Vol. 275, Issue 1, H57-H64, July 1998
17
-Estradiol effect on critical cardiac output with
reduction of cardiac output in oophorectomized sheep
Wayne
Evans1,3,
Terrance M.
Phernetton1, and
Ronald R.
Magness1,2
1 Perinatal Research
Laboratories, Department of Obstetrics and Gynecology and
2 Department of Meat and Animal
Sciences, University of Wisconsin Medical School, Madison 53792; and
3 Milwaukee Clinical Campus, Sinai
Samaritan Medical Center, Milwaukee, Wisconsin 53201-0342
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ABSTRACT |
Acute administration
of 17
-estradiol (E2) leads
to increases in cardiac output, oxygen delivery, and oxygen consumption and increases the critical cardiac output in the nonpregnant sheep. We
sought to determine whether the lack of a critical cardiac output or
flow-dependent oxygen consumption during states of low cardiac output
in late gestation can be reproduced in nonpregnant sheep treated with
estrogen. We studied five nonpregnant oophorectomized sheep in a
randomized crossover design by placing catheters in the pulmonary
artery, the right atrium, and the descending aorta. Three experiments
were randomly performed on each sheep 3 to 5 days apart:
1) without estrogen or vehicle,
2) 2-3 h after intravenous administration of vehicle, and 3)
2-3 h after intravenous E2 (3 µg/kg). Cardiac output was gradually reduced while hemodynamic, cardiorespiratory, acid-base, and metabolic variables were
simultaneously evaluated. There was a 70% increase in cardiac output
in animals given E2 compared
with that in the same animals given either vehicle or nothing (194.0 ± 13.0, 120.0 ± 14.5, and 114.0 ± 16.2 ml · min
1 · kg1,
respectively; P < 0.05). Oxygen
consumption was twofold higher in the
E2 series compared with that in
the no-treatment and vehicle series (10.01 ± 1.3, 6.04 ± 0.77, and 4.52 ± 0.42 ml
O2 · min1 · kg1,
respectively; P < 0.05). Tissue
oxygen extraction was unaltered by estrogen. However, tissue oxygen
extraction at the critical cardiac output was lower in the estradiol
group. In relation to oxygen consumption, all three groups demonstrated
a critical cardiac output when cardiac output was gradually reduced.
However, the level of critical cardiac output was significantly higher
in the E2 group (68.4 ± 2.4, 42.8 ± 2.6, and 46.2 ± 2.6 ml · min1 · kg1,
respectively; P < 0.05). We conclude
that E2 exhibits increases in
systemic tissue blood flow and oxygen consumption. Animals given
E2 show increases in critical
cardiac output and impairment of tissue oxygen extraction at critical
cardiac output, which leads to development of flow-dependent oxygen
consumption at higher cardiac outputs than in the control animals.
oxygen delivery; oxygen consumption; tissue oxygen extraction; lactate; glucose
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INTRODUCTION |
IN CONDITIONS OF low cardiac output, whole body oxygen
consumption, which is the oxygen transport variable that indicates the
effectiveness of tissue oxygen utilization, remains stable. However,
there is a point of decreased cardiac output called the "critical
cardiac output" below which tissue oxygenation cannot be maintained
(8, 10, 22, 24). At this critical point, whole body and
tissue oxygen consumption abruptly falls and tissue hypoxia occurs.
This is the phenomenon clinically referred to as "shock."
In certain pathological conditions [e.g., adult respiratory
distress syndrome (ARDS), sepsis, septic shock, and severe
preeclampsia], this biphasic cardiac output to oxygen consumption
relationship does not exist. In other words, for each decrease in
cardiac output, there is a corresponding decrease in oxygen
consumption. This condition is referred to as "flow-dependent oxygen
consumption" (22-24). Impairment of tissue oxygen extraction is
thought to be the major cause of flow-dependent oxygen consumption
(22-24).
We demonstrated that in late-gestation sheep, during gradual reductions
in cardiac output, oxygen consumption was flow dependent, i.e., there
was no critical cardiac output in late-gestation sheep (6). We
demonstrated that oxygen transport alterations in normal pregnancy are
associated with impairment of tissue oxygen extraction with reductions
in cardiac output. The physiological explanation for this
cardiorespiratory derangement noted in late-gestation sheep in response
to reductions in cardiac output is unclear.
The hormonal milieu of pregnancy, specifically the hyperestrogen state,
is associated with some of the characteristic cardiovascular (hemodynamic) adaptations. In previous studies, we demonstrated that
17-estradiol (E2)
administration increased cardiac output and mimicked nearly all of the
systemic cardiovascular alterations noted in pregnancy (14, 16).
Therefore, we hypothesized that the hyperestrogen state of pregnancy is
associated with the cardiorespiratory (oxygen transport)
characteristics demonstrated in late-gestation sheep. The objectives of
this study were 1) to determine
whether estrogen treatment alters the oxygen transport characteristics of adult nonpregnant sheep during reduction of cardiac output, and
2) to determine whether acute
estrogen administration reproduces the flow-dependent oxygen
consumption during states of low cardiac output noted in late-gestation
sheep.
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MATERIALS AND METHODS |
The study protocol was approved by the Institutional Animal Care and
Use Committee of the University of Wisconsin-Madison. We studied five
adult nonpregnant oophorectomized female sheep (61.2 ± 3.1 kg) of
mixed breed. For this study we used a modification of the method
developed by Fahey and Lister (7, 9) to reduce cardiac output in
neonatal and infant lambs.
Animal preparation.
Before surgical preparation, we administered an intramuscular injection
of 10 mg/kg of ketamine and 0.12 µg/kg of atropine to each animal. We
catheterized the pulmonary artery by way of percutaneous cannulation of
the left jugular vein with a 9-Fr introducer sheath (Arrow, Reading,
PA) and an 8.0-Fr Swan-Ganz continuous cardiac output/mixed venous
oxygen saturation (CCO/SvO2) thermodilution pulmonary artery catheter (Baxter-Edwards, Irvine, CA). After placing this catheter, we administered a continuous intravenous drip of 10% ketamine for anesthesia and then catheterized the right atrium of each sheep with a 20-Fr Foley catheter with a 75-ml
balloon (Bardex, C. R. Bard, Covington, GA) via a right jugular venous
cutdown.
We performed a midventral laparotomy and bilateral oophorectomy in each
sheep, followed by placement of 18-gauge polyvinyl catheters (Tygon,
Norton Performance Plastics, Akron, OH) in the descending aorta and
inferior vena cava via a cutdown of the superficial saphenous branches
of the femoral artery and vein. As in our previous study, we confirmed
proper pulmonary artery catheter placement by connecting this catheter
to a multichannel monitor (Beckman R611, Beckman Instruments,
Schaumberg, IL) and evaluating the characteristic pressure waveform (6,
7, 9, 18). All channels of the pulmonary artery catheter and each
aortic and vena caval catheter were flushed with a solution of heparin
and saline (100 U/ml). We administered 800,000 U of procaine penicillin and 500 mg of streptomycin (Combiotic, Pfizer Laboratories, New York,
NY) before surgery and then daily until the study was completed. We
allowed a 3- to 5-day recovery period before performing the experiments. During the postoperative recovery period, each animal received a 1 µg/kg daily intravenous dose of
E2, but not within 24-36 h
of an experimental protocol, similar to the protocols of other studies
(13, 14, 16, 20).
Study design.
We studied each animal in a randomized crossover design. Each animal
underwent the same protocol under three different experimental conditions: 1) no treatment, in
which the animals received no hormone or vehicle;
2) vehicle treatment, in which the
animals received 16% ethanol in saline solution intravenously; and
3) E2 treatment, in which the
animals received 3 µg/kg of
E2 dissolved in vehicle
intravenously as a bolus.
The sheep were allowed to recover for at least 48 h between each
treatment and experiment. The aortic and pulmonary artery catheters
were connected to the multichannel monitor via sampling stopcocks
connected to transducers. The thermodilution probe of the pulmonary
artery catheter was connected to the cardiac output computer (Vigilance
CCO/SvO2 Monitor, Baxter-Edwards). In
the no-treatment experiments, we studied the animals 2-3 h after
they were connected to the multichannel monitor. In the
vehicle-treatment experiments, we studied the animals 2-3 h after
administration of 0.50-0.65 ml 95% ethanol in 10 ml of saline. In
the E2-treatment experiments,
we studied the animals 2-3 h after administration of a 3 µg/kg
dose of E2.
The experiments were conducted in the same fashion as in our previous
study (6) by gradually reducing cardiac output via incremental
inflation of the right atrial balloon. We reduced cardiac output in
sequential order because there was no difference in our previous study
(6) between results of random-ordered reduction and sequential-ordered
reduction of cardiac output in nonpregnant and pregnant sheep.
During each experimental protocol, we continuously measured heart rate,
pulmonary artery pressure, aortic pressure, and core body temperature.
We collected data at a right atrial balloon volume of zero and with
each right atrial balloon inflation. All samples were collected and
measurements recorded when the sheep was quiet and exhibited stable
cardiovascular variables, i.e., at least 30 min of stable blood
pressure (aortic pressure), heart rate, cardiac output, and mixed
venous oxygen saturation. Blood pressure and heart rate were measured
from the aortic pressure tracing. Cardiac output was measured using the
intravenous bolus thermodilution technique and calculated using the
cardiac output computer connected to the pulmonary artery thermistor
(18). At each incremental balloon inflation we obtained five cardiac output measurements, eliminated the highest and lowest values, and
averaged the remaining values. Blood samples were obtained from the
aortic and pulmonary artery catheters for acid-base status and gas
tension (ILS 1302 pH/Blood Gas Analyzer, Instrumentation Laboratory
System, Lexington MA.). We also measured oxygen saturation as well as
hemoglobin (Radiometer OSM3, Medtron, Chicago, IL), glucose, and
lactate concentrations (Glucose and Lactate Analyzer model 2300, Yellow
Springs Instruments, Yellow Springs, OH). The experiment was terminated
when either the arterial blood pressure, cardiac output, or mixed
venous oxygen saturation failed to reach a stable steady state at a new
balloon volume.
Data analysis.
We calculated the derived hemodynamic variables (mean arterial pressure
and systemic vascular resistance) and cardiorespiratory variables
(systemic oxygen delivery, systemic oxygen consumption, and fractional
whole body tissue oxygen extraction). All variables were indexed to
body weight. Data are reported as means ± SE.
We used four methods to analyze our data, with
P < 0.05 considered statistically
significant. First, we compared mean hemodynamic, cardiorespiratory,
and metabolic variables of the three treatment groups to baseline
values using a paired Student's
t-test. Next, we compared mean
baseline hemodynamic and cardiorespiratory variables of all three study
groups using repeated-measures ANOVA and Newman-Keuls testing. A
multiple linear regression analysis developed by Samsel and Schumacker
(21) was then used to construct the curves to determine the response of
oxygen consumption during decreases in cardiac output. This technique
consists of constructing pairs of regression lines by using points only
once to define the response of oxygen consumption, serum lactate
concentrations, and serum glucose concentrations to decreased cardiac
output. We chose the grouping of points resulting in the least residual
sum of squares as the best pair of regression lines. Finally, we used a
polynomial regression analysis as described by Gutierrez et al. (12) to determine the precise value of the critical cardiac output and oxygen
delivery in relation to oxygen consumption. This method was used to
determine the point at which oxygen consumption changed as a function
of cardiac output. A polynomial with the highest R2 was fitted to
the data relating cardiac output
(x-axis) to oxygen consumption
(y-axis). The best fit was determined by
subjecting the data to varying orders of polynomials. The plateau of
the polynomial closest to the origin was obtained by differentiating the polynomial and making the result equal to zero. The critical cardiac output is defined by the intersection closest to the origin of
a line drawn parallel to the abscissa and passing through the lower
95% confidence limit of the mean-fitted polynomial at the plateau
point with the polynomial itself (12).
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RESULTS |
Each animal was studied under three conditions:
1) no treatment,
2) vehicle treatment, and
3)
E2 treatment. Table
1 provides baseline hemodynamic and
cardiorespiratory data and data obtained 2-3 h just before
reductions in cardiac output. There were no significant differences in
any of the hemodynamic, cardiorespiratory, or metabolic variables
before reductions in cardiac output between the untreated and
vehicle-treated groups or in these two groups compared with baseline
data. However, compared with either baseline or the untreated and
vehicle-treated groups, the
E2-treated group exhibited
elevations of heart rate (15-29%,
P < 0.05), cardiac output
(62-73%, P < 0.05), oxygen
delivery (71-91%, P < 0.05), and oxygen consumption (22-66%,
P < 0.05).
E2 treatment also decreased
systemic vascular resistance (41-49%,
P < 0.05); however, mean arterial
pressure, hemoglobin concentration, fractional oxygen extraction,
lactate, and glucose levels were unaffected
(P > 0.05).
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Table 1.
Hemodynamic, cardiorespiratory, and metabolic variables at baseline
and before reductions in cardiac output
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As expected, systemic oxygen delivery correlated directly with cardiac
output (Fig. 1). We also analyzed cardiac output and oxygen delivery in relationship to oxygen consumption. First, we
determined the relationship between cardiac output and oxygen consumption by using a multiple linear regression analysis that showed
that in all three study series there was a biphasic response of oxygen
consumption to changes in cardiac output, i.e., a critical cardiac
output was demonstrated in all three groups (Fig. 2). The critical cardiac output and the corresponding oxygen consumption were higher in the E2-treated
group than in the untreated and vehicle-treated groups, which were
similar. We also determined the precise level of cardiac output at that
critical level. The critical cardiac output was the same in the
untreated group (42.8 ± 2.6 ml · min1 · kg1)
and the vehicle-treated group (46.2 ± 2.6 ml · min1 · kg1),
but higher in the E2-treated
group (68.4 ± 2.4 ml · min1 · kg1;
P < 0.05). We then evaluated the
relationship between baseline oxygen extraction before reduction of
cardiac output and the change in fractional oxygen extraction in
response to reduction in cardiac output in all three groups (Fig.
3). Although there were no differences in initial as
well as maximal levels of oxygen extraction among all three
experimental groups, there was a significant difference in tissue
oxygen extraction at the critical cardiac output of each series. The
tissue oxygen extraction in the
E2-treated group was
significantly lower at the critical cardiac output than in the
untreated and vehicle-treated groups (0.61 ± 0.03, 0.72 ± 0.04, and 0.73 ± 0.06, respectively; P < 0.05 by ANOVA).
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Fig. 1.
Relationship of cardiac output to systemic oxygen delivery. Systemic
oxygen delivery correlates directly with cardiac output in untreated
(A; y = 0.121x + 1.485, R2 = 0.925),
vehicle-treated (B;
y = 0.121x + 2.203, R2 = 0.947), and
estradiol (E2)-treated animals
(C;
y = 0.136x + 1.046, R2 = 0.881).
Systemic oxygen delivery is derived as the product of cardiac output
and arterial oxygen content.
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Fig. 2.
Response of oxygen consumption to decreasing cardiac output. Critical
cardiac output was demonstrated in all 3 groups. Critical cardiac
output in untreated (A; 42.80 ± 2.62 ml · min1 · kg1)
and vehicle-treated sheep (B; 46.20 ± 2.60 ml · min1 · kg1)
was lower than in E2-treated
sheep (C; 68.40 ± 2.40 ml · min1 · kg1,
P < 0.05 by ANOVA, Newman-Keuls).
Oxygen consumption is derived as the product of cardiac output and the
arterial oxygen content and mixed venous oxygen content difference.
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Fig. 3.
Relationship of cardiac output to fractional tissue oxygen extraction.
There is a significant difference in oxygen extraction in response to
reductions in cardiac output. At critical cardiac outputs, oxygen
extraction in the untreated group (A;
y = 0.000x2  0.010x + 1.052, R2 = 0.840) and
vehicle-treated group (B;
y = 0.000x2 0.009x + 1.018, R2 = 0.915) were
the same (0.72 ± 0.04 and 0.73 ± 0.06%, respectively), whereas
oxygen extraction was significantly lower (0.61 ± 0.03%,
P < 0.05 ANOVA, Newman-Keuls) in the
E2-treated group
(C; y = 0.000x2 0.006x + 0.988, R2 = 0.835).
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Finally, we determined the relationship between changes in metabolic
variables and changes in cardiac output by evaluating the response of
serum lactate and glucose concentrations to reduction in cardiac output
(Fig.
4).
Similar to oxygen consumption, serum lactate and glucose concentrations
remained stable in response to reduced cardiac output, until cardiac
output was lowered to a certain critical level. After that level,
lactate and glucose concentrations abruptly rose. The lactate and
glucose responses to decreased cardiac output were similar. The break
points in serum lactate and glucose concentrations corresponded to the
critical cardiac outputs in relationship to oxygen consumption. We
demonstrated this by superimposing the oxygen consumption curves from
Fig. 2 on the graph of the lactate and glucose data. We then subjected the lactate and glucose data to the same method of analysis to determine the precise cardiac output and oxygen delivery level at the
break points as we used to determine the critical cardiac output and
critical oxygen delivery in relation to oxygen consumption (Table
2). This analysis demonstrated that the
break points in lactate and glucose concentrations corresponded to the
critical cardiac outputs.
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Fig. 4.
Comparison of metabolic response to cardiorespiratory response during
reductions in cardiac output. Both blood lactate and
glucose concentrations remain stable with decreasing
cardiac output until a critical level of cardiac output is reached
whereby blood lactate and glucose concentrations abruptly increase.
Curves relating cardiac output to oxygen consumption in Fig. 2 (dashed
lines) are superimposed on curves relating cardiac output to blood
lactate (left; continuous lines) and
glucose (right; continuous lines)
concentrations in untreated (A),
vehicle-treated (B), and
E2-treated animals
(C). Critical cardiac output as
determined from oxygen consumption curves approximately corresponds
with break points of blood lactate and glucose concentrations in
response to reductions in cardiac output. See Table 2 for critical
cardiac output values and cardiac output values at break points of
lactate and glucose concentrations.
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Table 2.
Critical cardiac outputs and cardiac outputs at break points in
blood lactate and glucose concentrations
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DISCUSSION |
We previously demonstrated that, in response to reductions in cardiac
output, late-gestation sheep displayed no critical cardiac output or
critical oxygen delivery; oxygen consumption was noted to be uniformly
flow dependent (6). This is contrary to what is observed in most, if
not all, nonpregnant mammalian organisms. Normally, the homeostatic
response to decreased cardiac output is that oxygen consumption remains
stable until a critical level is reached whereby oxygen consumption
abruptly decreases (8, 10, 22, 24). At this point, the maximum capacity
for tissue oxygen extraction is exceeded and systemic tissue hypoxia or
"shock" occurs. Pathological conditions such as ARDS, sepsis,
septic shock, multiple trauma, severe liver failure, and severe
pancreatitis demonstrate this abnormal phenomenon of flow-dependent
oxygen consumption (22-24). Severe preeclampsia, a condition
peculiar to pregnancy, has also been shown to display this oxygen
transport alteration (1, 11). However, it is difficult to determine the
significance of this flow-dependent oxygen consumption in severe
preeclampsia, considering that it is seen in normal pregnancy in states
of low cardiac output (6). It appears, therefore, that term pregnancy
is the only known nonpathological condition in which reduction of
cardiac output leads to this cardiorespiratory alteration. The
mechanism by which this occurs is unknown. In this study, we report for
the first time the relationship of the metabolic variables lactate and
glucose to reductions in cardiac output in nonpregnant control and
estrogen-treated sheep. We also report for the first time that glucose
concentration displays a critical cardiac output in response to
reductions in cardiac output.
Because there is evidence that administration of
E2 in nonpregnant sheep is
associated with some of the cardiovascular changes similar to those
seen in pregnant animals, we theorized that the hormonal milieu of
pregnancy may be linked to the cardiorespiratory profile observed in
late-gestation sheep. Until our study, there have been no studies
specifically describing the cardiovascular, oxygen transport, or
metabolic profile in relationship to estrogen treatment and reductions
in cardiac output. We observed and reported for the first time that the
critical cardiac output and oxygen consumption were significantly
higher in the E2-treated
animals than in the untreated and vehicle-treated animals. We observed that metabolic variables commonly measured in the clinical setting, such as lactate and glucose, also displayed a critical cardiac output
in response to reductions in cardiac output. Contrary to our
hypothesis, we demonstrated for the first time that acute estrogen
administration was associated with the normal biphasic response of
oxygen consumption during reductions in cardiac output, because there
was a critical cardiac output demonstrated in the E2-treated sheep.
The purpose of the present study was to determine what effect acute
administration of E2 has on
cardiorespiratory changes with gradual reductions in cardiac output in
nonpregnant sheep. We also sought to determine whether those changes
were similar to what we observed in late-gestation sheep. As noted in
other studies (14, 16), intravenous administration of
E2 to nonpregnant oophorectomized sheep mimicked most of the hemodynamic changes noted in
pregnant sheep. Magness and Rosenfeld (16) demonstrated that a 1 µg/kg treatment of E2 was
associated with increased cardiac output and heart rate and a decrease
in systemic vascular resistance within 2-3 h of treatment.
Increased heart rate, cardiac output, and decreased systemic vascular
resistance were also observed in a study (14) using a 5 µg/kg dose of
E2. We demonstrated in the
current study a similar hemodynamic profile using a 3 µg/kg dose of
E2; cardiac output and heart
rate were elevated 62-73% (P < 0.05) and 15-29% (P < 0.05),
respectively, whereas systemic vascular resistance decreased
41-43% (P < 0.05) and blood
pressure was unchanged (P > 0.05).
Cardiac output and systemic oxygen delivery increased significantly
with E2 treatment. This is
logical, considering that oxygen delivery is derived from the product
of cardiac output and arterial oxygen content. In this study, maximal
tissue oxygen extraction in all groups was as high as 95% in response
to decreased cardiac output. This change in cardiac output and systemic
oxygen delivery was similar to that observed in the nonpregnant sheep in our previous study (6). We also observed in the
E2-treated animals that tissue
oxygen extraction was significantly lower at the critical cardiac
output compared with that in the untreated and vehicle-treated animals.
Lower oxygen extraction at the critical cardiac output indicated
relative impairment of tissue oxygen extraction in response to
reduction of cardiac output in the
E2-treated animals. We also
observed an impairment of tissue oxygen extraction in the study of
pregnant animals (6). In the
E2-treated animals, we also
demonstrated a one- to twofold increase in basal whole body oxygen
consumption that is secondary to an increase in metabolism. Acute
administration of E2 produced a
hypermetabolic state that may be mediated by an increase in sympathetic
tone. Evidence for increased sympathetic tone is based on studies
showing that acute estrogen treatment lowered systemic vascular
resistance more in animals given estrogen plus phentolamine than in
animals given estrogen alone (4, 17).
We characterized the changes in oxygen transport variables in response
to gradual reductions in cardiac output in the absence and presence of
E2 treatment and found that
they resemble the cardiorespiratory profile of nonpregnant animals
noted in our previous study (6). In all three groups of animals, oxygen consumption remained stable with reduction of cardiac output until a
critical cardiac output was reached whereby oxygen consumption abruptly
decreased. Tissue oxygen extraction is the mechanism by which oxygen
consumption remains stable during decreased cardiac output. This is
referred to as flow-independent oxygen consumption. However, there is a
point at which tissue oxygen extraction is exceeded or impaired and can
no longer maintain oxygen consumption; at this point oxygen consumption
becomes flow dependent. Tissue oxygen extraction was observed to be
significantly decreased at the critical cardiac output in
E2-treated animals compared
with the untreated and vehicle-treated animals. However, critical
cardiac output was noted to be significantly higher in the
E2-treated animals compared
with that in the untreated and vehicle-treated animals (68 ± 2.4, 42.8 ± 2.6, and 46.2 ± 2.6 ml · min1 · kg1,
respectively). These increases in cardiac output, oxygen consumption, and fractional oxygen extraction 2-3 h after
E2 treatment are reflective of
regional increases in tissue/organ oxygen extraction to those areas of
the body to which cardiac output is redistributed with
E2 administration. In
nonpregnant sheep 1-2 h after
E2 injection (1-5
µg/kg), increases in blood flow were observed to both reproductive
(uterus, oviducts, cervix, vagina, and mammary gland) as well as
several nonreproductive tissues (coronary, skin, thyroid, bladder,
esophagus, adrenals, and possibly kidneys) (15, 19, 20).
In states of hyperdynamic, hypermetabolic disorders, cardiac output
rises despite a continued decrease in oxygen consumption. This is the
so-called flow-dependent oxygen consumption. Conditions characterized
by hypoperfusion and hypoxia, such as ARDS, sepsis, and severe
preeclampsia, display stable or elevated mixed venous oxygen
saturation. This condition indicates that there is an abnormality of
tissue oxygen extraction.
The adrenergic system may also play a role in tissue oxygen extraction
impairment. Cain (3) demonstrated that giving phenoxybenzamine to dogs
in a state of hypoxic hypoxia did not result in display of this oxygen
utilization defect. Also, compounds and conditions present in
damaged organs such as arachidonic acid and its metabolites, lactic
acid, uric acid, neutrophil activation, oxygen radical formation, and
complement system activation interfere with oxygen utilization at the
mitochondrial level.
In hypoperfusion disorders there is a heterogeneity of blood flow and
oxygen utilization to and within different organs that limits the
oxygen availability at normal to high states of cardiac output and
oxygen delivery. Tissues with high metabolic demand may receive low
oxygen delivery, whereas tissues of low metabolic demand may receive
high oxygen delivery. Also, in this condition, there may be mechanical
impairment of tissue oxygen extraction. Oxygen may not be able to move
from the microcirculation (capillaries) to the tissue. Edema and
vasoconstriction can increase diffusion distances from the
microcirculation to the oxygen-starved cells in the affected tissue.
Increased oxygen delivery will move the oxygen gradient within the
microcirculation toward the venous end of the capillary bed. This will
produce lower oxygen levels toward the tissue cellular level. This
diffusion impairment can be the result of
1) capillary blockade due to
endothelial damage, platelet aggregation, and the formation of
microemboli; 2) release of
substances such as thromboxane, endothelin, and serotonin, causing
intense local vasoconstriction; and
3) increased interstitial edema. All
of these mechanisms may play a critical role in tissue oxygen
extraction impairment in hypoperfusion states. Estrogen may be a
mediator or a potentiator of these effects.
Metabolic changes during low oxygen delivery and low cardiac output
have been described. These changes, until now, have not been described
as descriptors of shock. Our study is unique in that we not only
demonstrated the commonly known phenomena of increased lactic acidemia
and hyperglycemia in response to shock but also demonstrated a
"critical cardiac output" in relation to lactate and glucose
concentrations during reductions in cardiac output in nonpregnant sheep
with or without estradiol administration. We demonstrated a similar
response in lactate concentration in a previous study in both
nonpregnant and late-gestation sheep (6).
Lactate is described as a metabolic "dead end" (5). Lactate
levels are increased in response to hypoxia or decreased tissue perfusion. During these states, cellular metabolism changes from an
aerobic metabolism, which is a highly efficient energy-producing state,
to anaerobic glycolysis, which provides markedly decreased energy
substrates (2, 3, 6, 8, 10, 22-24). During aerobic metabolism,
carbohydrate substrate (i.e., glucose) is metabolized to pyruvate and
shunted to the tricarboxylic acid cycle, in which 32 moles of ATP are
produced. During anaerobic metabolism (secondary to states of markedly
low oxygen delivery for any reason such as hypoxia or decreased
perfusion), pyruvate is converted to lactate. This process generates
only 2 moles of ATP, which is insufficient energy to drive the normal
metabolic processes of the body.
Hyperglycemia is an intermediary metabolic event associated with injury
and shock regulated by major alterations in circulating hormones.
During states of low cardiac output, cortisol, glucagon, and
catecholamines are increased and insulin is decreased, leading to
impairment of glucose metabolism (2). However, our study demonstrated
that hyperglycemia occurs after a certain low level of cardiac output
is reached whereby glucose concentration abruptly rises. This abrupt
rise in glucose concentration coincided with the rise in lactate
concentration and the fall in oxygen consumption (Fig. 4).
The cardiorespiratory or oxygen transport response to low cardiac
output in E2-treated sheep
resembles that of the nonpregnant sheep; i.e., a critical cardiac
output does exist. The difference between nonpregnant sheep and
nonpregnant sheep treated with
E2 is that in the latter,
cardiac output, whole body tissue oxygen delivery, and oxygen
consumption are significantly elevated. Because pregnancy is not simply
a hyperestrogen state but is a chronic hyperestrogen state, and because
our study demonstrated the cardiorespiratory effects with acute
administration of estrogen, chronic estrogen infusion may provide
evidence that estrogen may be the factor in flow-dependent oxygen
consumption and the lack of a critical cardiac output in late
pregnancy. We must also consider other factors that may affect the
cardiorespiratory response to low cardiac output such as progesterone
and the size of the fetoplacental unit. Given these considerations,
further investigations are warranted.
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ACKNOWLEDGEMENTS |
This study was supported by National Institutes of Health Grants
HD-33255, HL-49210, and HL-57653 and by the Department of Obstetrics
and Gynecology, Sinai Samaritan Medical Center, Milwaukee, Wisconsin.
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FOOTNOTES |
This study was presented in part at the Forty-Third Annual Meeting of
the Society for Gynecologic Investigation, Philadelphia, PA, March
20-23, 1996.
Address for reprint requests: W. Evans, Dept. of Obstetrics and
Gynecology, Univ. of Wisconsin Medical School, Milwaukee Clinical
Campus, 2000 W. Kilbourn Ave., PO Box 342, Milwaukee, WI 53201-0342.
Received 7 April 1997; accepted in final form 16 March 1998.
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J. Anthony,
G. R. Saade,
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Abstract
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