techniques are often oflimited interest to most clinicians. Methods using a dye canlead to discoloration of the skin; Evans Blue is known tobe carcinogenic and indocyanine green has a very short half

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life which leads to results that are less accurate than thoseobtained with radioisotopes.

This article presents a novel method for determination ofTCBV using magnetic resonance (MR). In magnetic reso-nance imaging (MRI), contrast agents are used to enhancecontrast by shortening the relaxation time. We show that theshortening of the relaxation times due to these contrast agentscan be used to measure TCBV.

Theory

Blood, as any other substance, has natural longitudinal andtransversal magnetic resonance relaxation times, T1,0 andT2,0, respectively. MR contrast agents are specially designedto shorten these relaxation times. Here, we introduce the con-cept of measuring the TCBV using the longitudinal relaxa-tion time T1. However, the same would apply to transverserelaxation times T2.

After complete mixing of a contrast agent with a substrateor liquid, the observed relaxation time T1b depends on therelaxivity r1 and concentration c of the contrast agent in theliquid and on the natural relaxation time T1b,0 of the usedliquid [9]:

1

T1b= 1

T1b,0+ r1 · c (2)

The concentration c of the contrast agent in a volume dependson the amount of contrast agent n and the volume V : c =n/V . Equation (2) rewrites to

1

T1b= 1

T1b,0+ r1 · n

V(3)

By adding a known amount of a contrast agent n to anunknown volume V and measuring the relaxation time ofthe liquid containing the contrast agent, the unknown vol-ume can be calculated:

V = r1 · n

T −11b − T −1

1b,0

(4)

For the determination of TCBV using this technique, the fol-lowing points should be considered:

• The contrast agent must be distributed homogeneouslyover the entire blood volume.

• Due to temperature dependence of contrast agent relax-ivities temperature must be kept constant.

• Unspecific binding or diffusion into the extravascularspace must be prevented.

• To increase accuracy of the measurement, it is desirablethat the contrast agent be eliminated from the circulationslowly.

• The natural relaxation time T1b,0 of the blood sample andrelaxivity r1 of the contrast agent in this specific environ-ment must be known.

• A sufficient accuracy of the measurement is necessary.• There must be no contraindication to contrast agents in

the patient.• If assessment is to be made within the whole organism,

there must be no contraindication to MRI in the patient.If contraindication to MRI exists, assessment can be per-formed on blood samples.

So-called blood pool or intravascular contrast agents are ide-ally suited for the determination of TCBV. These contrastagents are specially designed to distribute homogeneouslyin the blood pool. Diffusion into extravascular space is sig-nificantly reduced, and the elimination from circulation isslow compared to extracellular agents [10,11].

The natural relaxation time of blood T1b,0 depends onhematocrit [12] and the magnetic field strength used for themeasurement [13]. T1b,0 can be determined in vivo, or bydrawing a blood sample before application of the contrastagent. The relaxivity r1 of a contrast agent varies primarilywith the magnetic field strength [14]. The relaxivity needsto be determined once using a dilution series, if not alreadyknown.

The accuracy of the volumetric measurement depends pri-marily on the accuracy of the T1b and T1b,0 measurement.T1b is not directly proportional to the volume of the liquid(Eq. 3). Figure 1 simulates the dependence of the observedrelaxation time T1b on the volume of the liquid for three dif-ferent amounts of contrast agents. In the determination of theblood volume, the unknown volume is expected to be withina certain range. The boundaries, Vmin and Vmax, respectively,are depicted as vertical lines in the diagram. The simulationshows that the difference �T1b between the observed relax-ation times for the two volume boundaries varies with theamount of contrast agent administered. �T1b can be calcu-lated using Eq. 3:

�T1b =(

1

T1b,0+ r1 · n

Vmax

)−1

−(

1

T1b,0+ r1 · n

Vmin

)−1

(5)

The quantification of an unknown volume within this rangewill be the more accurate the bigger the slope, i.e. the bigger�T1b.�T1b in Eq. 5 has a maximum at

nopt =√

Vmax · Vmin

r1 · T1b,0(6)

with the value

�T1b,opt = T1b,0

(√Vmax − √

Vmin√Vmax + √

Vmin

)(7)

Using Eq. 6, one can calculate the ideal amount of contrastagent required to accurately determine an unknown volume

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Magn Reson Mater Phy (2012) 25:215–222 217

Fig. 1 a Volume dependency of the longitudinal relaxation time T1bfor 3 amounts of contrast agent. The limits Vmin and Vmax are depictedas vertical lines. The observable difference in T1b at the volume bound-aries varies with the amount of contrast agent. Simulation parameters:T1b,0:1.5 s; r1: 4.95 l mmol−1s−1. b Observable difference in T1b at thevolume boundaries as a function of the amount of contrast agent. Simu-lation parameters: T1b,0 : 1.5s; r1 : 4.95l mmol−1s−1, Vmin3.9l, Vmax6.6 l

(which is assumed to be within the limits Vmin and Vmax).The desirable quality of the T1b-measurement is determinedwith Eq. 7. Note that the maximum achievable observed T1b-difference �T1b,optis independent of the properties of thecontrast agent and can, therefore, not be increased.

An adult’s expected TCBV (Vexp) can be predicted usinga method proposed by Feldschuh and Enson [15], which usesthe relationship between TCBV and body habitus. The Inter-national Committee on Standardization in Hematology rec-ommends a normal range of ±25% from the predicted norm[16]. It is therefore suitable to assume Vmin as 75% Vexp andVmax as 125% Vexp. Equation (6) then reduces to

nopt =√

15/16 · Vexp

r1 · T1b,0(8)

with the value

�T1b,opt =(√

5 − √3√

5 + √3

)· T1b,0 ≈ 0.127 · T1b,0 (9)

Note that in Eq. 8, nopt is a linear function of the predictednorm Vexp, and that �T1b,opt in Eq. 9 is independent of Vexp.

Example According to [15], an individual of ideal weighthas a predicted normal TCBV per unit mass of 70 ml/kg.An adult of 75 kg body mass therefore has a predicted nor-mal TCBV Vexp of 5.25 l. Using Gadofosveset trisodium(Vasovist�, Schering) as intravascular FDA approved con-trast agent (r1 ≈ 25 l mmol−1s−1 at 1.5 T) and assuming theaverage longitudinal relaxation time of blood (T1b,0 = 1.5s),the required amount of contrast agent nopt for this personis 0.14 mmol (0.0019 mmol/kg). This amount of substanceequals about 6.2% of the recommended dose for contrastenhanced MRI. The maximum achievable T1-difference is190 ms; this value does not depend on the properties ofthe contrast agent and is therefore valid for all contrastagents, considering the use of the optimal amount of con-trast agent nopt. Therefore, a precision δT1 � 190 ms of theT1-measurement is required.

Materials and methods

Phantom studies

The aims of the phantom experiments were to validate (i) thelinear relation between the concentration of contrast agentand the relaxation rate 1/T1b (Eq. 2), (ii) the theoretical depen-dency of the difference in relaxation times on the amount ofcontrast agent �T1b(n) (Eq. 5), and (iii) the feasibility of thevolumetric measurement.

To accomplish aims (i) and (ii) in one step, 20 sampleswith varying concentrations of a MR contrast agent were pre-pared, using an isotonic saline solution (0.9% NaCl in H2O)and the commercially available contrast agent Magnevist�(0.5 M Gd-DTPA, Bayer-Schering AG, Berlin, Germany;molecular weight 938 daltons). This contrast agent couldbe used, because no extravasal leakage takes place in thesephantom experiments. Between 0.125 and 5 mmol Magne-vist� were added to 10 samples containing 15 ml (Vmin) and25 ml (Vmax) saline solution, respectively; resulting in con-centrations between 5 µmol/l and 0.33 mmol/l Magnevist�.In addition, one sample without Magnevist� was prepared.Measurement of the relaxation times of all samples allowedthe examination of the linear relation between concentrationand relaxation rate. Additionally, by calculating the differ-ence between the measured relaxation times for samples con-taining 15 or 25 ml saline solution, but the same amount ofMagnevist�, the relation between �T1b and the amount ofthe contrast agent could be detected.

For volumetric measurements (aim (iii)), we prepared 20samples of saline solution with volumes ranging from 12.4 to27.6 ml. These volumes represent extreme hypovolemia and

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218 Magn Reson Mater Phy (2012) 25:215–222

Fig. 2 Left: Experimentalsetup: 21 NMR-tubes in Teflonholders. Right: ExemplaryT1-map. For the determinationof T1, regions of interest weredrawn in each tube, and themean value of T1 was calculated

extreme hypervolemia, respectively, for an organism withan expected blood volume of 20 ml. An amount of 1.5 µmolMagnevist� was added to each sample. Additionally, 7 sam-ples with known concentration of Magnevist�, ranging from0 to 0.14 mmol/l, were prepared for calibration, i.e. determi-nation of T1,0 and r1.

Two ml of each sample were transferred into 5 mm (Ø)NMR-tubes, sealed and placed into Teflon holders designedto hold 21 tubes (Fig. 2).

In vivo study

We investigated seven male Wistar rats (Charles River,Sulzfeld, Germany, 300–400g) conform to the European reg-ulations for care and use of laboratory animals and approvedby the local authorities. Rats were anesthetized with Propofol(Disoprivan 2%, Glaxo Wellcome, Bad Oldesloe, Germany,100mg/kg IP) and orally intubated and ventilated by a rodentventilator (BAS-7025, Föhr Medical Instruments, Germany).MR images were ECG triggered (Rapid Biomedical, Wuerz-burg, Germany) and during image acquisition, ventilationwas stopped automatically to avoid respiratory motion. Anes-thesia (Disoprivan 40 mg/(kg*min)) and intravascular con-trast agent were administered via tail vein.

The bolus of contrast agent was determined as fol-lows: According to [17], the blood volume of a Wistarrat can be calculated using the relationship V[ml] =0.06∗bodyweight[g] + 0.77. The contrast agent Gd-DTPA-albumin (0.75 mmol/l; r1 = 84.04l mmol−1s−1 at 7T and37◦C solved in distilled water) was used in this experiment.This contrast agent has a molecular weight of ∼91,000 dal-tons and remains intravascular at stable plasma levels for upto 1 h [18]. The natural relaxation time T1b,0 at 7T is approx-imately 1 s. Therefore, according to eq. 8, a single bolus of0.3 ml Gd-DTPA-albumin was injected. This volume waswithin the recommended maximal intravenous injection vol-ume of 5 ml/kg bodyweight in rats. To secure accurate volumeinjection a small hand-held microsyringe was used and thewarmed contrast agent was given in approximately 1 min.

Magnetic resonance imaging

MR-measurements were performed using a horizontal 7.0T Bruker Biospec MRI-System (Bruker Biospin Rheinstet-ten, Germany) equipped with a 72 mm proton quadraturebirdcage coil. In the phantom studies, the determination ofthe longitudinal relaxation time T1 was carried out using asegmented Inversion Recovery Snapshot FLASH sequence[19] at room temperature. The imaging parameters used were(FOV56 × 56 mm2, matrix size 132 × 128, 3 interleavedsegments, segment acquisition time 160 ms, flip angle 4◦,repetition time 15 s, 8 repetitions). Thirty two images wereacquired after each inversion pulse.

Data processing was carried out off-line using home-builtprocessing tools in the Matlab environment (MathWorks Inc,Natick, Massachusetts, USA). T1-maps were calculated byfitting

I (t) = A − B · exp

[− t

T ∗1

](10)

to the intensity of each voxel using a χ2-assay [20]. T1 wasobtained from the parameters A, B and T ∗

1 , T1 = T ∗1 (B/A−

1)+2�t, where �t is the delay between inversion and acqui-sition. In each tube, a region of interest (ROI) was defined,containing on average 75 pixels. T1 was determined as meanvalue in the ROIs along with standard deviation.

The relaxivity r1 of Magnevist� and the longitudinalrelaxation time T1,0 of saline solution were determined bylinear regression using Eq. 3. These parameters were usedto determine nopt for the phantom volumetry experiment.The progression of the �T1(n)-curve was simulated forthese parameters (solid line in Fig. 3; T1,0 = 3.30s, r1 =4.17l mmol−1s−1). We calculated the difference in T1-val-ues between the samples containing 15 and 25 ml salinesolution, as a function of the amount of Magnevist�. Theobtained data points were compared to the theoretical curve.

For the volumetric measurement, the relaxivity r1 ofMagnevist� and the longitudinal relaxation time T1,0 wereagain determined from the data of 7 samples for calibra-tion to take into account potential influence of temperature

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Magn Reson Mater Phy (2012) 25:215–222 219

Fig. 3 Top: Longitudinal relaxation rate 1/T1 of saline solution fordifferent concentrations of Magnevist�. The relaxation rate varies in alinear manner as a function of concentration. Bottom: Observable dif-ference in T1 at the volume boundaries as a function of the amount

of Magnevist�. Solid line: calculation of �T1 using Eq. 5, using thefollowing parameters: T1 : 3.30s, r1 : 4.17lmmol−1s−1; crosses: datapoints

differences during the experiment. Using Eq. 4, we calcu-lated the volume of each sample. The deviation from theactual volume (Vact − Vcal)/Vcal was calculated to determinethe accuracy of the method.

In the in vivo study, ECG triggered T1 images were deter-mined in a short axis slice perpendicular to the long axisof the heart using an Inversion Recovery Snapshot FLASHsequence. One image (FOV50 × 50 mm2, slice thickness3 mm, echo time 1 ms, repetition time 2.25 ms, flip angle3◦, matrix size 64 × 128) was acquired within a heartcycle (180–200 ms). 24 images were acquired after eachinversion pulse. TCBV was quantified by measurement ofT1 in the left ventricular heart chamber before and afterapplication of the intravascular contrast agent. In each leftventricular heart chamber of the investigated animals, aregion of interest (ROI) was defined, containing 50–75 pix-els. T1 was determined as mean value in the ROIs of theT1-maps.

Results

Validation of theory

A typical example of a T1-map is shown in Fig. 2. The T1-mapreflects the arrangement of the samples containing differ-ent concentrations of the used contrast agent. The relaxationrates 1/T1 plotted against the concentration of Magnevist� isshown in Fig. 3. The relaxation rate varied in a linear manneras a function of concentration (correlation coefficient 0.9996)as predicted in Eq. 2 for concentrations up to 0.33 mmol/l.The relaxivity r1 of Magnevist� at 7 T in saline solutionwas (4.17 ± 0.02) l mmol−1s−1, the longitudinal relaxation

time T1b,0 of saline solution without Magnevist� was (3.30± 0.07) s. Figure 3 shows the progression of the �T1(n)

curve for these parameters as a function of the amount of thecontrast agent according to Eq.5, equivalent to Fig. 1. Thedistribution of the measured data points is in good agreementwith the predicted progression.

These results show that

1. The relaxivity of Magnevist� is independent of the con-centration in the range of investigation. Equations 2 and 3are therefore valid and volume analysis can be conductedwithout difficulty.

2. The observed T1-difference depends on the amount ofcontrast agent and the calculated optimal amount of con-trast agent matches the measured optimal amount of con-trast agent. As shown in Fig. 3, the theory described herequantitatively matches results of the measurement.

Volumetry

The results of the volumetric measurement are summarizedin Fig. 4. Comparison of measured volume with actual vol-ume showed good agreement. The relaxation parameters forthe volumetric measurements were T1b,0(3.26±0.01) s, andr1(4.33 ± 0.01)l mmol−1s−1. These results are consistentwith those obtained for validation. The relative deviation ofthe measured volume from the actual volume was below 1%for 8 of 20 samples. Eighteen samples showed a deviationof <5%. The average deviation from the actual volume was1.8%. The precision of the measurement was approximately3.3% for all volume samples.

A comparable level of accuracy is reported for a semi-automated blood volume measurement system (BVA-100,

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220 Magn Reson Mater Phy (2012) 25:215–222

Fig. 4 Comparison of measured volume and actual volume. Left: phantom experiment; Right: in vivo experiment. Pearson correlation coefficients:0.9969 (phantom) and 0.9564 (in vivo), respectively

Daxor Corp.) [5]. An accuracy of 2.5% is achieved withina testing time of 90 min (www.daxor.com). In contrast withthis and other methods using the indicator dilution technique,our approach does not cause radiation contamination or tem-porary discoloration of the skin, nor does it require extensivepreparation.

In the in vivo study, we calculated the total circulatingblood volumes for seven Wistar rats with 350±40 g bodyweight using the blood-pool contrast agent Gd-DTPA-albu-min. T1 was measured in vivo in blood of the left ventricu-lar heart chamber. The observed relaxation times were, forexample in animal No. 1 (Table 1), T1b,0 1.53 s and T1b 0.53s, resulting in a total circulating blood volume of 18.9 ml.According to [17], a Wistar rat of 300 g should have a bloodvolume of 18.77 ml. Our results showed good agreement withthe theoretical values (Table 1).

Discussion

The determination of TCBV using magnetic resonance is aminimally invasive procedure. The measurement of the relax-

ation times of blood before and after injection of the contrastagent can be conducted non-invasively in the human body. Itis also conceivable to conduct these measurements on bloodsamples, which are drawn before and after injection of thecontrast agent. In this case, it is not necessary to examine thewhole organism by MRI. The relaxation times of the bloodsamples can be determined using magnetic resonance imag-ing for simultaneous and fast assessment of multiple samples,or using magnetic resonance spectroscopy, further increasingthe precision of the measurement. MR contrast agents are,unlike isotopic indicators, not subject to decay. This allowsthe possibility to draw blood samples at any doctor’s office,and send to a nearby MR-laboratory for conducting mea-surements. MR contrast agents are available with variouselimination rates. An indicator with low elimination rate willprovide more accurate results than one with high eliminationrate. However, indicators that are rapidly removed from thecirculation provide the possibility of repeated measurements.To obtain reasonable results in this case, multiple drawing ofblood samples over time is inevitable. The blood volume cal-culated using Eq. 4 seems to increase as the concentration ofthe contrast agent decreases according to

Table 1 Results of in vivo volumetric measurements

Animal (no.) Body weight (kg) Estimated blood T1,0 (s) T1 (s) Measured bloodvolume (ml) volume (ml)

1 0.300 18.77 1.53 0.53 18.91

2 0.304 19.01 1.50 0.53 19.49

3 0.394 24.41 1.49 0.75 25.76

4 0.400 24.77 1.12 0.37 25.35

5 0.357 22.19 1.64 0.81 22.92

6 0.368 22.85 1.66 0.78 21.59

7 0.330 20.57 1.58 0.66 20.67

Mean ± SD 0.350 ± 0.040 21.80 ± 2.43 1.50 ± 0.18 0.63 ± 0.16 22.10 ± 2.71

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Magn Reson Mater Phy (2012) 25:215–222 221

Vcalculated = 1

1 − �nn

Vreal (11)

Assuming exponential clearance of the contrast agent withhalf life Te lim, the real TCBV can be determined by linearregression of

log (V (t)) = log (V ) + (t/Te lim) (12)

to the data points. Biexponential and more refined models ofclearance have also been proposed [21] and could be incor-porated.

We used Magnevist� for the phantom experiments in thisstudy, even though in in vivo TCBV analysis blood poolagents are required. Currently, the only clinically approvedblood pool agent is Vasovist� (Bayer-Schering AG). Laufferet al. [22] studied the relaxivity of Vasovist� as a functionof concentration. Their findings suggest that the relaxivi-ty of Vasovist� decreases with increasing concentration.However, the relaxivity is approximately constant for lowconcentrations of Vasovist�. In blood volume analysis, theconcentration of Vasovist� does not exceed 0.05 mmol/l,and dependence of the relaxation on the contrast agent canbe disregarded. The results obtained in our phantom stud-ies using Magnevist� can therefore be directly translated toVasovist�.

Nevertheless, intravascular contrast agents are markersof the plasma volume and their concentration in the blooddepends on the hematocrit and is somewhat different incapillary blood (63–75%) when compared with ventricularblood (48%) [23]. This leads to lower relaxation rates inthe ventricular blood than that in capillary blood. Since T1b

and T1b,0were determined both in the ventricular blood andTCBV was calculated according Eq. 4 the dependence on thehematocrit can be neglected.

Conclusion

In this study we introduced a novel method for the deter-mination of the total circulating blood volume using mag-netic resonance contrast agents as tracers in the frameworkof the indicator dilution technique. We take advantage of theeffect of shortened relaxation times with increased concen-tration of the contrast agent. Measurement of the relaxationtimes of blood before and after administration of the contrastagent yields the TCBV.

A phantom study showed that this method measures thevolume with an accuracy of ±2% and a precision of ±3%.Our findings indicate that our method is capable of measuringvolumes accurately and precisely.

The relaxation times can be determined in the human bodywith no blood sampling required. Nevertheless, it shouldbe possible to draw blood samples before and after bolus

injection. Therefore it is not necessary to examine the wholeorganism by MRI.

TCBV determination using this minimally invasive MRmethod is accurate, rapid and has the potential to enhancemonitoring of various disease and therapy management.

Acknowledgments We gratefully acknowledge the expert technicalassistance of Sabine Voll, Xavier Helluy for his assistance in imageacquisition and programming image processing routines, and ThomasKampf for designing Teflon sample holders and helpful discussion. Thiswork was supported by grants from the Deutsche Forschungsgemeins-chaft (SFB 688) and the Bundesministerium für Bildung und Forschung(BMBF 01EO1004).

References

1. Androne AS, Katz SD, Lund L, LaManca J, Hudaihed A,Hryniewicz K, Mancini DM (2003) Hemodilution is common inpatients with advanced heart failure. Circulation 107(2):226–229

2. Mitchell JP, Schuller D, Calandrino FS, Schuster DP (1992)Improved outcome based on fluid management in critically illpatients requiring pulmonary artery catheterization. Am Rev RespirDis 145(5):990–998

3. Shoemaker WC, Montgomery ES, Kaplan E, Elwyn DH (1973)Physiologic patterns in surviving and nonsurviving shock patients.Use of sequential cardiorespiratory variables in defining crite-ria for therapeutic goals and early warning of death. Arch Surg106(5):630–636

4. Glass HI (1973) ICSH Panel on diagnostic applications of radioiso-topes in haematology: standard techniques for the measurement ofred-cell and plasma volume. A report by the international commit-tee for standardization in hematology. Br J Haematol 25(6):801–814

5. Manzone TA, Dam HQ, Soltis D, Sagar VV (2007) Blood volumeanalysis: a new technique and new clinical interest reinvigorate aclassic study. J Nucl Med Technol 35(2):55–63

6. Jaenike JR, Schreiner BF, Waterhouse C (1957) The relative vol-umes of distribution of I131-tagged albumin and high molecularweight dextran in normal subjects and patients with heart disease.J Lab Clin Med 49(2):172–181

7. Gibson JG, Evans WA (1937) Clinical studies of the blood volume.I. Clinical application of a method employing the azo dye “EvansBlue” and the spectrophotometer. J Clin Invest 16(3):301–316

8. Bradley EC, Barr JW (1968) Determination of blood volume usingindocyanine green (cardio-green) dye. Life Sci 7(17):1001–1007

9. Gadian DG, Payne JA, Bryant DJ, Young IR, Carr DH, BydderGM (1985) Gadolinium-Dtpa as a contrast agent in MR imaging–theoretical projections and practical observations. J Comput AssistTomogr 9(2):242–251

10. Rohrer M, Bauer H, Mintorovitch J, Requardt M, WeinmannHJ (2005) Comparison of magnetic properties of MRI contrastmedia solutions at different magnetic field strengths. Invest Radiol40(11):715–724

11. Caravan P, Cloutier NJ, Greenfield MT, McDermid SA, DunhamSU, Bulte JWM, Amedio JC, Looby RJ, Supkowski RM, HorrocksWD, McMurry TJ, Lauffer RB (2002) The interaction of MS-325with human serum albumin and its effect on proton relaxation rates.J Am Chem Soc 2002 124(12):3152–3162

12. Silvennoinen MJ, Kettunen MI, Kauppinen RA (2003) Effects ofhematocrit and oxygen saturation level on blood spin-lattice relax-ation. Magn Reson Med 49(3):568–571

123

222 Magn Reson Mater Phy (2012) 25:215–222

13. Dobre MC, Ugurbil K, Marjanska M (2007) Determination ofblood longitudinal relaxation time (T1) at high magnetic fieldstrengths. Magn Reson Imaging 25(5):733–735

14. Pintaske J, Martirosian P, Graf H, Erb G, Lodemann KP, Claus-sen CD, Schick F (2006) Relaxivity of gadopentetate dimeglumine(magnevist), gadobutrol (gadovist), and gadobenate dimeglumine(multihance) in human blood plasma at 0.2, 1.5, and 3 tesla. InvestRadiol 41(3):213–221

15. Feldschuh J, Enson Y (1977) Prediction of the normal bloodvolume. Relation of blood volume to body habitus. Circulation56(4):605–612

16. Pearson TC, Guthrie DL, Simpson J, Chinn S, Barosi G, Ferrant A,Lewis SM, Najean Y (1995) Interpretation of measured red cellmass and plasma volume in adults: expert panel on radionuclidesof the international council for standardization in haematology. BrJ Haematol 89(4):748–756

17. Lee HB, Blaufox MD (1985) Blood volume in the rat. J Nucl Med26(1):72–76

18. Ogan MD, Schmiedl U, Moseley ME, Grodd W, Paajanen H,Brasch RC (1987) Albumin labeled with Gd-DTPA. An intravas-cular

contrast-enhancing agent for magnetic resonance blood pool imag-ing: preparation and characterization. Invest Radiol 22(8):665–671

19. Haase A, Matthaei D, Bartkowski R, Dühmke E, LeibfritzD (1989) Inversion recovery snapshot FLASH MR imaging. JComput Assist Tomogr 13(6):1036–1040

20. Deichmann R (2005) Fast high-resolution T1 mapping of thehuman brain. Magn Reson Med 54(1):20–27

21. Radjenovic A, Ridgway JP, Smith MA (2006) A method for phar-macokinetic modelling of dynamic contrast enhanced MRI studiesof rapidly enhancing lesions acquired in a clinical setting. PhysMed Biol 51(9):N187–N197

22. Lauffer RB, Parmelee DJ, Dunham SU, Ouellet HS, DolanRP, Witte S, McMurry TJ, Walovitch RC (1998) MS-325: albu-min-targeted contrast agent for MR angiography. Radiology207(2):529–538

23. Rakusan K (1971) Vascular capacity and hematocrit in experimen-tal cardiomegaly due to aortic constriction in rats. Can J PhysiolPharmacol 49(9):819–823

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