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Departments of Anesthesiology and Critical Care Medicine, Internal Medicine, and Surgery, University of Pittsburgh, and Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15240
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Rozenfeld, Ranna A., Michael K. Dishart, Tor Inge
Tønnessen, and Robert Schlichtig. Methods for detecting local
intestinal ischemic anaerobic metabolic acidosis by
PCO2. J. Appl. Physiol. 81(4): 1834-1842, 1996.
Gut ischemia is
often assessed by computing an imaginary tissue interstitial pH from
arterial plasma HCO
3 and the
PCO2 in a saline-filled balloon
tonometer after equilibration with tissue
PCO2 (PtiCO2).
PtiCO2 may
alternatively be assumed equal to venous PCO2
(PvCO2) in that region of gut. The idea
is that as blood flow decreases, gut
PtiCO2 and
PvCO2 will increase to the maximum
aerobic value, i.e., maximum respiratory
PvCO2
(PvCO2 rmax). Above a "critical" anaerobic threshold, lactate
(La) generation, by
titration of tissue HCO3, should raise
PtiCO2
above
PvCO2 rmax.
During progressive selective whole intestinal flow reduction in
six pentobarbital-anesthetized pigs, we used
PCO2 electrodes to test the
hypotheses that critical
PtiCO2
is achieved earlier in mucosa than in serosa and that
PvCO2 rmax,
computed using an in vitro model, predicts critical
PtiCO2. We
defined critical
PtiCO2 as the
inflection of
PtiCO2-PvCO2
vs. O2 delivery
(
O2)
plots. Critical
O2
for O2 uptake was 12.55 ± 2 ml · kg1 · min1.
Critical PtiCO2 for mucosa
and serosa was achieved at similar whole intestine
O2
(13.90 ± 5 and 13.36 ± 5 ml · kg1 · min1,
P = NS). Critical
PtiCO2 (129 ± 24 and 96 ± 21 Torr) exceeded PvCO2 rmax
(62 ± 3 Torr). During ischemia,
La excretion into portal
venous blood was matched by K+
excretion, causing PvCO2 to increase
only slightly, despite
PtiCO2 rising
to 380 ± 46 (mucosa) and 280 ± 38 (serosa) Torr. These results
suggest that mucosa and serosa become dysoxic simultaneously, that
ischemic dysoxic gut is essentially unperfused, and that in vitro
predicted
PvCO2 rmax
underestimates critical
PtiCO2.
ischemia; acidosis; carbon dioxide; hypercarbia; strong ion
difference
INTRODUCTION CRITICAL WHOLE ORGAN
O2 delivery
( Another method might be use of intestinal tissue
PCO2
(PtiCO2)
itself, because the increase in
PtiCO2 during
ischemia correlated with the histological grade of intestinal injury
(1). Schlichtig and Bowles (15) suggested that the critical
PtiCO2 might be
determined by assuming that
PtiCO2
is a reasonable approximation of local venous
PCO2
(PvCO2). As blood flow and
venous O2 saturation
(SvO2)
fall, PvCO2 should increase slightly,
varying inversely with
SvO2. At
constant respiratory quotient (RQ), in the absence of "metabolic"
acid generation, the "respiratory" PvCO2
(PvCO2 r)
at any given
SvO2 can be
predicted from an arterial blood gas analysis with use of in vitro
assumptions (12, 15). When blood flow reaches a critical point,
anaerobically generated tissue lactate
(La Tissue PO2, as opposed to
PtiCO2, might
alternatively be measured. However, decreased
PO2 indicates only that
O2 supply is decreased, whereas
critically increased
PtiCO2 should
indicate not only that flow is decreased but also that the dysoxic
response (i.e., anaerobic glycolosis and liberation of
CO2 from
HCO In support of the
PtiCO2 idea,
intestinal mucosal PCO2 exceeded
PvCO2 rmax
at the onset of O2 supply
dependence in dogs subjected to progressive lethal cardiac tamponade
(15). However, mixed intestinal venous (i.e., portal venous)
PCO2 increased only slightly in these
dogs, even at near-zero flow, suggesting that the intestine became
dysoxic segmentally, rather than homogeneously, because it seemed not
to have excreted metabolic acid into venous effluent. Whereas we
hypothesized that the mucosa was the segment that became dysoxic first,
with the no-flow region spreading centrifugally toward the serosa (Fig.
1A),
dysoxia may alternatively have spread in a manner other than mucosal to
serosal (Fig. 1B). In addition, we
used slow-responding silicone rubber balloon tonometers to estimate
PtiCO2 and
administered NaHCO3 to maintain
normal arterial pH, suggesting the need for a closer examination of the
PvCO2 rmax
concept.
To clarify the relations of critical mucosal
PtiCO2,
critical serosal
PtiCO2, and
PvCO2 rmax,
critical PtiCO2
could be determined using a
METHODS
O2)
represents the threshold for ischemic dysoxia, i.e.,
O2 supply that is inadequate to
support tissue
O2
demand (3, 11, 15, 16). Critical O2
is that at which O2 uptake
(
O2) begins to decrease
in proportion to
O2
during flow reduction, this phase being termed O2 supply dependence (3). However,
because gut O2 and
O2 cannot be measured in patients, indirect methods have been proposed. One method is to measure PCO2 of
saline after equilibration in a silicone rubber balloon in intestine
and to estimate gut intramucosal pH
(pHi). However, this method
relies on unjustified assumptions concerning tissue
HCO3 (17).
) should
titrate tissue HCO3,
causing
PtiCO2 to exceed maximum
PvCO2 r
(PvCO2 rmax),
i.e.,
PvCO2 r at SvO2 of
zero.
3) has been activated.
Fig. 1.
Two hypothetical schemes that might account for a large local tissue
PCO2
(PtiCO2)-mixed
portal venous PCO2 difference at
one-half critical O2 delivery.
Both require that ischemic tissue be essentially unperfused.
A: our previous hypothesis (Ref. 15)
that ischemic dysoxia spreads centrifugally, from mucosa toward serosa.
M, mucosa; m, muscularis. B: an
alternative possibility, i.e., that ischemic dysoxia spreads
transmurally. In either event, local
PtiCO2 in some
tissue regions could be less than critical, despite whole gut
O2 supply dependence.
PvCO2 rmax, maximum respiratory venous PCO2.
[View Larger Version of this Image (51K GIF file)]
O2-O2
plot. However, given the heterogenity of flow (Fig. 1) implied by
PvCO2 remaining near
PvCO2 rmax (15), it seemed that a
O2
value one-half the critical value could signify that one-half of the
intestine has zero flow and the other one-half has adequate flow. In
the current investigation, we therefore used another method to identify
critical local
PtiCO2. During selective progressive flow stagnation of whole bowel, we defined critical
PtiCO2 as
PtiCO2 at
the point where an inflection occurred in the plot of the
difference between local PtiCO2 and
mixed portal venous PCO2
(
PCO2). Theidea was that this
PtiCO2 should
be specific for onset of local dysoxia with decomposition of tissue
HCO3. To further test whether ischemic
dysoxic intestine excretes metabolic acid into venous effluent, we
computed arteriovenous strong ion difference (SID), where a strong ion
is one that is always dissociated in physiological solution (6, 24,
25), on the basis of the whole blood base excess (BE) concentration
([BE]WB) model (22,
23), where [BE]WB is
the change in strong acid concentration or strong base concentration
needed to restore plasma pH to normal at normal
PCO2.
1 · h1,
and a catheter was advanced into the carotid artery to monitor arterial
pressure. Via a transverse incision through the three most inferior
left ribs, the retroperitoneal space was entered, the superior
mesenteric artery (SMA) and celiac artery were isolated at their
origins from the aorta, and elastic snares were placed around these
vessels. This retroperitoneal approach minimized bowel manipulation and
prevented bowel swelling that occurred when the SMA was approached from
a midline incision during pilot experiments. Through a low midline
incision, the inferior mesenteric artery was ligated, and the incision
was closed in two layers. Through a high midline incision, a
triple-lumen catheter was placed through a lymph node into the portal
vein at the level of the porta hepatis by the Seldinger technique, and
a Doppler flow probe was placed around this vessel. The small intestine
was isolated from potential proximal intestinal anastomotic collateral
flow by ligating the gastroduodenal junction.
4 cm from the
mucosal PCO2 electrodes. Tips of
serosal PCO2 electrodes were inserted
through 1-cm2 rubber gaskets, with
the PCO2 electrode tip positioned ~0.5 mm inside the surface of the gasket.
PCO2 electrodes were suspended by
their connecting wires from a clamp with enough slack to allow for
tissue movement during respiration.
Thirty minutes before data collection, the celiac artery was ligated
with umbilical tape, and the elastic SMA snare was attached to the
movable end of a C clamp. After all surgical manipulations had been
completed, curare (6 mg iv) was administered in intermittent boluses to
suppress respiration, after it was ensured that anesthesia was
complete. Mean arterial pressure (MAP) was maintained near baseline by
administration of 0.9% NaCl as necessary. Care was taken to administer
0.9% NaCl only immediately after each data collection to minimize
changes in blood SID concentration ([SID]). Dextrose (10%)
was administered at a rate to maintain arterial glucose concentration
([glucose]) at ~100 mg/dl to prevent ketosis.
Experimental protocol.
At time 0, portal flow was measured
and averaged by computer over 30 s,
PCO2 electrode readings were
recorded, and 1 ml each of arterial and portal venous blood was
withdrawn into heparinized glass syringes and placed in an ice bath for
later analysis of hemoglobin concentration ([Hb]), percent
oxyhemoglobin (HbO2),
O2 content, and plasma pH,
PO2, and
PCO2. An additional 4 ml each of
arterial and portal venous blood were withdrawn into heparinized glass
syringes, transferred to plastic vials, and centrifuged at 6,000 rpm
for 3 min, and the supernatant was removed. An aliquot of plasma was
immediately analyzed for plasma
La concentration
([La]p),
and the remainder was frozen at 
20°C for later analysis of
plasma Na+
([Na+]p),
K+
([K+]p),
Cl
([Cl]p),
Pi
([Pi]p),
and albumin
([albumin]p)
concentrations. Another series of baseline measurements was taken at 5 min. Immediately after each 5-min data collection,
PCO2 electrodes were removed, and
their sensitivity to PCO2 was
quantified.
At the start of flow reduction, flow to the intestine was decreased by
opening the C clamp and maintained near target values by varying the
tension on the elastic snare. Series of measurements were taken 20 and
25 min after each flow reduction. Immediately after each pair of data
collections, flow was reduced by 10% of the baseline value. The final
flow value produced was ~20 ml/min, to permit blood samples to be
withdrawn from the portal vein. After the final measurements were
taken, flow was reduced to zero. About 30 min later, the SMA snare was
released, and arterial and venous measurements were taken every minute
for 4 min. In anticipation of the profound hypotension and
hypoxemia that invariably followed release of the SMA snare,
1 liter of 0.9% NaCl was administered intravenously, and
FIO2 was increased
to 100%. At the termination of each protocol, animals that were not
asystolic were killed by bolus injection of KCl after injection of
pentobarbital sodium (10 mg/kg).
Measurements and calculations.
Plasma gas tensions and pH were measured at 37°C with a blood gas
analyzer (model ABL-30, Radiometer). Blood [Hb],
HbO2, and O2 content were measured with a
CO-oximeter (model 482, Instrumentation Laboratories).
[La] and
[glucose] of separated plasma
([La]p
and [glucose]p) were
measured with a glucose-lactate analyzer (model 2300, Yellow Springs
Instruments).
[Na+]p,
[K+]p,
and
[Cl]p
were measured in thawed plasma samples with an automated analyzer (model CX-3, Beckman).
[Albumin]p and
[Pi]p
were analyzed with a Beckman CX-7 analyzer. Portal blood flow was
measured with a Doppler flowmeter (Transonic Systems). Intestinal
O2
was calculated as the product of arterial
O2 content and portal flow.
Intestinal O2 was
calculated as the product of arteriovenous
O2 content and portal flow.
[SID]p was calculated
as
[Na+]p + [K+]p [Cl]p [La]p
(6, 24, 25). Whole intestine
La production rate
(La
)
was calculated as arteriovenous [La]p × flow.
Tissue PCO2 electrodes were
calibrated before each experiment in 40 mM
NaHCO3 baths at 40°C titrated
to pH ~7.0 with NaCl at PCO2 of
~25 and 300 Torr. Linearity of the relation between electrode
PCO2 and ABL-30 analyzer
PCO2 (measured at 37°C) was
analyzed in duplicate before and after each experiment for each
electrode in five baths with PCO2 of
25-300 Torr by linear regression. Although the relation between electrode PCO2 and analyzer
PCO2 was always linear before and
after each experiment, sensitivity tended to drift over time for some
electrodes. Consequently, the sensitivity of each electrode for
PCO2 was measured after each pair of
PtiCO2
measurements in baths with PCO2 of 25 and 300 Torr, allowing correction of the
PtiCO2
readings.
Determination of critical
PtiCO2.
Critical PtiCO2
was taken as
PtiCO2 at the
inflection of the
PCO2-O2
relation of each individual animal determined by dual-line regression
analysis (11). Because tissue generates CO2, we reasoned that the level of
PtiCO2 must be
at least that of mixed portal PvCO2 and
that PCO2 would therefore permit
better identification of inflections. To determine whether critical
O2
for PCO2 differed between mucosa
and serosa in each animal, we compared critical
O2
values for mucosa and serosa by paired-difference
t-test, taking significance as P < 0.05. To examine the possibility
that local anaerobic metabolism might commence before or after the
onset of O2 supply dependence, we
computed critical
O2
for whole intestinal
O2 for each
animal and compared it with critical
O2
for mucosa and for serosa.
Determination of tissue metabolic acid production.
We determined the presence or absence of intestinal metabolic acid
excretion, on the basis of the Siggaard-Andersen
[BE]WB concept, by
plotting arteriovenous
[SID]p against
arteriovenous HbO2 concentration
([HbO2]) (13) and
determining whether the slope and
y-intercept of this relation differed
(27) when arteriovenous [La]p
was greater than or less than 0.5 mM, with significance as P < 0.05. We reasoned that an
increase in the slope of this relation during
La efflux would represent
depletion of less than the expected quantity of strong anion from
plasma (normally Cl, lost
in exchange for erythrocyte HCO3) per change in [HbO2] and,
therefore, acidification of venous blood by strong acid (13). Our
assumption that [SID]p
was an accurate reflection of the metabolic component of plasma
acid-base status in vivo was checked by comparing measured arterial or
venous PCO2 with
PCO2 predicted by the formula of
Figge et al. (6) and Schlichtig (14). As an additional and independent
test of the presence or absence of tissue metabolic acid excretion into portal venous blood, we compared the response of arteriovenous [HCO3]p
with arteriovenous
[HbO2] (13) when arteriovenous
[La]p
was greater than or less than 0.5 mM.
Comparison of in vitro-predicted
PvCO2 r and
PvCO2 rmax
with in vivo PvCO2 and critical
PtiCO2.
PvCO2 r
at measured
SvO2,
[Hb], PaCO2, and
[BE]WB and
PvCO2 rmax
(i.e.,
PvCO2 r
computed for
SvO2 = 0) were computed using a previously described in vitro simulation (12), with
the assumption of an intestinal RQ of 0.85 (26).
PvCO2 r was compared (27) with observed PvCO2
for data sets where arteriovenous [La]p
was more than 0.5 mM, which we took as evidence that
PvCO2 was respiratory in origin.
Critical PtiCO2
values were compared with
PvCO2 rmax
predicted from arterial blood gases by paired-difference t-test.
Additional statistical considerations.
Data from one animal were excluded, because one serosal and both
mucosal PCO2 electrodes were
nonfunctional. In one additional animal (pig
2), a critical
O2
for PCO2 could not be identified
by this method, inasmuch as
PCO2 began to increase shortly
after the commencement of flow reduction. Although this animal might
also have been excluded from analysis, O2 was clearly
O2 supply independent during
several flow reductions, and pooled data suggested that the relation
between PCO2 and
O2
for this animal was not different from that for the remaining animals.
Consequently, we defined the supply-independent regression line for
this animal as the common supply-independent regression line for the
group.
RESULTS
Average
r2
of the 10-point PCO2 electrode vs.
blood gas analyzer regressions, performed before and after each
experiment, was 0.99 ± 0 (SE). Average drift of the
PCO2 electrodes between tissue
PCO2 measurements per 100 Torr was
0.1 ± 0.8 Torr. MAP, arterial [glucose], arterial
O2 content, and PaCO2 were maintained near baseline
throughout flow reduction (Fig. 2).
Arterial values at 20 and 25 min after each flow reduction were
generally the same, indicating that a reasonable approximation of
steady state had been achieved in arterial blood. Arterial pHp decreased from 7.39 ± 0.02 to 7.28 ± 0.04 during flow reduction, and arterial
[La]p
increased only slightly, by ~2.2 mM. After release of the SMA snare,
these animals abruptly became profoundly hypotensive, with MAP
declining precipitously within the first 4 min. Although arteriovenous differences in strong ions were only moderately larger during reperfusion than during flow stagnation, total ion fluxes during reperfusion were striking, as illustrated by the enormous increase in
La
during reperfusion (Fig. 2, bottom
right).
PV, portal
venous flow; %HbO2, percent
oxyhemoglobin; [Hb], hemoglobin concentration;
pHp, plasma pH;
[Cl]p,
[HCO3]p,
[albumin]p,
[Na+]p,
[La]p,
[glucose]p,
[Pi]p,
and
[K+]p,
plasma Cl,
HCO3, albumin,
Na+, lactate,
glucose, Pi, and
K+ concentrations. 
, Arterial
values; 
, venous values; +,
La flow rate
(La).
Commencement of critical PtiCO2 in mucosa vs. serosa. Figure 3 shows the pooled responses of
O2, tissue and venous
PCO2, and arteriovenous
[La]p
to
O2
reduction. The commencement of decreasing
O2, increasing PCO2, and decreasing arteriovenous
[La]p
was roughly simultaneous. As
O2 continued to decrease and tissue PCO2 to increase during
O2 supply dependence, arteriovenous
[La]p
returned toward baseline, suggesting a progressive isolation of
ischemic intestine from flowing blood. Figure
4 shows the response of mucosal
PCO2, serosal
PCO2, and whole intestine
O2 to
O2
reduction for individual animals. O2
was 13.90 ± 5 ml · kg1 · min1
for critical mucosal PCO2, 13.36 ± 5 ml · kg1 · min1
for critical serosal PCO2, and
12.55 ± 2 ml · kg1 · min1
for critical whole intestine
O2
(P = NS), indicating that anaerobic HCO3 decomposition commenced
simultaneously in mucosa and serosa at the vertically superior surface
of the bowel, coincident with the onset of whole bowel
O2 supply dependence but
inconsistent with the hypothetical scheme shown in Fig.
1A. Exclusion of
pig 2 from the analysis did not change
statistical conclusions. Critical
O2 extraction ratio was 62 ± 2%.
O2),
PCO2, and arteriovenous lactate
concentration in plasma
(a-v[La]p).
, Whole intestine values; 
, serosal values; 
, mucosal values;
, portal venous values.
O2,
O2 delivery.
O2 as
O2
decreased during progressive superior mesenteric artery snaring. Lines,
least-squares dual-regression lines.
Comparison of in vitro-predicted PvCO2 r and PvCO2 rmax with in vivo PvCO2 and critical PtiCO2. So long as arteriovenous [La
]p
remained greater than 0.5 mM,
PvCO2 r
was linearly related to observed
PvCO2 but provided a
progressive underestimation as PvCO2
increased (Fig. 5). At arteriovenous
[La]p
of less than 0.5 mM, i.e., during
La excretion,
PvCO2 deviated from
PvCO2 r
to a greater extent, presumably because excreted
La and
K+ were accompanied by some
anaerobically derived tissue CO2.
Table 1 gives values for initial, critical,
and final
PtiCO2 and
PvCO2 rmax. Critical serosal
PtiCO2 exceeded
critical
PvCO2 rmax
by ~30 Torr, whereas critical mucosal
PtiCO2 exceeded
critical
PvCO2 rmax by ~70 Torr.
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excretion. Hence,
enrichment of venous plasma with strong acid or base during
HbO2 desaturation was not
different during La
excretion. Our independent test (13), comparison of the slopes (P > 0.2) and
y-intercepts
(P < 0.05) of the arteriovenous
[HCO3]p vs. arteriovenous
[HbO2] relations (Fig.
5C) for arteriovenous [La]p
more than 0.5 mM vs. arteriovenous
[La]p
less than 0.5 mM, suggested slightly different behavior.
However, the relation, if anything, was steeper during
La production, again
indicating that, overall, metabolic acid was not excreted into mixed
portal venous blood, consistent with previous observations (15). The
apparent paradox of tissue
La efflux, without venous
acidification by strong acid, was due to the fact that arteriovenous
[La]p
decreased in direct proportion to arteriovenous
[K+] (Fig.
6D). Thus, whereas
La efflux favored plasma
HCO3 decomposition, this effect was
counterbalanced by K+ efflux (6,
24, 25). This finding localizes the site of HCO3 decomposition to cells, as
opposed to venous blood and, together with the finding of relatively
little La excretion (Fig.
3), accounts for the much higher PCO2 values in tissue than in venous blood during
O2 supply dependence.
3]p and arteriovenous [HbO2]. D:
relation between arteriovenous
[K+]p
and arteriovenous
[La]p
during flow stagnation.
Arteriovenous differences during reperfusion. Figure 7 shows arteriovenous differences during reperfusion. During reperfusion, arteriovenous [SID] at arteriovenous HbO2 was little different from that during flow stagnation, because Cl
was taken up in excess
of Na+ and because
La and
K+ production were similar.
However, arteriovenous PCO2 was
strikingly large in comparison to flow stagnation, showing that
anaerobically generated CO2 had
indeed been trapped in unperfused or poorly perfused tissue during flow
reduction. Although this PvCO2 was less
than PtiCO2 30 min earlier (Fig. 3, middle),
arteriovenous [HbO2]
had already returned to control values at the point that the first
blood samples were taken, and flow had increased to two-thirds the
baseline value (Fig. 3), suggesting that much of the decomposed tissue
HCO3 had been flushed from the tissues
during the early seconds of reperfusion.
,
Progressive superior mesenteric artery snaring; , reperfusion.
Values represent minutes after reperfusion. Scale after
x-axis break is in 1-min increments.
DISCUSSION
Findings of the present investigation of selective intestinal flow
reduction generally support previous findings (15) in dogs during whole
body flow reduction. Intestinal
PtiCO2 and
PvCO2 were again similar during
O2 supply independence and again
deviated strikingly during O2
supply dependence (Fig. 3). This finding again appeared due to the fact
that HCO3 was decomposed in cells,
rather than in venous blood (Fig. 6), and to the fact that ischemic
dysoxic intestine was nearly completely unperfused. However, our more
detailed methods seem to provide a clearer picture of events that occur
during whole intestinal ischemia.
PCO2 vs.
O2
is new. Critical
PtiCO2 should
be highly specific for dysoxia, representing a situation characterized
by increased tissue
[La] and by
flow so small as to permit CO2 to
accumulate in tissue. However, sensitivity of
PtiCO2 for
dysoxia is certainly a potential problem. Preliminary data (10)
indicate that porcine intestinal PtiCO2
increases by an average of ~300 Torr over 45 min of zero flow,
indicating a tissue HCO3 decomposition rate, or anaerobic CO2 production
rate, of 300 × 0.0306/45 or ~0.2 mM/min (19, 20), contrasting
with an aerobic CO2 production rate of ~0.8 mM/min. Hence,
PtiCO2 should
certainly increase considerably less at flow greater than zero. These
considerations, together with the present experimental finding of
markedly increased
PtiCO2, beg the
following question: "How common is intestinal ischemic dysoxia in
the presence of flow?" In the present investigation of selective
intestinal flow stagnation, as well as in a previous investigation
employing whole body flow stagnation (15), critical PCO2 commenced approximately
simultaneously with the onset of
O2 supply dependence (Fig. 4),
despite the fact that considerable flow remained. These findings
support the interpretation that ischemic dysoxic intestine was
essentially completely unperfused. To the extent that these two
different models of flow stagnation were an accurate representation of
whole intestinal ischemia, it therefore appears that
PCO2 is sensitive for local
intestinal ischemic dysoxia, at least acutely.
Did dysoxia commence simultaneously in mucosa and serosa?
Most striking was the finding (Fig. 4) that mucosal and serosal
PCO2 increased simultaneously, rather
than in tandem, suggesting that dysoxia in this preparation is a
transmural phenomenon, consistent with the scheme shown in Fig.
1B. We suspect that this finding can
be largely explained by the hydrostatic pressure difference (~25
mmHg) between the aorta and our PCO2
electrodes, which may have caused flow to be distributed
gravitationally in these supine animals, as in a previous investigation
(15) of whole body flow stagnation, where tonometers were similarly
positioned in ventral intestine of supine dogs.
It may seem possible that ischemic dysoxia actually commenced first in
mucosa, that muscularis was adequately perfused, and that the high
serosal PCO2 values represented
diffusion of CO2 from mucosa to
serosa. If so, however, portal PvCO2
should have been similar to serosal
PCO2, particularly at near-zero flow,
which we clearly did not observe. It may also seem possible that the
striking PCO2 values represented
failure of CO2 equilibration
between tissue and blood. However, if
O2 could diffuse into tissue,
which it did (Fig. 2), then CO2
must have been able to diffuse out, although it did not (Fig. 3).
Another potential explanation for increasing
PCO2 is shunting of arterial blood
past tissue. However, a shunt that could effectively dilute
arteriovenous PCO2 difference (~40
Torr during last flow reduction, Fig. 2) to one-ninth of
PaCO2-PtiCO2
difference (~340 Torr during last flow reduction, Fig. 3) not only
seems grossly maladaptive but should also have caused an equivalent effective dilution of venous percent
HbO2. For example, if venous HbO2 were 10% in tissue and if
dilution of venous blood by shunted arterial blood were on the order of
1:9, then venous HbO2 should have
been ~90%, which is not what we observed (Fig. 2).
Why did
PvCO2 r
underestimate PvCO2?
PvCO2 r
predicted by our simulation (12) underestimated observed critical
PtiCO2 in the
absence of La excretion
(Fig. 5). One possible explanation is that intestinal RQ is actually
>0.85, causing PvCO2 to be greater at
any given percent venous HbO2.
Another is that our simulation employed in vitro assumptions, whereas,
in vivo, blood buffers CO2
approximately as well as does blood with one-third actual
[Hb] in vitro, this observation forming the basis for the
standard [BE]WB
([SBE]WB) calculation (18).
Why did
PvCO2 rmax
underestimate critical
PtiCO2?
In our previous investigation, critical
PtiCO2 seemed
accurately predicted by
PvCO2 rmax,
possibly because we used tonometers rather than
CO2 electrodes. Tonometers occupy
much of the intestinal lumen in these comparatively small animals and
may have depleted tissue CO2 in
our previous study. In addition, we administered NaHCO3 to maintain constant
arterial pHp, which should tend to minimize in vivo vs. in vitro differences (12). One reason why PvCO2 rmax
may have underestimated critical
PtiCO2 in the present investigation was that its calculation employed the same assumptions as did the
PvCO2 r
calculation, which similarly underestimated
PvCO2. However, by use of the regression
equation relating
PvCO2 r
and PvCO2 (Fig. 5),
PvCO2 rmax
should have been ~72 Torr, leaving a 20- and 50-Torr
discrepancy between PvCO2 rmax
and critical
PtiCO2 of
serosa and mucosa, respectively. A seemingly very likely
explanation for the discrepancies is countercurrent exchange of
CO2, which should cause
PtiCO2 to be
somewhat greater than PCO2
of large vein. Increasing mucosal perfused capillary density (4)
and increasing mucosal blood transit time (8) during flow stagnation
should promote increasing diffusion of
CO2 from increasingly hypercarbic
venous blood to arterial blood. Although full equilibration of tissue
and large vein PCO2 is often assumed,
more recent evidence contradicts this thinking, at least during
low-flow states. For example, O2
appeared to diffuse in a countercurrent manner from arteriole to venule
in muscle (5). If O2 diffuses from
arteriole to venule, then CO2 must diffuse from venule to arteriole, causing
PtiCO2 to
exceed large venous PCO2 to some
extent. In one investigation, muscle arteriolar
PCO2 appeared fully equilibrated with
muscle PCO2 when the muscle was
selectively superfused with a high
PCO2 solution, and there appeared to
be a step-up in PCO2 from large to
small arteriole (9).
The current investigation provides information from two locations where
countercurrent CO2 exchange should
be minimum (serosa) and maximum (mucosa). Capillary supply of the
muscularis (represented by serosal
PtiCO2) is
arranged similarly to that of skeletal muscle, where countercurrent
exchange is minimized by the parallel arrangement of capillaries about
muscle fibers (2). In serosa, the difference between true in vivo
PvCO2 rmax
(Fig. 6) and critical serosal PCO2
seemed to have been ~20 Torr. In contrast, this difference seemed to
have been ~50 Torr in mucosa, where capillaries are arranged in a
hairpin loop, permitting maximum countercurrent gas exchange (21). The
model of Shepherd and Kiel (21) predicts that countercurrent gas
exchange should be greatest at the onset of
O2 supply dependence.
How reliable were our methods for detecting tissue metabolic acid
production?
Our use of arteriovenous
[SID]p and
arteriovenous
[HCO3]p
represents the first application of this method (13) for detecting
metabolic acid production in vivo. Although it is based directly on the
in vitro [BE]WB model,
it avoids assumptions regarding buffering that may be problematic
during hypercarbia. Because venous blood is hypercarbic relative to
arterial blood, we considered direct measurement of arteriovenous
[SID]p preferable to
estimation of arteriovenous
[BE]WB.
Although intestine appeared not to excrete metabolic acid into venous
effluent, arterial pHp decreased
progressively at constant PaCO2, from
7.39 to 7.28 (Fig. 2), corresponding to a decrease in arterial
[SBE]WB (18) and
arterial plasma [SID] of ~7 mM. However, the
corresponding increase in arterial plasma
[La]p
was only ~2.2 mM, whereas arterial
[K+]p
increased by ~1 mM (Fig. 3), accounting for a decrease in arterial [SID]p by only ~1.2
mM, consistent with the more rapid clearance of plasma
K+ than of plasma
La during exercise (7).
Hence, the major portion of progressive arterial acidification does not
seem attributable to efflux of strong acid from intestine. The main
contributor to the progressive arterial acidification seems to have
been a decrease in arterial [Na+]p
by ~5 mM at constant arterial
[Cl] (Fig. 3).
In any event, our conclusion that intestinal strong acid does not
directly acidify venous effluent is significant mainly in that it
localizes the site of anaerobic intestinal
HCO3 decomposition to cells, as
opposed to venous effluent.
Unifying hypothesis.
Our data support the hypothesis that ischemic dysoxia of whole
intestine is a patchy, as opposed to diffuse, phenomenon and occurs
transmurally, as opposed to spreading from mucosa toward serosa. Stated
differently, our data support the hypothesis that a decrease in
O2 by 50% from the
O2 supply-independent value signifies not that whole intestine is homogeneously half dysoxic, but
rather that half of it is dysoxic. The border zone of tissue that is
ischemic and yet still perfused seems to be a minor fraction of whole
intestine, causing anaerobically produced strong acid to be effectively
trapped in tissue segments without flow and permitting
PtiCO2 to
increase to extraordinary values. Hence, our data suggest that
PtiCO2 can be
used to detect local dysoxia in intestine during flow reduction.
ACKNOWLEDGEMENTS
The authors thank Tracy Ann Gavidia for technical and surgical assistance and Dr. J. W. Severinghaus for considerable assistance in the preparation of the manuscript.
FOOTNOTES
Address for reprint requests: R. Schlichtig, Dept. of Anesthesiology (124), VA Medical Center, University Drive C, Pittsburgh, PA 15240.
Received 4 November 1994; accepted in final form 13 May 1996.
REFERENCES
| 1. | Bass, B. L., E. J. Schweitzer, J. W. Harmon, and J. Kraimer. Intraluminal PCO2: a reliable indicator of intestinal ischemia. J. Surg. Res. 39: 351-350, 1985. |
| 2. | Bennett, R. A. O., R. N. Pittman, and S. M. Sullivan. Capillary spatial pattern and muscle fiber geometry in three hamster striated muscles. Am. J. Physiol. 260 (Heart Circ. Physiol. 29): H579-H585, 1991. |
| 3. | Cain, S. M. Peripheral oxygen uptake and delivery in health and disease. Clin. Chest Med. 4: 139-148, 1983. |
| 4. | Drazenovic, R., R. W. Samsel, M. E. Wylam, C. M. Doerschuk, and P. T. Schumacker. Regulation of perfused capillary density in canine intestinal mucosa during endotoxemia. J. Appl. Physiol. 72: 259-265, 1992. |
| 5. | Ellsworth, M. L., and R. N. Pittman. Arterioles supply oxygen to capillaries by diffusion as well as by convection. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H1240-H1243, 1990. |
| 6. | Figge, J., T. Mydosh, and V. Fencl. Serum proteins and acid-base equilibria: a follow-up. J. Lab. Clin. Med. 120: 713-719, 1992. |
| 7. |
Lindinger, M. I.,
R. S. McKelvie,
and
G. J. F. Heigenhauser.
K+ and Lac distribution in humans during and after highintensity exercise: role in muscle fatigue attenuation?
J. Appl. Physiol.
78:
765-777,
1995.
|
| 8. | Lundgren, O. Physiology of the intestinal circulation. In: Splanchnic Ischemia and Multiple Organ Failure, edited by A. Marston, G. B. Bulkley, R. G. Fiddian-Green, and U. H. Haglund. St. Louis, MO: Mosby, 1989, p. 29-40. |
| 9. | Pittman, R. N., and B. R. Duling. Effects of altered carbon dioxide tension on hemoglobin oxygenation in hamster cheek pouch microvessels. Microvasc. Res. 13: 211-224, 1977. |
| 10. |
Raza, O.,
J. F. Stremple,
and
R. Schlichtig.
Intestinal PCO2 changes in proportion to [L] at zero flow (Abstract).
Am. J. Respir. Crit. Care Med.
151:
A324,
1995.
|
| 11. | Samsel, R. W., and P. T. Schumacker. Determination of the critical O2 delivery from experimental data: sensitivity to error. J. Appl. Physiol. 64: 2074-2082, 1988. |
| 12. | Schlichtig, R. Simulation of maximum respiratory venous PCO2 in vitro. Acta Anaesth. Scand., 39, Suppl. 107: 143-149, 1995. |
| 13. | Schlichtig, R. [Base excess] and [strong ion difference] during O2-CO2 exchange. Adv. Exp. Med. Biol. In press. |
| 14. | Schlichtig, R. [Base excess] vs. [strong ion difference]: which is more helpful? Adv. Exp. Med. Biol. In press. |
| 15. | Schlichtig, R., and S. A. Bowles. Distinguishing between aerobic and anaerobic appearance of dissolved CO2 in intestine during low flow. J. Appl. Physiol. 76: 2443-2451, 1994. |
| 16. | Schlichtig, R., H. A. Klions, D. J. Kramer, and E. M. Nemoto. Hepatic dysoxia commences during O2 supply dependence. J. Appl. Physiol. 72: 1499-1505, 1992. |
| 17. | Schlichtig, R., N. Mehta, and T. J. P. Gayowski. Tissue-arterial PCO2 difference is a better marker of ischemia than intramural pH (pHi) or arterial pH-pHi difference. J. Crit. Care 11: 51-56, 1996. |
| 18. |
Severinghaus, J. W.
Acid-base balance nomograma Boston-Copenhagen detante.
Anesthesiology
45:
539-541,
1976.
|
| 19. | Severinghaus, J. W., M. Stupfel, and A. F. Bradley. Accuracy of blood pH and PCO2 determinations. J. Appl. Physiol. 9: 189, 1956. |
| 20. |
Severinghaus, J. W.,
M. Stupfel,
and
A. F. Bradley.
Variations of serum carbonic acid pK with pH and temperature.
J. Appl. Physiol.
9:
197,
1956.
|
| 21. | Shepherd, A. P., and J. W. Kiel. A model of countercurrent shunting of oxygen in the intestinal villus. Am. J. Physiol. 262 (Heart Circ. Physiol. 31): H1136-H1142, 1992. |
| 22. | Siggaard-Andersen, O. The Acid-Base Status of Blood (4th ed.). Copenhagen: Munksgaard, 1974, p. 80-83. |
| 23. | Siggaard-Andersen, O. The Van Slyke equation. Scand. J. Clin. Lab. Invest. 37, Suppl. 146: 15-20, 1977. |
| 24. | Stewart, P. A. How to Understand Acid-Base: a Quantitative Acid-Base Primer for Biology and Medicine. New York: Elsevier/North-Holland, 1981. Table 7.3. |
| 25. | Stewart, P. A. Modern quantitative acid-base chemistry. Can. J. Physiol. Pharmacol. 61: 1444-1461, 1983. |
| 26. | Windmueller, H. G., and A. E. Spaeth. Identification of ketone bodies and glutamine as the major respiratory fuels in vivo for postabsorptive rat small intestine. J. Biol. Chem. 253: 69-76, 1978. |
| 27. | Zar, J. H. Comparing simple linear regression equations. In: Biostatistical Analysis, edited by J. H. Zar. Englewood Cliffs, NJ: Prentice-Hall, 1984, p. 292-298. |
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