1 Institute for Surgical
Research, The role of
endotoxin (lipopolysaccharide, LPS) and nitric oxide in hepatic oxygen
metabolism was investigated in 36 pigs receiving
1) LPS (1.7 µg · kg
NG-nitro-L-arginine methyl
ester; liver circulation; liver oxygen consumption; septic shock
SEPSIS AND ENDOTOXEMIA ARE characterized by systemic
hypotension and vascular hyporeactivity to vasopressor agents (23). Enhanced formation of nitric oxide (NO) by the inducible isoform of
NO synthase (iNOS) contributes significantly to this
"vasoplegia" in animals and humans (5, 11, 31, 32). NO (at high
concentrations) has cytotoxic properties (18), possibly through the
formation of peroxynitrite (30), and thus sustained NO production in
sepsis may also contribute to the tissue damage and organ dysfunction observed (3, 17, 23, 34). Inhibition of NO synthesis in sepsis and
endotoxemia may therefore be of therapeutic benefit. However, the
evidence of increased organ damage during endotoxemia and NOS
inhibition makes this a controversial approach (2, 9, 10, 28).
NO produced by the endothelial constitutive NOS (ecNOS) regulates
vascular tone and blood pressure as well as organ blood flow
distribution (18, 34). NO also modulates vascular permeability (14) and
inhibits platelet aggregation and leukocyte adhesion to the endothelium
(15).
A general problem in sepsis seems to be a failure in the ability of
tissues and organs to increase oxygen extraction to compensate for
reductions in oxygen delivery, which often appear in combination with
increased oxygen demand (26). Treatment of septic shock should
therefore not only be aimed at increasing arterial pressure, which NOS
inhibition seems to do, but also should be aimed at improving tissue
oxygenation and ultimately tissue viability.
Although there is substantial evidence that nonselective NOS inhibition
(i.e., inhibition of both ecNOS and iNOS) reduces regional blood flows
and oxygen delivery (12, 25, 34), the role of NO in the regulation of
oxygen metabolism is controversial (26, 27, 29, 33, 35).
The aim of the present study was to investigate the effect of
NG-nitro-L-arginine methyl ester
(L-NAME), a nonselective
inhibitor of NO synthase activity, on hepatic oxygen metabolism in a
porcine model of endotoxemia.
Changes in hepatic oxygen metabolism caused by
L-NAME might occur secondary to
vasoconstriction and reduced oxygen delivery or potentially by a
specific NO-related effect on oxygen metabolism. To separate the two
potential mechanisms of action, hepatic oxygen metabolism after NOS
inhibition was compared with measurements obtained at comparable blood
flow obtained by mechanical reduction of hepatic inflow.
Animals
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
1 · h
1)
for 7 h and NG-nitro-L-arginine
methyl ester (L-NAME; 25 mg/kg)
after 3 h, 2) LPS,
3) NaCl and
L-NAME, and
4) NaCl. Infusion of LPS reduced hepatic oxygen delivery
(DO2H) from
60 ± 4 to 30 ± 5 ml/min (P < 0.05) and increased the oxygen extraction ratio from 0.29 ± 0.07 to
0.68 ± 0.04 after 3 h (P < 0.05). Hepatic oxygen consumption (
O2H) was maintained (18 ± 4 and 21 ± 4 ml/min, change not significant), but acidosis
developed. Administration of
L-NAME during endotoxemia caused
further reduction of
DO2H from
30 ± 3 to 13 ± 2 ml/min (P < 0.05) and increased hepatic oxygen extraction ratio from 0.46 ± 0.04 to 0.80 ± 0.03 (P < 0.05). There was a decrease in
O2H from 13 ± 2 to 9 ± 2 ml/min that did not reach statistical significance,
probably representing a type II error. Acidosis was aggravated.
Administration of L-NAME in the
absence of endotoxin also increased the hepatic oxygen extraction
ratio, but no acidosis developed. In a different experiment, liver
blood flow was mechanically reduced in the presence and absence of
endotoxin, comparable to the flow reductions caused by
L-NAME. The increase in hepatic oxygen extraction ratio (0.34) and maximum hepatic oxygen extraction ratio (~0.90) was similar whether
DO2H was
reduced by occlusion or by
L-NAME. We concluded that
L-NAME has detrimental
circulatory effects in this model. However, neither endotoxin nor
L-NAME seemed to prevent the
ability of the still circulated parts of the liver to increase hepatic
oxygen extraction ratio to almost maximum when oxygen delivery was
reduced. The effect of L-NAME on
oxygen transport thus seems to be caused by a reduction in
DO2H rather than by alterations in oxygen extraction capabilities.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
Anesthesia
The pigs were premedicated with ketamine chloride (25 mg/kg im) and atropine (0.3-0.5 mg im), and anesthesia was subsequently induced with pentobarbital sodium (5 mg/kg iv) and maintained with supplementary infusions of pentobarbital sodium (1-2 mg/kg) and morphine (10-20 mg · kgSurgery
Surgery was performed under sterile conditions. The left internal jugular vein was cannulated for infusion of anesthetics and fluid. A tracheotomy was performed for mechanical ventilation. Through a midline incision, ultrasound transit time flow probes (Transonic Systems, Ithaca, NY) were placed around the hepatic artery and the portal vein for continuous flow measurements by a flowmeter (Transonic T201, Transonic Systems). Two mesenteric veins were cannulated for the infusion of either endotoxin or drugs. Catheters connected to pressure transducers (model AE840, SensoNOR, Horten, Norway) were passed from the right external jugular vein to a hepatic vein from the left femoral artery to the abdominal aorta and from a mesenteric vein into the portal vein. A Swan Ganz thermodilution catheter (model 93A-131H-7F, American Edwards Lab, Anasco, Puerto Rico) was passed from a femoral vein to a branch of the pulmonary artery and intermittently placed in a wedge position.Recordings were performed on a multichannel recorder (Gould ES 2000 V20 recorder, Gould Recording Systems Division, Cleveland, OH). The Swan Ganz catheter was connected to a cardiac output computer (Edwards Lab, Santa Ana, CA). A Foley catheter was introduced into the bladder via a cystotomi, and urine output was measured. Rectal temperature was measured with a thermistor probe.
After surgery, the animals were allowed to stabilize for 1 h, and then baseline measurements and plasma samples were obtained.
Endotoxin was infused into the portal vein to mimic the possible event of endotoxemia caused by bacterial translocation from the gut. Because we wanted to study the effects of a treatment regimen on liver derangement caused by endotoxin, endotoxin was infused for 3 h before intervention.
Treatment Protocols
The animals were randomly assigned to one of the following protocols. Endotoxin (lipopolysaccharide, LPS), L-NAME, or their vehicles (NaCl) were infused into the portal vein. Group 1 pigs were given LPS and L-NAME (n = 9). Endotoxin (1.7 µg · kgIn a separate set of experiments (n = 3), we measured the effect of repeated mechanical reductions of liver blood flow on hepatic oxygen extraction. Vascular occluders (In Vivo Metric, Healdsburg, CA) were placed around the hepatic artery (OC6, 6 mm) and the portal vein (OC12HD, 12 mm), and blood flow was reduced in a stepwise manner by 80-90% at baseline (n = 9 partial occlusions in the absence of endotoxin) and after 2-4 h of endotoxemia (n = 22 partial occlusions in the presence of endotoxin). The effect of mechanical reductions in hepatic oxygen delivery (DO2H) was compared with the corresponding effects caused by L-NAME.
The experiments were carried out in accordance with the Norwegian National Guidelines for Animal Care and were approved by the local ethics committee.
Hemodynamic measurements. The hemodynamic data have previously been published in part (25).
Portal venous blood flow (Calculation of DO2H and Hepatic Oxygen Consumption
Blood samples were obtained from catheters in the aorta and the portal and hepatic veins and analyzed in a blood gas analyzer (AVL 945, AVL, Graz, Austria), which calculates PO2, PCO2, standard bicarbonate, and base excess. Oxygen saturation (SO2) was measured in a cooximeter (model 282, Instrumentation Laboratories, Lexington, KY). Hemoglobin was measured in arterial blood samples by the hospital laboratory for clinical chemistry.
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(2) |
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(3) |
Statistical Analysis
Results are expressed as means ± SE. Differences within and between groups were determined by ANOVA for repeated measurements, using the SPSS software (MANOVA), with the Greenhouse-Geisser correction for time dependency of variables. When the recorded baseline values for any parameter differed between groups, the changes in that parameter were used in the MANOVA analysis. When the MANOVA procedure detected significant differences at up to 195 min with 34 of 36 animals still alive, it was followed by t-tests with appropriate corrections for multiple tests (Bonferroni). Evaluation of survival data was done by ![]() |
RESULTS |
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Survival
Five of nine animals died in group 1 (LPS + L-NAME) after 3.5, 4, 5, 6, and 6 h, respectively; however, they all lived long enough to be included in the evaluation of the L-NAME effects after 15 min. Two animals died in group 2 (LPS alone) after 3 and 6 h, and one animal died in group 3 (NaCl + L-NAME) after 5 h. There were no deaths in the control group (group 4). Group 1 survival was significantly reduced compared with the other groups (P < 0.05).Changes in Cardiac Output
LPS infusion caused within 3 h a reduction in cardiac output from 3.2 ± 0.2 to 2.4 ± 0.3 l/min (P < 0.05; Fig. 1). The injection of L-NAME caused a further reduction (by 41%) in cardiac output (LPS + L-NAME, group 1), and in the absence of endotoxin (NaCl + L-NAME, group 3) L-NAME also caused a marked reduction in cardiac output (by 30%; Fig. 1).
|
Changes in Liver Blood Flow
In the saline control group, there were no significant changes in liver blood flow.Endotoxin effects.
Continuous infusion of LPS for 3 h resulted in a reduced liver
perfusion (Fig. 2).
pv was reduced
by 26% (from 450 ± 70 to 330 ± 40 ml/min,
P < 0.05) and
ha by 41% (from
150 ± 15 to 80 ± 10 ml/min, P < 0.05). After 3 h, there were no further changes in liver blood
flow. The hepatic arterial fractional flow
(
ha/cardiac output) was reduced from 5.1 to 3.1%
(P < 0.05; Fig.
3), indicating that endotoxin causes
relatively larger reductions in
ha than in
cardiac output.
|
|
L-NAME effects.
During endotoxemia (LPS + L-NAME,
group 1), the injection of
L-NAME caused further reductions
in liver perfusion by 50%, and maximal effects were observed after 15 min (pv from 320 ± 30 to 160 ± 20 ml/min and
ha from 100 ± 20 to 50 ± 10 ml/min, P < 0.05; Fig. 2). Compared with measurements before endotoxin infusion was
started, liver blood flow was reduced by two-thirds. There was no
further change in hepatic arterial fractional flow after L-NAME injection (Fig. 3).
Changes in Blood Gases and Hepatic Oxygen Metabolism
In the saline control group (group 4), there were no significant changes in blood gases or oxygen metabolism.Endotoxin effects.
Continuous infusion of endotoxin caused within 3 h a reduction in
DO2H from
56 ± 4 to 30 ± 5 ml/min
(P < 0.05, Fig.
4). The hepatic oxygen extraction ratio
increased from 0.29 ± 0.07 to 0.68 ± 0.04 (P < 0.05), and
O2H remained unchanged (from
18 ± 4 to 21 ± 4 ml/min, not significant; see Table 4). The
increased extraction ratio was mirrored by a decrease in hepatic venous PO2 from
31.9 ± 2.1 to 15.8 ± 2.7 mmHg
(P < 0.05; see Table 3).
|
|
L-NAME effects.
During endotoxemia, L-NAME
injection caused further reductions in
DO2H from
30 ± 3 to 13 ± 2 ml/min after 15 min
(P < 0.05; see Fig. 4). This was not
only due to the reduced liver perfusion but also to the reduced portal
venous oxygen saturation (Table 2).
DO2H was
thus reduced by 80% compared with baseline. The hepatic oxygen
extraction ratio was increased by 90% (from 0.45 ± 0.04 to 0.80 ± 0.03, P < 0.05; see Table 4),
with a corresponding reduction in hepatic venous
PO2 (from
22.0 ± 3 to 12.3 ± 2.1 mmHg, P < 0.05; Table 3).
O2H tended to fall (from 13 ± 2 ml/min to 9 ± 2 ml/min, not significant; Table
4). At this point, the amount of oxygen
delivered was 13 ± 2 ml/min, which is lower than the extracted
amount of oxygen at baseline in this group (17 ± 3 ml/min; Fig.
5).
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The effect of mechanical reductions in liver blood flow on hepatic oxygen extraction. After 2-4 h of endotoxemia, stepwise reductions in liver blood flow (n = 22 partial occlusions in 3 pigs) to 10-30% of baseline (average total liver blood flow reduction from 320 to 80 ml/min) caused a 90% increase in oxygen extraction ratio from 0.46 ± 0.03 to 0.80 ± 0.02 (Fig. 7). Individual extraction ratios after partial occlusion during endotoxemia ranged from 0.67 to 0.92. Compared with the increase in extraction ratio after L-NAME injection during endotoxemia (from 0.46 ± 0.04 to 0.80 ± 0.03), there was no difference at comparable total liver blood flow (80 and 100 ml/min, respectively; Fig. 7). Individual extraction ratios after L-NAME ranged from 0.72 to 0.97.
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DISCUSSION |
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Endotoxin infusion caused significant reductions in liver blood flow
and oxygen delivery followed by a marked increase in the hepatic oxygen
extraction ratio. There was no significant change in
O2H, but acidosis
developed, indicating inadequate organ perfusion. Administration of
L-NAME during endotoxemia caused immediate and profound further reductions in liver perfusion and in
DO2H,
accompanied by aggravated acidosis. The oxygen extraction ratio
increased to 0.80, and
O2H
tended to decrease. This indicates that the hepatic oxygen extraction
capability was remarkably well preserved even during late (>3 h)
endotoxemia, which is somewhat contradictory to the impairments in
oxygen extraction during sepsis and endotoxemia observed in other
studies (23). Increased
O2H in early sepsis has, however, previously been reported in the pig (1).
Also, similar experiments in our porcine model show that, during 6 h of
endotoxemia, the
O2H is
unchanged (8).
In a canine model, Nelson and co-workers (20) demonstrated that
endotoxin caused a reduction in intestinal oxygen extraction ability:
critical
DO2 (the
DO2 below
which O2 becomes supply dependent) was increased by 88%, and the corresponding critical extraction ratio was reduced by 30% (from 0.69 to 0.47), whereas maximum intestinal extraction ratio was reduced from 0.83 to 0.71. In
the present study, we have not calculated the critical
DO2H, but
the pooled data show that the maximum hepatic oxygen extraction ratio
during endotoxemia was not reduced. On the contrary, the maximum
hepatic oxygen extraction ratio during reductions in
DO2H (vascular occlusion) tended to be even higher in the presence than in
the absence of endotoxin (hepatic oxygen extraction ratio of 0.92 and
0.84, respectively). Thus oxygen transport during endotoxemia seems to
be better preserved in the porcine liver than, at least, in the canine intestine.
Although there was no significant decrease in total
O2H during
endotoxemia, the low hepatic venous
PO2 and
acidosis indicated that in some regions
DO2
probably was too low to meet tissue metabolic needs. After
L-NAME was given in the saline + L-NAME group,
DO2H was
abruptly reduced from 50 ml/min to the same level as in the endotoxin
alone group (30 ml/min), but there were no signs of oxygen supply
dependency or ischemia, i.e.,
O2H, pH, and base excess were unchanged.
Therefore, the observed acidosis during endotoxemia cannot be explained exclusively by a global reduction in DO2H, but more likely it reflects heterogeneous perfusion causing focal ischemia.
This interpretation is consistent with previous studies that have demonstrated marked heterogeneity in liver perfusion during endotoxemia, ranging from areas with shutdown of sinusoids (16) to areas with apparent hyperperfusion (4). There are several possible explanations for this flow pattern, including vasospasm, swelling of sinusoidal lining cells, sinusoidal contraction of Ito cells, and platelet plugs/thrombosis. The poorly circulated areas of the liver will produce H+, which causes acidosis in the main hepatic vein.
The marked decrease in liver blood flow caused by
L-NAME may have been accompanied
by increasing heterogeneity of flow (21) and thus caused increasing
acidosis and organ damage. The ischemic areas producing
H+ during anaerobe glycolysis will
contribute less to oxygen consumption than well-perfused areas, and the
overall hepatic O2 should logically decrease.
The reduction in liver O2
after L-NAME was not
statistically significant in the present study. This may be due to a
type II error because there were large variations in oxygen transport between pigs. A power analysis of the test shows that, to detect a true
difference in means of 8 ml/min (the observed difference in
O2H at baseline and
15 min after L-NAME during
endotoxemia) with 80% probability, a sample size of 23 is required,
assuming a standard deviation of differences of 9, using a paired
t-test with a 0.05 two-sided
significance level.
During the last 3 h of the study, several of the pigs in the LPS + L-NAME group (group 1) died, making the group too small (n = 7, 6, and 4, respectively) to draw definite statistical conclusions. As the sickest animals (having probably the lowest oxygen uptake) died, the values reported may not be representative of values for the survivors.
However, the marked decrease in liver blood flow, the very low hepatic
venous oxygen saturation, and the severe acidosis are consistent with
severe hepatic ischemia and tissue injury. This will probably
cause irreversible organ damage. Therefore, in a larger study, we
predict there will be a significant decrease in
O2H after L-NAME
in endotoxemia.
One of the questions in this study was whether endotoxin or L-NAME affected the ability of the liver to increase its oxygen extraction ratio when oxygen delivery was reduced. Therefore, separate experiments with vascular occluders were performed to evaluate the effect of profound reductions in oxygen delivery. Even after 4 h of endotoxemia, extraction ratios up to 0.9 were measured, comparable with the extraction ratios after L-NAME injection (see Fig. 7). The very high oxygen extraction ratios suggest that those parts of the liver that still circulate function well, and these regions appear to have a potential for increasing the oxygen extraction. We suggest that the main reason for the acidosis during endotoxemia is the contribution of H+ from anaerobic metabolism in poorly circulating areas, possibly combined with specific cellular effects of endotoxin.
Another possible mechanism for the acidosis in endotoxemia might be increased NO production, which inhibits mitochondrial respiration. This would be in accordance with studies in cell cultures in which increases in NO, either exogenously applied or endogenously induced, cause an inhibition of mitochondrial respiration due to enzyme inhibition (28, 30). In a model of porcine endotoxemia comparable to ours, enhancement of NO production was indeed demonstrated (13). With the assumption that L-NAME, in the dose used in the present study, causes complete NOS inhibition, the increase in the hepatic oxygen extraction ratio might be explained by reactivation of mitochondrial enzymes. However, the similar increases in the oxygen extraction ratio after reductions in oxygen delivery caused by L-NAME and liver blood flow occlusion makes this explanation less plausible. Thus the effect of L-NAME on hepatic oxygen metabolism in the present study can most logically be explained by the reduction in oxygen supply.
Endotoxin is known to inhibit ecNO production (19, 22), which is of fundamental importance in regulation of microvascular functions. The finding that further inhibition of endothelial NOS by L-NAME had detrimental effects on liver perfusion supports the notion that some basal NO production is necessary to secure adequate organ perfusion and oxygen delivery. Thus the unfavorable inhibition of the constitutive NOS caused by endotoxin as well as by L-NAME would probably by far outweigh any favorable effects of reduced NO production from iNOS caused by L-NAME.
The present study does not exclude specific effects of endotoxin on
cellular metabolism causing increased energy requirements or uncoupling
of oxidative phosphorylation compromising ATP production (6). Under
these conditions, "normal" levels of
O2 would be inadequate and
acidosis would subsequently develop. Endotoxin may cause defects in
cellular metabolic pathways in such a manner that anaerobic glucose
utilization is preferred, thus leading to tissue acidosis independent
of either tissue
PO2 or
O2 (7).
In a clinical setting without invasive measurements of organ blood flow and oxygen transport, treatment with NOS inhibitors in septic shock could seem attractive due to the increase in arterial pressure observed in animals (32) and humans (24). However, any agent reducing organ blood flow and oxygen delivery, as demonstrated in this study, is potentially hazardous.
In conclusion, we found that, whereas endotoxin caused a 50% reduction in DO2H, oxygen extraction ratios increased, and there was no significant decrease in oxygen consumption. Still, the acidosis indicates insufficient tissue oxygen delivery relative to oxygen demand.
The NOS inhibitor L-NAME caused
further reductions in
DO2H, and,
whereas the oxygen extraction ratio increased (by 87%),
O2 tended to fall. The
accompanying aggravated hepatic venous acidosis indicates that parts of
the liver were ischemic. However, neither endotoxin nor
L-NAME seemed to reduce the
capacity of the liver to increase oxygen extraction when oxygen
delivery was reduced. Maximal oxygen extraction ratios during
endotoxemia were similar after
L-NAME and after comparable
reductions in
DO2H caused
by vascular occluders. Thus the
L-NAME-induced changes in
hepatic oxygen metabolism in endotoxemia appear to be mediated
predominantly by vasoconstriction, reduced liver inflow, and the
subsequent reduction in oxygen delivery rather than by alterations in
oxygen extraction capabilities.
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ACKNOWLEDGEMENTS |
---|
We very much appreciate the technical assistance and never-ending helpfulness of Roger Ødegård. The very skilled surgical assistance of Marie Närbo, Vivi Bull Stubberud, Sera Sebastian, and Joran Valen is highly appreciated. We are grateful to Elisabeth Fahlstrøm, Mariann Madsen, and Grethe Dyrhaug for their accurate work in handling all blood specimens. All these co-workers are especially thanked for creating a good atmosphere in the lab.
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FOOTNOTES |
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This work was supported by The Norwegian Research Council and The Laerdal Foundation For Acute Medicine.
Address for reprint requests: T. Saetre, Surgical Dept., Ullevaal Hospital, Kirkeveien 166, 0407 Oslo, Norway.
Received February 24 1997; accepted in final form 20 August 1998.
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