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Vol. 291, Issue 3, 1308-1316, December 1999
Northwestern University Medical School, Department of Anesthesiology, Chicago, Illinois
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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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% 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.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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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 administration 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 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 concentration-versus-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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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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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 ± 1.9 kg; Table 1), were studied on four occasions each in this Institutional Animal Care and Use Committee-approved study.
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). 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 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 = 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 µCi 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 = 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 µg/ml with c.v. values of 5% or
less (Henthorn et al., 1992).
). 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 µg/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 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):
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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).
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).
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 · CO) and the central
intravascular volume codetermined by ICG and inulin (MTTICG,
inulin · 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 Pentium-based 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-versus-time 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 three-compartment
models, ClE was modeled from the arterial
(sampling) compartment to enable comparison of these results with
previous ones.
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 = dose/AUCfirst-pass). Therefore, the AUC resulting from
recirculation of a marker was determined by subtracting the first-pass
AUC from that of the full model over 3 min:
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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.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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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 = 1.21 COICG 
1.09, r2 = 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).
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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 ClE
values of ICG, inulin, and antipyrine were unaffected by altered blood
volume (Tables 1-4).
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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 = 0.06 CO + 0.58, r2 = 0.64;
VND-F = 0.08 CO 0.14, r2 = 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.
2.02, r2 = 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 = 0.02 CO + 0.17, r2 = 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 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 = 0.08 CO 0.17; r2 = 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 = 0.85 CO 2.25; r2 = 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 = 0.80 CO + 1.30; r2 = 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.
0.58, r2 = 0.93; ClT-S = 0.21 CO + 0.08, r2 = 0.61). In addition, because
the diminution in CO was reflected exclusively in decreased tissue
distribution clearances, the tissue distribution clearances
(ClT-F + 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 = 1.01 CO + 16.28; r2 = 0.60) and when it was not (e.g., AUCrecirc = 0.35 CO + 7.23; r2 = 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 = 0.25 CO + 6.71; r2 = 0.42; inulin AUC0-3 min = 2,600 CO + 71,500;
r2 = 0.40).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Seyde et al. (1985) studied regional blood flow redistribution in
awake rats before and after hemorrhage with the use of radioactive 15-µm 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 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 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 = 0.65 ICG ClND-F + 1.63, r2 = 0.68; ClT-S = 0.21 ICG ClND-F + 0.69, r2 = 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 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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Footnotes |
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Accepted for publication August 31, 1999.
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].
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: mja190{at}nwu.edu
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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;
Cl, total (sum of) all (peripheral and elimination) clearances;
LSD, least
significant difference.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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, solid line), when it was volume loaded (
, dashed
line), and when it was moderately hypovolemic (
, dotted line). The
symbols represent drug concentrations, and the lines represent
concentrations predicted by the models.
