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Vol. 84, Issue 3, 791-797, March 1998
Department of Research and Development, Veterans Affairs Medical Center, Pittsburgh 15240; and Departments of Anesthesiology and Critical Care Medicine, Internal Medicine, and Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Dysoxia can
be defined as ATP flux decreasing in proportion to
O2 availability with preserved ATP
demand. Hepatic venous 
-hydroxybutyrate-to-acetoacetate ratio
(-OHB/AcAc) estimates liver mitochondrial NADH/NAD and may detect
the onset of dysoxia. During partial dysoxia (as opposed to anoxia),
however, flow may be adequate in some liver regions, diluting effluent
from dysoxic regions, thereby rendering venous -OHB/AcAc unreliable.
To address this concern, we estimated tissue ATP while
gradually reducing liver blood flow of swine to zero in a nuclear
magnetic resonance spectrometer. ATP flux decreasing with
O2 availability was taken as
O2 uptake
(
O2) decreasing in
proportion to O2 delivery
(
O2);
and preserved ATP demand was taken as increasing
Pi/ATP.
O2, tissue
Pi/ATP, and venous -OHB/AcAc
were plotted against
O2
to identify critical inflection points. Tissue dysoxia required mean
O2
for the group to be critical for both
O2 and for
Pi/ATP. Critical
O2
values for O2 and
Pi/ATP of 4.07 ± 1.07 and 2.39 ± 1.18 (SE) ml · 100 g
1 · min1,
respectively, were not statistically significantly different but not
clearly the same, suggesting the possibility that dysoxia might have
commenced after O2 began
decreasing, i.e., that there could have been
"O2 conformity." Critical
O2
for venous -OHB/AcAc was 2.44 ± 0.46 ml · 100 g1 · min1
(P = NS), nearly the same as that for
Pi/ATP, supporting venous -OHB/AcAc as a detector of dysoxia. All issues considered, tissue mitochondrial redox state seems to be an appropriate detector of
dysoxia in liver.
adenosine 5'-triphosphate; nuclear magnetic resonance; oxygen delivery; ischemia; pig
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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DETECTION OF TISSUE DYSOXIA, i.e., O2 supply that is inadequate to support O2 demand (5, 24), may facilitate understanding and management of critically ill patients. Current clinical management of O2 transport to tissue in critically ill patients typically involves measurement (6) and improvement (9, 11) of cardiac output. However, these practices are currently intensely debated (21). Cardiac output is certainly essential for rapid diagnosis of hemodynamic instability but is a whole body parameter. Use of it to guide therapy requires the clinician to assume that it is evenly distributed to all organs under all conditions, including septic vasodilation or constriction, infusion of pressor agents, and positive-pressure mechanical ventilation. Hence, an "adequate" cardiac output does not necessarily signify adequate O2 supply to all organs. A potential improvement on clinical trials of cardiac output measurement and manipulation might be to look for dysoxia directly in suspect tissues such as the splanchnic viscera. However, such methods do not currently exist for these organs.
In time, liver dysoxia causes leakage of intracellular hepatic enzymes
that can be measured in plasma. However, nondysoxic conditions such as
inflammation after autologous liver transplantation produce the same
abnormalities. Lactate accumulates during dysoxia but also during
seemingly nondysoxic conditions such as exercise (10) and septic
inhibition of pyruvate dehydrogenase (7, 28). Tissue
PO2 and related parameters (12) are
frequently measured but by themselves do not distinguish between
adapted hypoxia and dysoxia (5). Bulk
O2 delivery
(O2),
the product of blood O2 and flow,
can be progressively reduced until organ O2 uptake
(O2) begins to
decrease, so as to identify a critical O2
that no longer supports O2
(O2 supply dependence) (2, 20).
However, application of this biphasic
O2-O2
model to liver is not practical in patients.
Part of the problem has been that, until recently, criteria for
recognizing dysoxia have not been carefully defined. Connett et al. (5)
proposed that tissue dysoxia is probable if changes in intracellular
O2 availability are accompanied by
parallel changes in ATP flux at constant ATP demand. We (24) evaluated
mitochondrial redox state as a detector of dysoxia in liver from the
perspective of the biphasic
O2-O2
model by reducing liver blood flow progressively to zero. Using whole
organ
O2
as our measure of intracellular O2
availability, O2 as our
estimate of ATP flux, and hepatic mitochondrial redox state
as our measure of ATP demand (32), we observed parallel decreases
in ATP flux below a critical
O2, with ATP demand increasing relative to supply approximately
simultaneously. These findings suggested that whole liver
O2 supply dependence represented
dysoxia and that mitochondrial redox state might be an appropriate
method for detecting it.
The measure of mitochondrial redox state that we had used was hepatic
venous -hydroxybutyrate-to-acetoacetate concentration ratio (-OHB/AcAc). -OHB/AcAc equilibrates with
hepatic mitochondrial NADH/NAD because the enzyme, -hydroxybutyrate
dehydrogenase, resides in mitochondrial cristae (15). However, we
did not sample -OHB/AcAc in tissue. Several investigations (19, 23,
29) suggest a sharp demarcation between adequately perfused and
completely unperfused tissue. Hence, it was not clear why -OHB/AcAc
in liver effluent should reliably identify the onset of dysoxia. For
example, CO2 produced
anaerobically in ischemic dysoxic intestine seems to detect intestinal
dysoxia (19, 23). However, this
CO2 is trapped in tissue, such
that CO2 must be measured directly
in tissue, as opposed to portal venous effluent.
To begin further addressing the sensitivity for dysoxia of venous
-OHB/AcAc specifically, and hepatic mitochondrial redox state in
general, we measured Pi and ATP by
31P-nuclear magnetic resonance
(NMR) in livers of six supine swine. Tissue dysoxia was defined as ATP
flux (estimated as organ O2), which decreased with cellular O2
availability (estimated as organ O2)
accompanied by an increase in tissue ATP demand relative to supply
(estimated as Pi/ATP). The
concurrance of these phenomena (dysoxia) was compared with the increase
in hepatic venous -OHB/AcAc relative to liver
O2.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Surgical preparation. In a protocol
approved by the Institutional Animal Care and Use Committee, six
juvenile swine weighing 22.6 ± 0.6 kg each were fasted for 12 h
with unlimited access to water, sedated with intramuscular ketamine
hydrochloride (10 mg/kg), and anesthetized with intravenous
pentobarbital sodium (20 mg/kg). A tracheostomy was performed, and
mechanical ventilation was initiated through a 7-mm cuffed tracheal
tube. Ventilator rate, tidal volume, and inspired
O2 concentration were adjusted to
keep arterial PO2 near 150 Torr and
arterial PCO2 near 40 Torr. Through
extension of the tracheostomy incision, the right internal jugular vein
was cannulated, and pentobarbital infusion was started at 3-5
mg · kg1 · h1.
The right carotid artery was cannulated, and mean arterial pressure was
continuously monitored. Through an incision in the left flank, the
origins of the superior mesenteric artery and the celiac artery, the
main conduits of cardiac output to liver, were
dissected free through a retroperitoneal approach, and elastic snares
were placed loosely around these vessels. Through a low midline
incision, the inferior mesenteric artery was ligated to prevent
uncontrolled flow to liver via this source. This incision was closed in
two layers. Through a high midline incision, the liver was isolated from potential diaphragmatic collateral flow as completely as possible,
and the diaphragm was separated from the vena cava. The bile duct was
divided, and both ends were ligated to expose the common hepatic
artery, and a drainage tube was placed in the gallbladder, to prevent
increased pressure in the biliary system. The common hepatic artery was
exposed by blunt dissection, and pancreatic, gastric, and duodenal
branches were ligated. The portal vein was exposed, and a 7-Fr
triple-lumen catheter was inserted into it through a lymph node to the
level of the porta hepatis by the Seldinger technique (25). A 6-mm
ultrasonic flow probe (Transonics Systems no. 6RB) was placed around
the hepatic artery, and a 10-mm flow probe (no. 10SB) around the portal
vein. The left hepatic vein was identified by palpation, and a 16-gauge catheter was inserted into it through the liver capsule by the the
Seldinger technique to a distance of ~5 cm from the vena cava. A
temperature probe was placed on the surface of the liver. The high
midline incision was then partially closed, leaving an opening large
enough for placement of a 35-mm NMR coil. The remaining exposed liver
surface was covered with transparent plastic wrap to prevent tissue
dehydration, and the animal was transported to the NMR suite. All
monitoring and life-supporting devices were equipped with extra lengths
of cable or tubing as appropriate. Ventilator tubing of a larger than
usual diameter proved necessary to prevent unwanted positive
end-expiratory pressure and consequent decreased venous return.
31P-NMR spectroscopy. A single-turn NMR surface coil, 35 mm in outer diameter, was placed on the ventral liver surface, and its stability with ventilatory hepatic movement was verified. The NMR coil was single tuned to 81 MHz, the resonance frequency of 31P. An external standard consisting of 0.25 mM methylenediphosphonic acid (MDPA) in 2H2O was affixed to the coil. The entire preparation was then placed inside a 40-cm horizontal-bore 4.7 T superconducting magnet, with a Bruker BIOSPEC II spectrometer operating at 81 MHz. The homogeneity of the magnetic field was optimized by shimming on the water proton signal. Typical line widths of 60-90 Hz were obtained. The animal was supine inside a cradle fashioned from large-diameter polyvinyl chloride pipe, with the elastic snares around celiac and superior mesenteric arteries secured to a pair of plastic screws, which were attached to the cradle. One operator adjusted these screws, directed by another who monitored the flow meter, thereby permitting maintainence of reasonably constant target blood flow values.
To acquire 31P-NMR spectra, 60 scans with an optimum radio-frequency pulse of 80 µs, spectral width of 6 KHz, and size of 1,024 points were averaged for a period of ~4.5 min/spectrum. An interpulse delay of >4 s was necessary to achieve full relaxation of all phosphorous peaks. The triggering pulse for each acquisition was synchronized with ventilation, by using a gating device activated by the ventilator at the same point in each respiratory cycle. Measurements and calculations. Mean arterial pressure was monitored with a pressure transducer (Hewlett Packard 78304A). Blood hemoglobin concentration and percent oxyhemoglobin were measured with an Instrumentation Laboratory 482 CO-oximeter. Plasma pH, PCO2, and PO2 were measured with a Radiometer ABL-620 blood-gas analyzer. Hepatic arterial and portal venous blood flows were measured with a Transonics T-201 two-channel meter. Accuracy of the meter had previously been ascertained by placing the flow probes around latex surgical drains submersed in saline without air bubbles, permitting saline to flow by gravity through the drains at various rates, and comparing timed collection of saline drainage to Doppler flow averaged over the same time period by computer. Hepatic venous AcAc concentration was measured by using the enzymatic technique of Mellanby and Williamson (16). Hepatic venous-OHB
concentration was measured by using Brashear's modification of
the technique of Williamson and Mellanby (1). Hepatic
O2 and hepatic O2 were
calculated by standard methods as previously described (24), with the
exception that here hepatic arterial flow was surgically isolated.
31P-NMR spectral peak areas for
ATP, Pi, and MDPA were determined
by integration with the use of the Bruker software package. Before
integration, baseline correction with the polynomial curve-fitting routine from the same software package was applied for each spectrum. All peaks were normalized to the MDPA peak to reduce variability among
measurements. Hepatic Pi/ATP was
calculated as Pi peak area divided
by -ATP peak area.
Pi/ATP, as opposed
to relative ATP concentration, corrected for the apparent liver
contraction that occurred during flow stagnation.
Experimental protocol. At
t = 0, hepatic arterial and portal
venous blood flows were collected for 30 s and averaged by computer. Immediately afterward, arterial, portal venous, and hepatic venous blood samples were taken, followed by two
31P-NMR spectra, followed
immediately by a second set of blood samples. After each data
collection, blood flows to the celiac and the superior mesenteric
arteries were immediately reduced by 10% of baseline flow value. This
process was repeated 10 times, allowing 20 min between data
collections. 31P-NMR data
acquisition required ~10 min, so that each period of constant flow
lasted 30 min. The animal was then killed with a bolus of intravenous
pentobarbital sodium (10 mg/kg) followed by concentrated potassium
chloride. At necropsy, correct placement of the hepatic venous cannula
was confirmed, and the livers (751 ± 39 g) were weighed.
Data analysis.
Dysoxia was defined as ATP flux, which decreases in proportion to
O2 availability with preserved ATP
demand (5). We used whole organ
O2 as our measure of ATP
flux, since the two are usually tightly coupled. To check this
assumption, we retrospectively plotted relative ATP against
O2, reasoning that a positive correlation between these variables would indicate that
O2 is a reasonable measure
of ATP flux. We used
O2
as our measure of O2 availability.
Most evidence indicates that, for practical purposes, tissue
O2 availability depends on bulk transport or convection of O2
(i.e.,
O2),
as opposed to venous PO2, or
diffusion, at rest (22). Hence, ATP flux decreasing in proportion to
O2 availability was taken as
O2 supply dependence (2, 20). We
also plotted O2
as a function of hepatic venous PO2,
to be certain that ATP flux also decreased in proportion to this
alternative measure of tissue O2
availability. We used tissue
Pi/ATP as our measure of preserved
ATP demand, since Pi/ATP, like
mitochondrial redox state, increases as cellular
PO2 approaches dysoxic levels (32).
O2 supply dependence or ATP flux
decreasing in proportion to O2
availability was defined for each individual animal by plotting O2 against
O2
and obtaining critical inflection points by the standard method of
Samsel and Schumacker (20). Onset of increasing ATP demand relative to
supply (32) was defined in the same manner for each animal, by plotting
Pi/ATP against
O2. To determine whether the onset of these two criteria required for
dysoxia was different, we compared these two critical
O2 values by two-tailed paired difference
t-test, taking significance as
P < 0.05. To determine whether
hepatic venous -OHB/AcAc increased at a
O2
value different from that which defined dysoxia, we compared critical
inflection values for O2
and -OHB/AcAc (computed in the same manner) and
Pi/ATP by two-tailed paired
difference t-test, with significance
taken as P < 0.05. In one instance
(-OHB/AcAc vs.
O2
relation of subject 6), the least
and second-least sum of squares regression lines intersected
outside the range of
O2 studied. In this instance, the third-least sum of squares pair of
regression lines was used to calculate critical
O2.
Statistical significance would support the hypothesis that critical
values were different, although statistical insignificance would not necessarily indicate that they were the same. This was a limitation of
our analysis.
A more rigorous method might be to define dysoxia as the lowest
critical
O2
value satisfying both decreasing
O2 and increasing Pi/ATP for each individual animal
and to compare this lowest common O2
value with that for hepatic venous -OHB/AcAc. However, data collection proved more difficult in an NMR scanner than during our
usual laboratory conditions, causing increased data scatter, such that
this alternative method would have biased the data toward lower
O2
values for dysoxia.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Figure 1 shows average values ± SE for
directly measured variables. Mean arterial pressure remained reasonably
constant as flow to the splanchnic viscera was progressively decreased.
Flow in the superior mesenteric and hepatic arteries decreased linearly in proportion to time intervals. Divergence of venous -OHB from venous AcAc occurred approximately simultaneously with divergence of
tissue Pi from tissue ATP. Figure
2 shows
31P-NMR spectra data for one
animal. Unlike skeletal muscle, liver contains no creatine phosphate
(13). Figure 3 shows pooled data for the
group of six animals. Figure 3A shows
whole liver O2 (or ATP flux)
as a function of hepatic venous PO2.
Venous PO2 values associated with the
lowest O2 values were widely
variable, presumably reflecting aspiration of some inferior vena caval
blood. O2 was relatively
constant at venous PO2 >20 Torr,
below which this estimate of ATP flux decreased with decreasing
PO2. Figure
3B shows
O2 and relative ATP as a
function of whole liver bulk
O2.
ATP was relatively constant during
O2 supply independence, decreasing
at the onset of O2 supply dependence. The assumption that
O2 was a reasonable
reflection of ATP flux in our preparations was supported by the linear
relation (r2 = 0.59) between ATP and whole organ
O2 (Fig.
3C). Figure
3D shows the relation between venous
-OHB/AcAc and ventral tissue Pi/ATP as a function of
O2.
These pooled venous -OHB/AcAc and ventral parenchymal
Pi/ATP vs.
O2
relations were superimposable, with inflections commencing at
the approximate onset of O2 supply dependence. These pooled data support ATP flux
(O2) decreasing in proportion
to tissue O2 availability (venous
PO2 and whole organ
O2),
with O2 demand increasing relative
to supply approximately simultaneously in tissue
(Pi/ATP), satisfying the three
criteria for recognizing dysoxia (5). The strikingly similar behavior
of venous -OHB/AcAc and tissue
Pi/ATP as
O2 and O2 decreased supported
our hypothesis that venous -OHB/AcAc in particular, and
mitochondrial redox state in general, detect dysoxia in liver.
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Figure 4 shows venous -OHB/AcAc
(left), ventral parenchymal
Pi/ATP
(middle), and
O2
(right) as a function of whole organ O2
for each of the six animals. In several instances, critical values
given by the dual-line regression program were not where intuition
might have placed them. However, dual-line regression is the only
available observer-unbiased method for detecting inflection points
(20). Critical
O2
was 2.44 ± 0.46 (SE) ml · 100 g1 · min1
for venous -OHB/AcAc; 2.39 ± 1.18 ml · 100 g1 · min1
for ventral parenchymal Pi/ATP;
and 4.07 ± 1.07 ml · 100 g1 · min1
for O2
(P = not significant), indicating that
critical values were not different, although not necessarily that they
were the same.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Measurement of mitochondrial redox state in intact liver was introduced by Chance and colleagues (4) in the 1960s. Their subsequent use of dual O2 indicators later showed that tissue with PO2 approaching the dysoxic range was practically nonexistant in working rat heart (3) and in isolated perfused liver (27). These findings were important because mitochondria of isolated cells (stirred at homogeneous PO2) become ~50% reduced as O2 availability approaches inadequate (PO2 decreasing from ~5-15 Torr) (32). If PO2 of all cells in an intact organ were in the range of 5-15 Torr as the organ approached the dysoxic threshold, then mitochondrial reduction would be nonspecific for dysoxia. Hence, the dual O2-indicator technique supported the idea that hepatocytes residing together in a dysoxic organ ought to be segregated into a group that has sufficient O2 to saturate mitochondrial cytochromes and into another one that has so little O2 as to fully reduce mitochondrial cytochromes, with a small or nonexistent "border zone" of hepatocytes with intermediate O2. Such a segregation would permit partial (mean) mitochondrial reduction in whole organ to indicate that some parts of it are dysoxic.
Our previous investigation of venous -OHB/AcAc (24) supported
hepatic mitochondrial redox state as a detector of liver dysoxia in situ, during the natural condition of
progressive hemorrhagic ischemia. However, we had used venous
-OHB/AcAc both as our measure of ATP demand and as our
potential detector of dysoxia. Venous -OHB/AcAc is an indirect
measure of tissue mitochondrial reduction and subject to potential
dilution by blood flow from adequately perfused tissue. Here we defined
dysoxia independently and compared the behavior of venous -OHB/AcAc
to it. Convergence of all three phenomena: decreasing
O2 availability
(O2),
decreasing ATP flux (O2), and
preserved ATP demand (increasing
Pi/ATP) demonstrated dysoxia. The
virtual superimposibility of tissue
Pi/ATP and vein -OHB/AcAc as
ATP flux decreased in parallel with
O2 availability (Fig.
3D) suggests, contrary to some views
(5), that mean mitochondrial reduction in general, and venous
-OHB/AcAc specifically, are potentially viable methods for detecting
dysoxia in liver.
Flow in dysoxic regions. In isolated
perfused heart (29) and in intestine in situ (19, 23),
it appears that the dysoxic group of cells has not only no
O2 but also very little blood
flow, the remainder being adequately perfused. Metzger and Schywalsky (17, 26) provided data for intact dysoxic liver showing that perfused
sinusoids are surrounded by unperfused sinusoids, suggesting a similar
segregation of adequately perfused and completely unperfused segments
in liver. However, both this and our previous (24) investigation
indicate that sufficient dysoxic liver is perfused to permit detection
of dysoxia by venous effluent -OHB/AcAc. The fraction of perfused
dysoxic liver appears to increase as O2
approaches zero.
Limitations of our findings. Scatter
of data obtained from within an NMR scanner, particularly for
O2 (Fig. 4), produced variable critical inflection points, some not where intuition might
have placed them. This limitation precluded defining dysoxia for each
individual animal as a single
O2
value satisfying both O2 supply
dependence (ATP flux decreasing with
O2 availability) and increasing
ATP demand. Hence, we cannot conclude that mitochondrial reduction
identified the onset of dysoxia precisely. Both venous -OHB/AcAc and
tissue Pi/ATP increased at
a somewhat lower
value (~2.4 ml · 100 g1 · min1)
than that at which O2
increased (~4 ml · 100 g1 · min1).
This discrepancy, although not statistically significant, could be
interpreted to mean that hepatocytes down-regulated ATP demand (and,
therefore, O2) to adapt for
decreased ATP supply, i.e., "O2
conformity," early in the progression of organ dysoxia.
Another limitation of our findings relates to the fact
that we measured Pi/ATP only in
ventral liver tissue, to a depth of ~1 cm. It is possible that some
portions of liver were dysoxic while tissue monitored by the NMR probe
was still adequately perfused, in which event venous
-OHB/AcAc might have been insensitive for the onset
of dysoxia. However, we measured
Pi/ATP in an area of liver that we
considered to be most vulnerable to dysoxia. This portion of liver was
the greatest distance from inflowing portal venous and hepatic arterial
blood supply, where resistance to blood flow might have been greatest.
In addition, the hydrostatic pressure difference between aorta and
monitored tissue in these supine animals, ~15-20
cmH2O (19), was maximum and
presumably a substantive fraction of mean pressure distal to our
vascular snares. In this regard, Lautt et al. (14) observed a tendency for both portal venous and hepatic arterial blood flow to distribute less to ventral than to dorsal liver in supine dogs and cats at normal
flow values. This tendency might be more pronounced at pressures
associated with critical flow values.
We could have avoided our problem of data scatter near critical had we
employed hemodilution or anoxia. Flow would then have been greater at
critical liver
O2,
permitting better separation of potential differences in critical
values. However, flow distribution during such high-flow dysoxic
conditions might then be different than that occurring during ischemic
dysoxia, predisposing to more homogeneous flow distribution near
critical and favoring our idea that tissue redox state is sensitive for
dysoxia. Both profound hypoxia and anemia are generally unusual, or at
least short lived, in hospitalized patients, who are our concern. More
importantly, the preparations studied earlier by Sies et al. (27)
employing isolated perfused livers, i.e., high-flow dysoxia, had
produced results similar to those reported here.
Clinical implications. An ideal
clinical dysoxia-detection method would be sensitive, specific, safe,
and practical at the bedside. Considerable evidence supports arterial
AcAc/-OHB as a clinical tool, particularly for patients undergoing
liver surgery (18). However, the enzyme, -hydroxybutyrate
dehydrogenase, is contained in tissues in addition to liver (15).
Therefore, we are not certain that -OHB/AcAc obtained from artery or
from a vein other than the hepatic is specific for
liver dysoxia in unstable patients, who have the potential for critical
perfusion deficits in multiple organs. Hepatic vein catheters have been safely employed in some clinical investigations (8, 12) and might be
used to assay -OHB/AcAc for investigative purposes, although probably not routinely to detect liver dysoxia in patients. The "critical" value for hepatic vein -OHB/AcAc
seems to be near 1.0, although "critical" was
defined by our dual-line regression program in one animal as 5.0 (Fig.
4). Hence, use of arterial or venous -OHB/AcAc as a
potential clinical detector of liver dysoxia requires additional
investigation. Alternatively, available noninvasive monitors of tissue
mitochondrial redox state (30) could be further developed for clinical
use, proving more practical than blood -OHB/AcAc in clinical
management.
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ACKNOWLEDGEMENTS |
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We thank Tracy Ann Gavidia for providing technical and surgical assistance.
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FOOTNOTES |
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This work was supported by the Department of Veterans Affairs and by a Shertz fellowship of Dept. of Anesthesiology and Critical Care Medicine, University of Pittsburgh, Peter M. Winter, Chairman (to M. K. Dishart).
Address for reprint requests: R. Schlichtig, 45 Longuevue Dr., Pittsburgh, PA 15228.
Received 15 August 1996; accepted in final form 7 November 1997.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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, Arterial values; 
, portal venous values; 
, hepatic
venous values. Brackets indicate concentration. MAP, mean arterial
pressure; pHp, plasma pH;
La
