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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
JPET 291:1308 –1316, 1999
Vol. 291, No. 3
Printed in U.S.A.
Modifications of Blood Volume Alter the Disposition of Markers
of Blood Volume, Extracellular Fluid, and Total Body Water1
TOM C. KREJCIE, THOMAS K. HENTHORN, W. BROOKS GENTRY, CLAUS U. NIEMANN, CHERI ENDERS-KLEIN,
COLIN A. SHANKS, and MICHAEL J. AVRAM
Northwestern University Medical School, Department of Anesthesiology, Chicago, Illinois
Accepted for publication August 31, 1999
This paper is available online at http://www.jpet.org
In a 10-year survey (1967–1976) of mortality associated
with 240,483 anesthetics, Harrison (1978) found that the
induction of anesthesia in hypovolemic subjects was the most
common cause of death attributed to anesthesia and of an
unknown amount of anesthetic-associated complications.
The challenge of providing general anesthesia for hypovolemic patients is well recognized (Graves, 1974) and is perhaps
best illustrated by the tragic consequences of the adminis-
Received for publication June 4, 1999.
1
This study was supported in part by National Institutes of Health Grants
GM43776 and GM47502. Portions were presented in part at the 1994 and 1997
annual meetings of the American Society of Anesthesiologists [Krejcie TC,
Henthorn TK, Gentry WB, Shanks CA, Enders C, Van Drie J and Avram MJ
(1994) The effect of altered blood volume on intravascular mixing. Anesthesiology 81:A410; and Krejcie TC, Henthorn TK, Niemann CU, Klein C, Shanks
CA and Avram MJ (1997) The effect of blood volume on drug disposition from
the moment of injection. Anesthesiology 87:A351].
during hypovolemia. Early inulin disposition changes reflected
those of ICG. The ICG and inulin elimination clearances were
unaffected by altered blood volume. Neither antipyrine-defined
total body water volume nor antipyrine elimination clearance
changed with altered blood volume. The fraction of CO not
involved in drug distribution had a significant effect on the area
under the antipyrine concentration-versus-time relationships
(AUC) in the first minutes after drug administration. Hypovolemia increased the fraction of CO represented by nondistributive
blood flow and increased the antipyrine AUC up to 60% because nondistributive blood flow did not change, despite
decreased CO. Volume loading resulted in a smaller (less than
20%) antipyrine AUC decrease despite increased fast tissue
distributive flow because nondistributive flow also increased
with increased CO.
tration of thiopental to the hypovolemic casualties of the
Japanese attack on Pearl Harbor (Halford, 1943).
Price (1960) explained the increased reactivity of hypovolemic patients to drugs such as thiopental on the basis of the
increased percentage of cardiac output (CO), hence drug delivery, received by both the brain and the myocardium in the
hypovolemic state. Subsequent studies have confirmed
Price’s prediction of increased reactivity to drugs and increased plasma drug concentrations in hypovolemic subjects.
Benowitz et al. (1977) found significantly increased arterial
plasma lidocaine concentrations after an i.v. bolus dose in
monkeys subjected to 30% exsanguination, which they attributed to decreases in both initial and steady-state volumes of
distribution and elimination clearance (ClE). In addition, using data from studies in monkeys, they predicted marked
increases in brain lidocaine concentrations after drug administration to a human after 30% hemorrhage. Decreases in
ABBREVIATIONS: CO, cardiac output; AUC, area under the blood concentration-versus-time relationship; Hct, hematocrit; ICG, indocyanine
green; PA, pulmonary artery; MAP, mean arterial pressure; MTT, mean transit time; VC, central volume; VT-P, pulmonary tissue volume; VND-F, fast
nondistributive peripheral pathway volume; ClND-F, clearance to the fast nondistributive peripheral pathway; VND-S, slow nondistributive peripheral
pathway volume; ClND-S, clearance to the slow nondistributive peripheral pathway; VT-F, rapidly (fast) equilibrating tissue volume; ClT-F, clearance
to the rapidly (fast) equilibrating peripheral tissue compartment; VT-S, slowly equilibrating tissue volume; ClT-S, clearance to the slowly equilibrating
peripheral tissue compartment; ClE, elimination clearance; VSS, total (steady-state) volume of distribution; SCl, total (sum of) all (peripheral and
elimination) clearances; LSD, least significant difference.
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ABSTRACT
Recirculatory pharmacokinetic models for indocyanine green
(ICG), inulin, and antipyrine describe intravascular mixing and
tissue distribution after i.v. administration. These models characterized physiologic marker disposition in four awake, splenectomized dogs while they were normovolemic, volume
loaded (15% of estimated blood volume added as a starch
solution), and mildly and moderately hypovolemic (15 and 30%
of estimated blood volume removed). ICG-determined blood
volumes increased 20% during volume loading and decreased
9 and 22% during mild and moderate hypovolemia. Dye (ICG)
dilution cardiac output (CO) increased 31% during volume
loading and decreased 27 and 38% during mild and moderate
hypovolemia. ICG-defined central and fast peripheral intravascular circuits accommodated blood volume alterations and the
fast peripheral circuit accommodated blood flow changes. Inulin-defined extracellular fluid volume contracted 14 and 21%
1999
Blood Volume Changes and Kinetics of Physiologic Markers
Materials and Methods
Experimental Protocol. The design of this pharmacokinetic
study entailed 16 individual experiments. Four purpose-bred male
coonhounds, weighing 25 to 28.5 kg (26.6 6 1.9 kg; Table 1), were
studied on four occasions each in this Institutional Animal Care and
Use Committee-approved study.
Approximately 1 month before being studied, the dogs were surgically prepared while under isoflurane anesthesia. The tip of a
Vascular-Access-Port catheter (Access Technologies, Skokie, IL) was
positioned near the aortic bifurcation via a femoral artery of each
dog, and the access port was secured to the muscle fascia of the upper
hind leg to facilitate frequent percutaneous arterial blood sampling
(Garner and Laks, 1985). A splenectomy was also performed to
prevent autotransfusion during acute hypovolemia (Carniero and
Donald, 1977). The dogs were allowed to recover from surgery for at
least 4 weeks before being studied for the first time.
All dogs were studied when normovolemic (control), when a targeted 15 and 30% of their calculated blood volume had been removed
acutely (mild and moderate hypovolemia, respectively) and when
acutely volume loaded with a starch solution targeted to equal 15%
of their calculated blood volume (volume-loaded). The order in which
these studies were conducted in each dog was randomized using a
repeated measures Latin square experimental design. Studies were
conducted at intervals of not less than 4 weeks. The dogs were
trained for several weeks to lie in the left lateral decubitus position
for these awake studies.
For all studies, after an overnight fast during which the dog was
allowed water ad libitum, it was brought to the laboratory and
positioned. When it was determined that the dog was calm and
cooperative, the neck was prepped and the skin overlying the right
external jugular vein was infiltrated liberally with 2% chloroprocaine. Using a modified Seldinger technique, an 8 Fr percutaneous
sheath introducer was inserted into the external jugular vein. If the
insertion could not be accomplished in a timely and humane fashion,
the study was abandoned and rescheduled.
Arterial access for blood sampling by roller pump or syringe was
achieved by inserting a 20-gauge Huber needle percutaneously in the
Vascular-Access-Port; this also allowed systemic arterial blood pressure to be monitored via a solid-state pressure transducer (Trantec;
Baxter-Edwards, Irvine, CA). A flow-directed thermal dilution pulmonary artery (PA) catheter (Baxter-Edwards 93A-140-7F, with a
20-cm proximal port) was inserted through the sheath introducer,
positioned, and secured. The PA catheter was subsequently used to
determine thermal dilution CO as well as to facilitate right atrial
administration of the physiological markers. The side arm of the
sheath introducer was used for maintenance fluid administration
and the readministration of autologous blood. Hydration was maintained throughout the study by an infusion of 0.9% saline at a rate of
TABLE 1
Subject characteristics and global pharmacokinetic parameters
VSS is the sum of all compartmental volumes; HR, heart rate; MAP, mean arterial pressure; CO, CO determined by thermal dilution at the time of injection, which was
correlated with dye (ICG) dilution CO (p , .05); SVR 5 (MAP 3 80/CO), assuming central venous pressure 5 0. Values are mean (S.D.).
Experimental
Condition
Volume
loaded
Normovolemic
Mildly
hypovolemic
Moderately
hypovolemic
a
ICG
Weight
Hct
HR
MAP
CO
kg
%
beats/min
mm Hg
liters/min
26.6
(1.9)
26.6
(1.9)
26.6
(1.9)
26.6
(1.9)
33.0b
(3.6)
38.4
(3.2)
36.5c
(4.4)
35.5b,c
(4.1)
99
(17)
81
(7)
91
(31)
90
(21)
117
(15)
107
(10)
113
(17)
93b,c,d
(7)
9.27
(2.39)
6.19
(3.19)
4.55c
(1.11)
3.60c
(1.49)
Inulin
SVR
25
dynes z s z cm
1460
(435)
2159
(594)
2173
(351)
2180
(807)
ClE
VSSa
ClEa
VSSa
ClEa
liters/kg
ml/min/kg
liters/kg
ml/min/kg
liters/kg
ml/min/kg
0.120b
(0.012)
0.100
(0.002)
0.091c
(0.010)
0.078b,c
(0.010)
13.0
(2.3)
11.7
(3.4)
10.7
(2.2)
9.9
(2.2)
0.249
(0.024)
0.248
(0.022)
0.225
(0.043)
0.205
(0.002)
4.70
(0.94)
4.54
(0.27)
4.31
(1.07)
4.16
(0.37)
0.843
(0.089)
0.786
(0.065)
0.750
(0.034)
0.735
(0.059)
11.6
(4.0)
10.7
(2.7)
10.2
(1.8)
9.4
(0.8)
Inulin and antipyrine VSS and ClE values are here presented on the basis of plasma rather than blood concentrations.
Significantly different from normovolemic control (p , .05), as determined by Fisher’s LSD test.
Significantly different from volume loaded (p , .05), as determined by Fisher’s LSD test.
d
Significantly different from mildly hypovolemic (p , .05), as determined by Fisher’s LSD test.
b
c
Antipyrine
VSS
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anesthetic requirements for both thiopental (33%) and ketamine (40%) in the pig after 30% blood loss (Weiskopf and
Bogetz, 1985) were nearly identical with those predicted by
the perfusion model of Price (1960). Increased reactivity of
the hypovolemic dog to midazolam has also been reported by
Adams et al. (1985), with increased arterial plasma midazolam concentrations yet no detected changes in the volumes of
distribution.
Price (1960) also predicted that patients with increased
blood flow to indifferent tissues such as muscle and portal
tissues (e.g., thyrotoxic or apprehensive patients) would require larger doses of thiopental because a smaller fraction of
the i.v. administered drug would appear in the brain. Data
from a study of lidocaine disposition during an isoproterenol
infusion in a single rhesus monkey (Benowitz et al., 1977) are
consistent with this prediction; the isoproterenol infusion
apparently increased the initial volume of distribution in a
two-compartment model of lidocaine disposition by 16% and
increased lidocaine ClE by 40%.
Factors affecting the early arterial drug concentrationversus-time profile influence the intensity and timing of the
onset of drug effect for rapidly acting i.v. anesthetics such as
thiopental (Sheiner et al., 1981); these factors include intravascular mixing, pulmonary uptake, and distribution to
highly perfused tissues by blood flow and transcapillary diffusion (Riggs, 1963; Krejcie et al., 1997). Our recently developed recirculatory pharmacokinetic model describes these
processes by referencing them to the disposition of markers
of intravascular space, extracellular fluid space, and body
water (Krejcie et al., 1996a; Avram et al., 1997). Indocyanine
green (ICG) binds to plasma proteins rapidly and completely,
impeding its extravascular distribution (Henthorn et al.,
1992). The polysaccharide inulin distributes from intravascular space to interstitial fluid by free water diffusion
through aqueous endothelial fenestrations (Henthorn et al.,
1982; Krejcie et al., 1996a). Antipyrine, a marker of total
body water (Soberman et al., 1949) including pulmonary
extravascular water (Brigham et al., 1971), distributes to a
volume as large as total body water in a blood flow-dependent
manner in many tissues and thus is a prototype for many
lipophilic drugs (Renkin, 1952; Krejcie et al., 1996a).
The purpose of the present study was to examine the
relationship of the cardiovascular and systemic effects of
mild and moderate hypovolemia and volume loading to the
distribution of drugs through mixing, flow, and diffusion.
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Krejcie et al.
respective drug assuming a red blood cell/plasma partition coefficient of 1. As the central blood flow of the antipyrine model was
constrained to that of ICG and inulin (i.e., CO), the apparent antipyrine dose was estimated as a linear scalar using blood ICG and
plasma antipyrine concentrations, obtained before the first evidence
of recirculation according to the relationship (Krejcie et al., 1996a):
Apparent doseantipyrine 5
DoseICG
AUCICG, blood
z AUCantipyrine, plasma
Pharmacokinetic Model. The pharmacokinetic modeling methodology has been described in detail previously (Avram et al., 1997).
It is based on the approach described by Jacquez (1996) for obtaining
information from outflow concentration histories, the so-called inverse problem (Fig. 1). Inulin and antipyrine distributions to extracellular fluid space and total body water space, respectively, were
analyzed as the convolution of their intravascular behavior, determined by the pharmacokinetics of concomitantly administered ICG,
and tissue distribution kinetics (Krejcie et al., 1996a).
A delay element is a mathematical description of the frequency
distribution of drug transit times that can be described by the mean
transit time (MTT). The apparent volume of a delay element
[e.g., central volume (VC), fast nondistributive peripheral pathway
volume (VND-F), and slow nondistributive peripheral pathway volume (VND-S); Fig. 1] can be determined as the product of the flow
through the delay and its MTT. The delay elements of the SAAM II
kinetics analysis software (SAAM Institute, Seattle, WA) are composed of a linear chain (or tanks-in-series) of n identical compartments connected by identical rate constants k such that n/k is equal
to the MTT of the delay. The solution for a linear chain obtained by
Fig. 1. The general model for the recirculatory pharmacokinetics of ICG,
inulin, and antipyrine (Krejcie et al., 1996a). The central circulation of
the three drugs receives all of CO, defined by the delay elements (VC). The
delay elements are represented generically by rectangles surrounding
four compartments, although the number of compartments needed in a
delay varied between 2 and 30. The VT-P, a subset of VC, is calculated for
antipyrine by subtracting the VC of ICG from that of antipyrine. Beyond
the central circulation, CO distributes to numerous circulatory and tissue
pathways that lump, on the basis of their blood volume/flow ratios or
tissue volume/distribution clearance ratios (MTTs), into fast (ClND-F,
VND-F) and slow (ClND-S, VND-S) peripheral blood circuits (ICG) or nondistributive peripheral pathways (inulin and antipyrine) and fast (ClT-F,
VT-F) and slow (ClT-S, VT-S) tissue volume groups. ICG, which distributes
only within the intravascular space, does not have fast and slow tissue
volumes. The nondistributive flows for ICG and inulin were resolved into
fast and slow components; antipyrine does not have an identifiable second nondistributive peripheral circuit. The ClE of all three markers are
modeled from the arterial sampling site without being associated with
any particular peripheral circuit.
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3 ml/kg/h. Once the study was well under way, a lubricated 7 Fr
single-lumen balloon-tipped catheter was inserted through the urethra into the bladder to facilitate urine ([14C]inulin) collection. All
dogs easily tolerated this procedure without sedation or restraint.
When the dogs were studied while mildly or moderately hypovolemic, hypovolemia was achieved by a targeted removal of 15 or 30%
of the calculated blood volume (approximately 12 or 24 ml/kg based
on an estimated 80 ml/kg blood volume), respectively, over a period
of 20 min after preparation of the animals (Adams et al., 1985). One
hundred milliliters of this blood was heparinized (1000 U) and set
aside for i.v. return over 10 min, from time t 5 0, to replace the
volume of the arterial blood samples obtained over that time. The
balance of the blood removed was heparinized and returned to the
dog 2 h after study drug injection. No compensatory volume replacement was administered before the study to the dogs when they were
made moderately or severely hypovolemic.
In the volume loading study, a volume of starch solution equal to
15% of the calculated blood volume, plus an additional 100 ml, was
infused over 30 min. After the volume load, 100 ml of blood was
removed, to be returned over 10 min to compensate for the rapid
blood sampling.
For the normovolemia study, 100 ml of whole blood was removed
from the dog, anticoagulated with 1000 U of heparin, and set aside to
be reinfused during the period of frequent blood sampling. This blood
was immediately replaced with 300 ml of 0.9% saline solution administered i.v. over 20 min to allow for equilibration of this volume
throughout the extracellular fluid space.
The study was begun not less than 30 min after volume perturbation. ICG (5 mg in 1 ml of diluent; Cardio-Green; Hynson, Westcott, and Dunning, Baltimore, MD), [14C]inulin (30 mCi in 1.5 ml of
diluent; DuPont-NEN, Boston, MA), and antipyrine (25 mg in 1 ml of
diluent; Sigma Chemical Co., St. Louis, MO) were placed sequentially in a 76-cm length of i.v. tubing (4.25 ml priming volume) and
connected to the proximal injection port of the PA catheter. At the
onset of the study (time t 5 0 min), the 3.5-ml drug volume was
flushed into the right atrium within 4 s using 10 ml of 5% dextrose
in water, allowing the simultaneous determination of dye and thermal dilution COs. Arterial blood samples were collected every 0.05
min for the first minute and every 0.1 min for the next minute using
a computer-controlled roller pump (Masterflex; Cole-Parmer, Chicago, IL), set at a withdrawal rate of 1 ml/s, and a chromatography
fraction collector (model 203; Gilson, Middleton, WI). Subsequently,
30 arterial blood samples of 3 ml were drawn manually at 0.5-min
intervals to 4 min, at 5 and 6 min, every 2 min to 20 min, at 25 and
30 min, every 10 min to 60 min, 15 min to 120 min, and 30 min to 360
min.
Analytical Methods. Plasma ICG concentrations of all samples
obtained up to 20 min were measured on the study day by the HPLC
technique of Grasela et al. (1987) as modified in our laboratory to
provide sensitivity of 0.2 to 20.00 mg/ml with c.v. values of 5% or less
(Henthorn et al., 1992).
Plasma [14C]inulin concentrations of all samples were determined
by liquid scintillation counting with the use of an external standard
method for quench correction (Bowsher et al., 1985). Counts that
were less than three times the background count were considered to
be below the lower limit of detection. The c.v. of the assay was less
than 3%.
Plasma antipyrine concentrations were measured in all samples
using a modification of an HPLC technique developed in our laboratory (Krejcie et al., 1994, 1996a). The antipyrine method is linear
from plasma concentrations of 0.10 to 10.00 mg/ml with c.v. values of
5% or less.
Plasma ICG and inulin concentrations were converted to blood
concentrations by multiplying them by one minus the hematocrit
(Hct), as neither ICG nor inulin partitions into erythrocytes. To
interpret antipyrine intercompartmental clearances in relation to
blood flow, plasma antipyrine concentrations were corrected for partitioning into erythrocytes by calculating the apparent dose of the
Vol. 291
1999
Blood Volume Changes and Kinetics of Physiologic Markers
successive integration for the exit rate from compartment n is given
by the Erlang frequency distribution function:
f~t! 5
k
n
z t
n21
~n 2 1!!
z e
2kt
The 8 model variables determined from arterial blood ICG concentrations, the 10 model variables determined from arterial blood
antipyrine concentrations, and the 12 model variables determined
from arterial blood inulin concentrations have been determined to be
both sensible and identifiable for our sampling schedule by the
IDENT2 program of Jacquez and Perry (1990).
Area under Blood Concentration-versus-Time Relationship
(AUC). The AUC was determined for both the first-pass fit (sum of
two parallel Erlang functions, AUCfirst-pass) and for the full recirculatory model. The AUCs for the full model were calculated for the
interval of 0 to 3 min (AUC0 –3 min). The AUCs for the full model were
influenced by AUCfirst-pass, which is affected solely by changes in CO
(i.e., CO 5 dose/AUCfirst-pass). Therefore, the AUC resulting from
recirculation of a marker was determined by subtracting the firstpass AUC from that of the full model over 3 min:
AUCrecirc 5 AUC0 –3 min 2 AUCfirst-pass .
Statistical Analysis. The effects of treatment and the order of
treatment on observed pharmacokinetic variables were assessed using a general linear model ANOVA for a repeated measures Latin
square experimental design (NCSS 6.0.2 Statistical System for Windows; Number Cruncher Statistical Systems, Kaysville, UT). Post
hoc analysis was carried out using Fisher’s least significant difference (LSD) test. The relationships of the pharmacokinetic variables
to CO were sought using standard least-squares linear regression
with the Bonferroni correction of the criterion for rejection of the
null hypothesis. The criterion for rejection of the null hypothesis was
p , .05.
Results
Blood volume estimated by ICG total (steady-state) volume
of distribution (VSS) increased 20% during volume loading
and decreased 9 and 22% during mild and moderate hypovolemia, respectively (Tables 1 and 2). Volume loading and both
mild and moderate hypovolemia resulted in a decrease in the
Hct compared with the normovolemic control (Table 1). The
thermal dilution and dye (ICG) dilution COs (Tables 1 and 2,
respectively) were similar (COTD 5 1.21 COICG 2 1.09, r2 5
0.91), indicating our sampling schedule and identification of
first-pass data were appropriate; dye dilution CO increased
30% during volume loading and decreased 27 and 38% during
mild and moderate hypovolemia, respectively, compared with
the normovolemic control. Mean arterial pressure (MAP) decreased slightly (12%) relative to control only during moderate hypovolemia (Table 1). Neither heart rate nor systemic
vascular resistance changed significantly during either volume loading or hypovolemia (Table 1).
The blood ICG, inulin, and antipyrine concentration-versus-time relationships were well characterized by the models
from the moment of injection. (Figs. 2– 4) The one-sample
runs test confirmed that there were no systematic deviations
of the observed data from the calculated values. As described
later, our recirculatory model of drug disposition was able to
describe the effect of altered blood volume on CO and its
distribution (the ICG model, Table 2) and the effect of altered
and redistributed CO on inulin (Table 3) and antipyrine
(Table 4) disposition. Our model was able to account for the
more than 50% increase in the area under the first minutes
of the antipyrine AUC produced by moderate hypovolemia.
(Fig. 4, Table 5). The extracellular fluid volume defined by
the VSS of inulin contracted 14 and 21% during the hypovolemic studies, mirroring changes in intravascular volume
due to the transvascular fluid shift. Antipyrine VSS and the
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which is a special case (integer values for n) of the gamma distribution function (Krejcie et al., 1996b).
Arterial ICG, inulin, and antipyrine concentration-versus-time
data before evidence of recirculation (i.e., first-pass data) were
weighted uniformly and first fit to the sum of two right-skewed
gamma distribution functions using TableCurve2D (version 3.0; Jandel Scientific, San Rafael, CA) on a Pentium-based PC (Dell Dimension, Austin, TX; Krejcie et al., 1996b). The two n values from the fit
to the gamma functions were then rounded to the nearest integer
value and fixed, and the data were refit to the sum of two Erlang
distribution functions. Because neither ICG nor inulin distributes
beyond the intravascular space before recirculation, they were modeled simultaneously to improve the confidence in the model parameters of the central (first-pass) circulation. Antipyrine has measurable tissue distribution during this time and was modeled
independently; the antipyrine pulmonary tissue volume (VT-P) is the
difference between the antipyrine VC (MTTantipyrine z CO) and the
central intravascular volume codetermined by ICG and inulin (MTTICG, inulin z CO). The optimum number of tanks-in-series of the peripheral delay elements, VND-F and VND-S, were determined iteratively without the use of gamma or Erlang functions.
In subsequent pharmacokinetic analysis, the descriptions of the
central circulation (the blood and apparent tissue volume between
the right atrial injection site and the aortic bifurcation sampling site)
were incorporated as parallel linear chains, or delay elements, into
independent recirculatory models for the individual markers using
SAAM II kinetics analysis software implemented on a Pentiumbased PC (Krejcie et al., 1996b, 1997). The first-pass data were
excluded from further data fitting; the results of the Erlang model of
the central circulation were placed as fixed parameters into the
recirculatory model, reducing the number of parameters to be optimized. The concentration-time data were weighted using the default
relative reciprocal weighting of the SAAM II program. Possible systematic deviations of the observed data from the calculated values
were sought (Berman et al., 1962) using the two-tailed one-sample
runs test, with p , .05, corrected for multiple applications of the runs
test, as the criterion for rejection of the null hypothesis (Siegel,
1956). Possible model misspecification was sought by visual comparison of the measured and predicted marker concentration-versustime relationships.
In general, peripheral drug distribution can be lumped into identifiable volumes and clearances: a fast nondistributive peripheral
pathway (VND-F and ClND-F); a slow nondistributive peripheral pathway (VND-S and ClND-S); rapidly (fast) equilibrating tissues (VT-F and
ClT-F); and slowly equilibrating tissues (VT-S and ClT-S). The fast and
slow nondistributive peripheral pathways (delay elements) represent intravascular circuits in the ICG and inulin models; the single
nondistributive peripheral pathway in the antipyrine model, determined by the recirculation peak, represents blood flow that quickly
returns the lipophilic marker to the central circulation after minimal
apparent tissue distribution (i.e., it is a pharmacokinetic shunt;
Krejcie et al., 1996a; Avram et al., 1997). ICG has no identifiable
tissue distribution. In the inulin and antipyrine models, the parallel
rapidly and slowly equilibrating tissues are the fast and slow compartments of traditional three-compartment pharmacokinetic models, respectively; therefore, the central circulation and nondistributive peripheral pathways are detailed components of the ideal VC of
the three-compartment model (Krejcie et al., 1994). Because of the
direct correspondence between the recirculatory model and threecompartment models, ClE was modeled from the arterial (sampling)
compartment to enable comparison of these results with previous
ones.
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Krejcie et al.
Vol. 291
TABLE 2
Pharmacokinetic variables for recirculatory ICG kinetic model
Values are mean (S.D.).
Volumea
Clearanceb
Experimental Condition
VCc
VND-Fc
1.10
(0.08)
1.03
(0.08)
0.86d,e
(0.03)
0.71d,e,f
(0.18)
0.67d
(0.20)
0.30
(0.24)
0.08d,e
(0.03)
0.15e
(0.06)
VND-S
VSS
ClND-Fc
ClND-S
1.42
(0.45)
1.33
(0.34)
1.47
(0.28)
1.23
(0.26)
3.19d
(0.33)
2.66
(0.18)
2.41e
(0.24)
2.09d,e
(0.37)
5.65d
(2.09)
3.58
(1.89)
1.42d,e
(0.80)
1.48d,e
(0.62)
2.23
(0.81)
2.64
(1.19)
2.81
(0.54)
2.11
(1.17)
liters
Volume loaded
Normovolemic
Mildly hypovolemic
Moderately hypovolemic
ClEc
SCl
0.35
(0.06)
0.31
(0.10)
0.29
(0.06)
0.26
(0.07)
8.22
(1.74)
6.53
(2.05)
4.52d,e
(1.29)
3.85d,e
(1.70)
liters/min
Fig. 2. Arterial blood ICG concentration histories for the first minute
(illustrating the first- and second-pass peaks) and for 20 min (inset) after
right atrial injection in one dog when it was normovolemic (F, solid line),
when it was volume loaded (Œ, dashed line), and when it was moderately
hypovolemic (, dotted line). The symbols represent drug concentrations,
and the lines represent concentrations predicted by the models.
Fig. 3. Arterial blood inulin concentration histories for the first minute
(illustrating the first- and second-pass peaks) and for 360 min, or to the
limit of detection (inset), after right atrial injection in one dog when it was
normovolemic (F, solid line), when it was volume loaded (Œ, dashed line),
and when it was moderately hypovolemic (, dotted line). The symbols
represent drug concentrations, and the lines represent concentrations
predicted by the models.
ClE values of ICG, inulin, and antipyrine were unaffected by
altered blood volume (Tables 1– 4).
ICG. The increase in total blood volume estimated by ICG
VSS as a result of volume loading and the decrease during
mild and moderate hypovolemia were due to changes in VC
and VND-F (Fig. 1, Table 2), both of which were correlated
with CO (VC 5 0.06 CO 1 0.58, r2 5 0.64; VND-F 5 0.08 CO 2
0.14, r2 5 0.42). Although VC increased in volume loading
and decreased during hypovolemia, it always contained approximately one-third of the total blood volume. VND-F represented approximately 10% of the total blood volume in the
awake normovolemic dogs; as a result of selective blood volume loss from VND-F during both mild and moderate hypovolemia, VND-F represented less than 10% of the total blood
volume. The bulk of the increase in blood volume during
volume loading was in VND-F, when it represented more than
20% of the estimated blood volume. No change in the volume
of the slow peripheral circulations (VND-S) was observed during either volume loading or hypovolemia, as a result of
which it represented less than the control 50% of estimated
blood volume during volume loading and more than 50%
during hypovolemia.
The increase in CO during volume loading and the decreases during mild and moderate hypovolemia were reflected almost exclusively in changes in ClND-F, which was
correlated with CO (ClND-F 5 0.87 CO 2 2.02, r2 5 0.84).
ClND-F increased more than 50% during volume loading and
decreased more than 50% during both mild and moderate
hypovolemia. The slow intercompartmental clearance of ICG
(ClND-S) and ICG ClE did not change significantly during
either volume loading or hypovolemia, although ClE was
correlated with CO (ClE 5 0.02 CO 1 0.17, r2 5 0.54). The
majority of the systemic distribution of CO not represented
by ClE (93–96% of CO) was in ClND-F during volume loading
and normovolemia but was in ClND-S during mild and moderate hypovolemia.
Inulin. Most of the changes in the recirculatory inulin
pharmacokinetic model produced by altered intravascular
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
a
The volumes (V) of the central (C), rapidly equilibrating (fast) nondistributive (ND-F), and slowly equilibrating nondistributive (ND-S) intravascular circuits and VSS,
which equals the sum of all volumes.
b
The clearances (Cl) of the rapidly (fast) equilibrating nondistributive (ND-F) and slowly equilibrating nondistributive (ND-S) intravascular circuits, ClE, and SCl, which
equals the ICG (dye dilution) CO determined at the moment of marker injection.
c
Correlated with CO (p , .05).
d
Significantly different from normovolemic control (p , .05), as determined by Fisher’s LSD test.
e
Significantly different from volume loaded (p , .05), as determined by Fisher’s LSD test.
f
Significantly different from mildly hypovolemic (p , .05), as determined by Fisher’s LSD test.
1999
Blood Volume Changes and Kinetics of Physiologic Markers
volume were in the central and fast nondistributive circuits
and were, therefore, very similar to those observed for ICG
(Table 3). Because VC of both ICG and inulin were modeled
together, changes in VC were the same in both models. Like
VND-F in the ICG model, that in the inulin model was correlated with CO (VND-F 5 0.08 CO 2 0.17; r2 5 0.80), nearly
doubling during volume loading and decreasing more than
50% during hypovolemia. VND-S and the volumes of the rapidly and slowly equilibrating tissue volumes (VT-F and VT-S,
respectively), which represented more than two-thirds of the
total inulin volume of distribution, were unaffected by altered intravascular volume. Changes in CO were largely
reflected in inulin ClND-F, which was correlated with CO
(ClND-F 5 0.85 CO 2 2.25; r2 5 0.91), increasing more than
50% during volume loading and decreasing more than 50%
during mild and moderate hypovolemia, like that of the ICG
model. Nearly 90% of CO not involved in ClE was nondistributive in the inulin models in the dogs under all conditions
because the transcapillary distribution of inulin is limited by
free water diffusion. ClND-F represented the majority of the
blood flow during control and volume loading studies,
whereas ClND-S represented the majority of the blood flow
during mild and moderate hypovolemia. Neither clearances
to the rapidly and slowly equilibrating tissues (ClT-F and
ClT-S, respectively) nor inulin ClE (i.e., glomerular filtration
rate) changed as a result of altered intravascular volume.
Antipyrine. The antipyrine distribution volumes determined by the recirculatory model were modestly affected by
alterations in blood volume (Table 4). The only peripheral
nondistributive volume that could be independently resolved
in the antipyrine model, VND (Krejcie et al., 1996a), increased
significantly as a result of volume loading but was unaffected
by hypovolemia. Although the VC defined by ICG and inulin
was increased by volume loading and decreased by hypovolemia, antipyrine VT-P did not change. While antipyrine VT-F
did not change significantly with alterations in blood volume,
it was correlated with CO (VT-F 5 0.80 CO 1 1.30; r2 5 0.60).
VT-F and the much larger VT-S, which also did not change
with changes in blood volume, together accounted for approximately 95% of the total distribution volume of antipyrine.
Alterations in blood volume affected antipyrine disposition
mainly through changes in the clearances and the fraction of
CO they represent (Table 4). As CO increased with volume
loading, nondistributive clearance (ClND) more than doubled.
However, ClND did not change during hypovolemia despite
the decrease in CO, as a result of which it represented over
16% of CO during moderate hypovolemia, which was nearly
twice the fraction of CO (8.5%) it represented in normovolemic dogs. Antipyrine tissue distribution clearances (ClT-F
and ClT-S) decreased as a result of hypovolemia and were
correlated with CO (ClT-F 5 0.72 CO 2 0.58, r2 5 0.93; ClT-S
5 0.21 CO 1 0.08, r2 5 0.61). In addition, because the
diminution in CO was reflected exclusively in decreased tissue distribution clearances, the tissue distribution clearances (ClT-F 1 ClT-S) represented a smaller percentage of CO
in moderately hypovolemic dogs (75 versus 85% in normovolemic dogs). Antipyrine ClE was unaffected by altered blood
volume.
AUC. The antipyrine AUC for at least the first 3 min after
drug administration increased more than 30% during mild
hypovolemia and more than 60% during moderate hypovolemia (Fig. 4, Table 5). Because the first-pass antipyrine AUC
represented approximately 50% of the AUC during the first 3
min, the increased AUC0 –3 min was due to not only the increase in first-pass AUCs secondary to the decreased CO but
also the increase in nondistributive clearance and the decrease in distributive clearance during hypovolemia. The antipyrine AUC during the first 3 min after drug administration was only modestly (less than 20%) decreased during
volume loading. Antipyrine AUC was correlated with CO
both when first-pass AUC was included (e.g., AUC0 –3 min 5
21.01 CO 1 16.28; r2 5 0.60) and when it was not (e.g.,
AUCrecirc 5 20.35 CO 1 7.23; r2 5 0.31). Lesser changes in
the AUC0 –3 min and AUCrecirc of ICG and inulin were observed during alterations in blood volume (Figs. 2 and 3,
Table 5). ICG and inulin AUC0 –3 min values were also correlated with CO, but the correlations were not as strong as
those of antipyrine (e.g., ICG AUC0 –3 min 5 20.25 CO 1 6.71;
r2 5 0.42; inulin AUC0 –3 min 5 22,600 CO 1 71,500; r2 5
0.40).
Discussion
Seyde et al. (1985) studied regional blood flow redistribution in awake rats before and after hemorrhage with the use
of radioactive 15-mm microspheres. They reported that blood
flow from skin, muscle, gastrointestinal tract, and, to a lesser
extent, kidneys was redistributed to the brain, heart, and
liver in awake rats after hemorrhage of 30% of estimated
blood volume resulting in a 35% decrease in CO with a 9%
decrease in MAP. The relative decreases in the peripheral
vascular circuits of the recirculatory pharmacokinetic models
of ICG and inulin disposition during moderate canine hypovolemia (Tables 2 and 3) are consistent with these observations. ICG and inulin ClND-F, which represent the nonsplanchnic circulation (Krejcie et al., 1996), decreased nearly
60% in our moderately hypovolemic dogs and more than 50%
in their hypovolemic rats. ICG and inulin ClND-S, which
represent the splanchnic circuit (Krejcie et al., 1996), decreased 20% in our moderately hypovolemic dogs and total
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
Fig. 4. Arterial blood antipyrine concentration histories for the first
minute (illustrating the first- and second-pass peaks) and for 360 min, or
to the limit of detection (inset), after right atrial injection in one dog when
it was normovolemic (F, solid line), when it was volume loaded (Œ, dashed
line), and when it was moderately hypovolemic (, dotted line). The
symbols represent drug concentrations, and the lines represent concentrations predicted by the models.
1313
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Krejcie et al.
Vol. 291
TABLE 3
Pharmacokinetic variables for recirculatory inulin pharmacokinetics
Values are mean (S.D.).
Volumea
Experimental
Condition
V Cc
VND-Fc
VND-S
1.10
(0.08)
1.03
(0.08)
0.86d,e
(0.03)
0.71d,e,f
(0.18)
0.59d
(0.15)
0.32
(0.23)
0.12d,e
(0.08)
0.13d,e
(0.05)
1.50
(0.52)
1.45
(0.27)
1.33
(0.20)
1.11
(0.22)
Clearanceb
VT-F
VT-S
VSS
ClND-Fc
ClND-S
ClT-F
3.27
(0.41)
3.39
(0.96)
2.95
(0.79)
2.43
(0.22)
3.45
(0.90)
4.57
(0.82)
4.07
(1.05)
4.14
(0.69)
9.92
(1.32)
10.77
(1.43)
9.33
(1.14)
8.53
(1.13)
4.97d
(2.18)
3.23
(1.71)
1.43d,e
(1.10)
1.15d,e
(0.75)
2.40
(0.61)
2.40
(0.49)
2.33
(0.40)
2.01
(0.87)
0.57
(0.10)
0.61
(0.16)
0.49
(0.05)
0.42
(0.17)
liters
Volume loaded
Normovolemic
Mildly
hypovolemic
Moderately
hypovolemic
ClT-S
ClE
SCl
0.19
(0.03)
0.20
(0.02)
0.18
(0.04)
0.17
(0.02)
8.22
(1.74)
6.53
(2.05)
4.52d,e
(1.29)
3.85d,e
(1.70)
liters/min
0.09
(0.04)
0.11
(0.02)
0.09
(0.02)
0.09
(0.04)
TABLE 4
Pharmacokinetic variables for recirculatory antipyrine pharmacokinetics
Values are mean (S.D.).
Volumea
Experimental
Condition
VCc
VT-P
VND
1.10
(0.08)
1.03
(0.08)
0.86d,e
(0.03)
0.71d,e,f
(0.18)
0.09
(0.10)
0.08
(0.07)
0.09
(0.03)
0.11
(0.01)
0.36d
(0.20)
0.12
(0.07)
0.06e
(0.02)
0.11e
(0.09)
Clearanceb
VT-Fc
VT-S
VSS
ClND
ClT-Fc
7.67
(1.14)
6.51
(2.99)
4.27
(1.51)
5.24
(2.87)
12.76
(2.02)
14.82
(2.08)
14.73
(3.64)
13.38
(1.22)
21.98
(2.09)
22.56
(0.99)
20.01
(2.41)
19.56
(2.50)
0.99d
(0.30)
0.48
(0.29)
0.40e
(0.27)
0.51e
(0.31)
5.31
(0.87)
4.12
(1.69)
2.57e
(1.10)
2.37e
(1.70)
liters
Volume
loaded
Normovolemic
Mildly
hypovolemic
Moderately
hypovolemic
ClT-Sc
ClE
SCl
0.30
(0.08)
0.31
(0.07)
0.27
(0.06)
0.25
(0.04)
8.22
(1.74)
6.53
(2.05)
4.52d,e
(1.29)
3.85d,e
(1.70)
liters/min
1.63
(0.92)
1.63
(0.55)
1.28
(0.32)
0.72d,e
(0.28)
a
The volumes (V) of the central (described by ICG and inulin) circuit (C), pulmonary tissue (the difference between the antipyrine central circuit volume and that described
by ICG and inulin) (T-P), nondistributive (ND) circuit, and the rapidly equilibrating (fast) (T-F) and slowly equilibrating (T-S) tissues, and VSS, which equals the sum of all
volumes.
b
The clearances (Cl) of the nondistributive (ND) circuit and the rapidly equilibrating (fast) (T-F) and slowly equilibrating (T-S) tissues, elimination clearance (ClE), and
SCl, which equals the ICG (dye dilution) CO determined at the moment of marker injection.
c
Correlated with CO (p , .05).
d
Significantly different from normovolemic control (p , .05), as determined by Fisher’s LSD test.
e
Significantly different from volume loaded (p , .05), as determined by Fisher’s LSD test.
f
Significantly different from mildly hypovolemic (p , .05), as determined by Fisher’s LSD test.
TABLE 5
Areas under the blood concentrations of the physiological markers versus time relationships (AUC0 –3 min) and those due to recirculation alone
(AUCrecirc) for the first 3 min after right atrial injection of ICG, inulin, and antipyrine
Values are mean (S.D.).
ICG
Inulin
Antipyrine
Experimental Condition
AUC0–3 min
Volume loaded
Normovolemic
Mildly hypovolemic
Moderately hypovolemic
a
b
c
4.16
(0.20)
4.93
(0.40)
5.43
(0.25)
6.47b,c
(1.59)
a
AUCrecirc
3.53
(0.34)
4.09
(0.53)
4.26
(0.29)
5.00b,c
(1.17)
AUC0–3 min
a
AUCrecirc
3104
3104
4.61
(0.35)
4.92
(0.70)
5.84
(0.44)
6.98b,c
(1.53)
3.77
(0.52)
3.80
(0.67)
4.28
(0.55)
5.03b,c
(0.90)
Correlated with CO (p , .05).
Significantly different from normovolemic control (p , .05) as determined by Fisher’s LSD test.
Significantly different from volume loaded (p , .05), as determined by Fisher’s LSD test.
AUC0–3 min
a
7.43
(0.99)
8.62
(2.49)
11.12
(4.88)
14.02b,c
(5.53)
AUCrecirca
4.27
(0.41)
4.42
(1.04)
5.24
(3.57)
6.68
(3.25)
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
a
The volumes (V) of the central (C), rapidly equilibrating (fast) nondistributive (ND-F), and slowly equilibrating nondistributive (ND-S) circuits and the rapidly
equilibrating (fast) (T-F) and slowly equilibrating (T-S) tissues, and VSS, which equals the sum of all volumes.
b
The clearances (Cl) of the rapidly equilibrating (fast) nondistributive (ND-F) and slowly equilibrating nondistributive (ND-S) circuits and the rapidly equilibrating (fast)
(T-F) and slowly equilibrating (T-S) tissues, ClE, and SCl, which equals the ICG (dye dilution) CO determined at the moment of marker injection.
c
Correlated with CO (p , .05).
d
Significantly different from normovolemic control (p , .05), as determined by Fisher’s LSD test.
e
Significantly different from volume loaded (p , .05), as determined by Fisher’s LSD test.
f
Significantly different from mildly hypovolemic (p , .05), as determined by Fisher’s LSD test.
1999
Blood Volume Changes and Kinetics of Physiologic Markers
central circulation and not to a first-pass increase resulting
from decreased CO.
Despite increased fast tissue distributive flow with increased CO in volume-loaded animals, the less than 20%
decrease in antipyrine AUC for the first minutes after drug
administration (Table 5) was not as profound as might be
expected based on results observed in hypovolemic dogs because nondistributive flow also increased during volume
loading (Table 4). Nevertheless, one would expect a modest
increase in the dose requirements for rapidly acting drugs in
volume loaded subjects based on the decrease in AUC.
The majority of CO in the recirculatory inulin model is
nondistributive (Table 3). Thus, although inulin nondistributive clearance, especially ClND-F, changed significantly with
CO in animals with altered blood volume, inulin AUC increases during hypovolemia and its decrease during volume
loading were approximately half those observed for antipyrine (Table 5). As a result, the onset and duration of effect
of the hydrophilic drugs for which inulin is a prototype (e.g.,
neuromuscular blockers) will not be as profoundly increased
in hypovolemia and decreased in volume loading as those of
the lipophilic drugs for which antipyrine is the prototype.
Although the decrease in CO during hypovolemia did not
affect antipyrine ClND, it decreased ClT-F by 42% and ClT-S by
56% (Table 4). The rapidly equilibrating (fast) tissue volume
represents splanchnic tissues, whereas the slowly equilibrating tissue volume represents nonsplanchnic tissues (Sedek et
al., 1989), to which distributive blood flows were proportional
to the blood flows of the fast intravascular circuit of the ICG
model (ClT-F 5 0.65 ICG ClND-F 1 1.63, r2 5 0.68; ClT-S 5
0.21 ICG ClND-F 1 0.69, r2 5 0.52). The decreased intercompartmental clearance of urea (like antipyrine, a marker of
total body water) during dialysis that we observed in an
earlier study (Bowsher et al., 1985) may reflect the decrease
in blood volume observed in the absence of significant hypotension during hemodialysis (Mann et al., 1989). Antipyrine
hepatic ClE did not change during hypovolemia because it is
not blood flow limited.
Hemodynamic responses to acute hypovolemia in conscious
mammals have two well-defined phases: a sympathoexcitatory phase and a sympathoinhibitory phase (Schadt and
Ludbrook, 1991). As a result of sympathetic vasoconstriction,
acute blood losses of less than 25 to 30% of blood volume are
characterized by little or no decrease in MAP despite a decrease in CO. General vasodilation (except in skin) at more
extreme acute blood losses results in a precipitous fall in
MAP with a continued decrease in CO. The blood volumes
removed in the present mild and moderate hypovolemic studies were designed to be less than those required to precipitate
the sympathoinhibitory phase of blood loss because we intended to perform repeated studies in the same animals and
extreme blood loss is associated with potential organ damage
and death. The 22% decrease in blood volume in moderately
hypovolemic animals of the present study produced only a
12% decrease in MAP despite a 38% decrease in CO, suggesting successful avoidance of the sympathoinhibitory response
to blood loss (Table 1). The effects of more extreme blood loss
cannot be extrapolated from these results, given the significantly different physiology accompanying more extreme
acute blood loss.
The studies were conducted in splenectomized dogs because the canine spleen is capable of autotransfusing 5 to 6
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
hepatic flow decreased 19% in their hypovolemic rats. ICG
hepatic ClE did not change as a result of hypovolemia because
it is not hepatic blood flow dependent in the dog, whereas
inulin ClE did not change as a result of hypovolemia because
canine renal blood flow does not change during nonhypotensive hemorrhage (Vatner, 1974).
To identify a pharmacokinetic basis of differences in reactivity to drugs with rapid onsets of effect, drug distribution
kinetics during the time of expected onset and offset of effect
must be described in detail. This requires a model that accounts for the role of CO and its distribution on drug disposition. The present study found significant changes in antipyrine disposition in dogs during mild and moderate
hypovolemia using a recirculatory pharmacokinetic model
based on frequent early arterial blood samples (Table 4).
Another study of drug pharmacokinetics during canine hypovolemia (Adams et al., 1985) failed to find an explanation
for increased reactivity to drugs with a rapid onset of central
nervous system effects during hypovolemia. However, their
study described midazolam disposition using infrequent
blood samples obtained beginning at 15 min, which is long
after the drug has produced its maximal effect. As a result of
their sampling schedule, they were only able to characterize
late drug distribution and global pharmacokinetic parameters, which are unlikely to explain differences in reactivity to
drugs with a rapid onset of effect.
An important observation of the present application of the
recirculatory pharmacokinetic model is that mild hypovolemia increased antipyrine AUC by approximately one-third in
the critical first minutes after drug administration, whereas
moderate hypovolemia increased antipyrine AUC by more
than 50% (Table 5). Increased AUC during mild and moderate hypovolemia was due to maintenance of the apparent
flow of blood not involved in drug distribution to the tissues
(i.e., ClND), despite a hypovolemia-induced CO decrease. (Table 4). The nondistributive blood flow, or clearance, described
by the recirculatory model returns the lipophilic marker to
the central circulation after minimal tissue equilibration due
to arteriovenous anastomoses, the presence of significant
diffusion barriers, or both, acting as pharmacokinetic shunts.
Hypovolemia-induced changes in CO and its distribution alter the balance of distributive and nondistributive blood
flows to various tissues that are not proportional to CO
changes. Not only are blood flows to muscle and splanchnic
tissues affected differently by hypovolemia, but also renal
blood flow, which is essentially nondistributive because the
kidney has a high blood flow and low apparent tissue volume,
is maintained during nonhypotensive hemorrhage (Vatner,
1974). Because nondistributive blood flow quickly returns the
lipophilic marker to the central circulation, the increased
fraction of CO represented by nondistributive blood flow during hypovolemia increases the arterial blood AUC in the
early minutes after drug administration. AUC is often used
as a measure of drug exposure (Powis, 1985); increased arterial drug concentrations resulting from a larger nondistributive clearance increase drug exposure of the sites of
action of lipophilic drugs with a rapid onset of effect, for
which antipyrine is a pharmacokinetic prototype, and would
be expected to result in a more profound and prolonged effect
of these drugs, as predicted by Price (1960). Most of this
increase in AUC is due to an increased return of drug to the
1315
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Krejcie et al.
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Send reprint requests to: Michael J. Avram, Ph.D., Department of Anesthesiology, Northwestern University Medical School, 303 E. Chicago Ave.,
CH-W139, Chicago, IL 60611-3008. E-mail: [email protected]
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ml of erythrocytes/kg of body weight during hemorrhage
(Hoekstra et al., 1988). The blood volume reductions in the
present hypovolemia studies were less than those targeted
because the blood volume removed was based on low initial
blood volume estimates from our previous studies in nonsplenectomized dogs and because transvascular fluid shifts replace 20 to 35% of the bled volume rapidly and reduce the
extravascular fluid volume (inulin VSS; Hinghofer-Szalkay,
1986). The dilutional effects of the transvascular fluid shifts
account for the reduced Hct in the hypovolemia studies,
whereas the dilutional and osmotic effects of the starch solution explain the reduced Hct in the volume-loading studies.
Because anesthesia not only affects blood flow and drug
distribution (Avram et al., 1997) but also attenuates or eliminates the vasoconstriction characteristic of the sympathoexcitatory phase of hemorrhage (Schadt and Lubrook, 1991),
the present study was conducted in awake animals. Changes
in blood flow distribution accompanying hypovolemia are
further complicated by the changes caused by potent volatile
anesthetics (Seyde and Longnecker, 1984) and i.v. anesthetics (Seyde et al., 1985), with unknown consequences for drug
disposition.
Hypovolemia caused an increase in antipyrine AUC for the
first minutes after drug administration due to the increased
fraction of CO represented by nondistributive blood flow during hypovolemia. For rapidly acting drugs, such as the centrally acting i.v. anesthetics for which the lipophilic marker
antipyrine is a prototype, maintenance of nondistributive
blood flow despite a decrease in CO would produce a more
profound and longer-lasting drug effect due to exposure of
potential sites of drug action to higher drug concentrations
for a longer period of time. This provides a rationale for
altered drug dosing in patients with altered blood volume.
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