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Vol. 83, Issue 5, 1681-1689, 1997
Departments of Pediatrics and Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Curtis, Scott E., Thomas A. Walker, W. E. Bradley, and
Stephen M. Cain. Raising P50
increases tissue PO2 in canine
skeletal muscle but does not affect critical
O2 extraction ratio.
J. Appl. Physiol. 83(5):
1681-1689, 1997.
Affinity of hemoglobin (Hb) for
O2 determines in part the rate of
O2 diffusion from capillaries to
myocytes by altering capillary PO2.
We hypothesized that a decrease in Hb
O2 affinity (increased
P50) would increase capillary and tissue PO2
(PtiO2) and
improve O2 consumption during
ischemia. To test this hypothesis, blood flow to the pump-perfused left
hindlimb of 18 anesthetized and paralyzed dogs was progressively decreased over 90 min while hindlimb O2 consumption and
O2 delivery (
O2)
and PtiO2 were
measured at the muscle surface. Arterial PO2 was maintained at 150 ± 10 Torr in all dogs. We increased P50
by 12.3 ± 0.9 (SE) Torr in nine dogs with RSR-13, an allosteric modifier of Hb. This decreased arterial
O2 saturation to 90-92% but
increased mean
PtiO2 from 35.5 ± 11.6 to 44.1 ± 15.2 (SD) Torr
(P < 0.05) with no change in
controls (n = 9).
O2 extraction ratio at critical
O2
was 74 ± 2% in controls and 79 ± 1% in RSR-13-treated dogs
(P = not significant).
PtiO2 was
30-40% higher in the RSR-13-treated group at any
O2
above critical but did not differ between groups below critical
O2.
Perfusion heterogeneity and convergence of the dissociation curves
near critical
O2 may have mitigated any effect of increased
P50 on
O2 diffusion. Still, increasing
P50 by 12 Torr with RSR-13
significantly increased PtiO2 at
O2
values above critical.
oxyhemoglobin dissociation curve; oxygen extraction ratio; ischemia; Mehrdraht-Dortmund-Oberfläche electrode; allosteric
modifier; partial pressure of oxygen
INTRODUCTION OXYGEN TRANSPORT from the lungs to the cells of
peripheral tissues depends first on convective transport of blood to a
capillary close enough to the cells where diffusive transport can occur in timely fashion. In skeletal muscle, diffusive
O2 transport depends on the
partial pressure gradient from the interior of red blood cells (RBCs)
to that of myocyte mitochondria, the time available for diffusion (RBC
transit time), the length of the diffusion path, and the conductance of
that path. Conductance, in turn, depends on factors such as
O2 solubility in the plasma and
tissue membranes, RBC spacing, the presence of myoglobin, and
hemoglobin (Hb) off-loading kinetics (for reviews see Refs. 8 and 28).
A high affinity of Hb for O2 may
aid oxygenation of Hb in the lungs but could retard
O2 release in the tissues, with
the reverse situation in the case of lowered affinity.
Patients with chronic hypoxia of various causes are noted to have
increased RBC 2,3-diphosphoglycerate (2,3-DPG), which shifts the
oxyhemoglobin dissociation curve to the right and increases P50 (the
PO2 required to half-saturate Hb).
This action has been interpreted as an aid to tissue oxygenation (20,
21). With severe ischemia, the O2
extraction ratio [O2ER,
i.e., ratio of O2 production
( METHODS
O2) to
O2 delivery
(O2)]
in healthy muscle may reach upward of 80-90% (6). Whether Hb
O2 affinity significantly affects
the efficiency of O2 extraction
has been extensively studied in the laboratory but with conflicting
results (4, 11, 12, 18, 19, 24, 26, 27, 29, 33). This study addresses this question by examining the response of healthy skeletal muscle to
progressively severe ischemia in terms of critical
O2 transport parameters and muscle
surface PO2. We used RSR-13, an allosteric modifier of Hb O2
affinity, at doses expected to increase P50 by 10-12 Torr.
Preliminary studies have shown that this derivative of methylpropionic
acid (1) can increase P50 and
skeletal muscle PO2 in rats (17) and
decrease hypoxia-induced cerebral vasodilation in cats (36). We
hypothesized that RSR-13 administration would raise capillary
PO2
and muscle tissue PO2 (PtiO2)
for a given
O2
and would increase efficiency of
O2 extraction during ischemia.
O2, we paralyzed all dogs
with an intravenous bolus of 30 mg/kg succinylcholine chloride followed by a 0.1 mg/min iv infusion. An Oximetrix Swan-Ganz catheter (Abbott Laboratories, Chicago, IL) was floated into the pulmonary artery via
the right internal jugular vein for continuous measurement of mixed
venous oxyhemoglobin saturation and for blood sampling. A catheter was
also placed in the proximal aorta via cut down of the left common
carotid artery to monitor mean arterial pressure and heart rate and for
blood sampling. Core body temperature was maintained near 37°C with
a heat lamp.
O2 and
CO2 production were continuously
calculated from analysis of inspiratory and expiratory gas volumes and fractions, as previously described (32). Hindlimb venous, systemic mixed venous, and arterial blood-gas tensions and pH were determined in
an acid-base analyzer (ABL-30, Radiometer, Westlake, OH) at 37°C
and later corrected to core temperature at the time of sampling. Blood
O2 content was calculated from the
Hb concentration and O2 saturation
was measured with a CO-oximeter using wavelengths specific for canine
Hb (model IL-282, Instrumentation Laboratory, Lexington, MA). Dissolved
O2 was added by calculation using
the measured PO2 and the solubility
coefficient, 0.0031 ml O2 · dl
1 · Torr
PO21.
Cardiac output and hindlimb
O2 were calculated using
the Fick principle. Systemic and hindlimb vascular resistance were
calculated as arterial pressure divided by the appropriate indexed flow
(assuming a venous pressure of zero) and reported in millimeters of Hg
per milliliter per minute per kilogram.
O2ER was calculated as the ratio
of arteriovenous O2 content
difference and arterial O2
content. At the end of each experiment, all muscle below the tourniquet was dissected from the bone and weighed so that hindlimb hemodynamics and O2 transport could be indexed
to muscle mass [564 ± 116 (SD) g].
PtiO2 data
were collected once every 2 s from each of eight wires throughout the
130-min protocol, yielding 31,200 measurements per muscle. To simplify
presentation and statistical analysis, PtiO2 data are
presented from 2-min periods coincident with the periodic blood
sampling (11 times) throughout the study.
P50 was estimated at the beginning
and end of each study in controls and at minutes 10, 40, 90, and 130 in
RSR-13-treated dogs as follows. Arterial blood was tonometered for 30 min (model IL-237, Instrumentation Laboratory) with three different gas
mixtures estimated to yield O2
saturation values of 30, 50, and 70% with PCO2 of ~40 Torr. Hb saturation,
bloodgas tensions, and pH were then measured as described above,
and PO2 was standardized to pH 7.4 (
logP50/pH 
0.498), as
described by Reeves et al. (23) for dog Hb.
P50 was then estimated from Hill
plots.
Experimental protocol.
Before the start and after the completion of each experiment, adequate
vascular isolation and reactive hyperemia were demonstrated by
occlusion of femoral arterial inflow for 60 s followed by a period of
autoperfusion. This also served to show good placement and
responsiveness of the
PtiO2
electrodes. The hindlimb was then pump perfused at a flow estimated to
equal 100 ml · min1 · kg1
(hindlimb muscle weight). After all measured variables appeared stable,
the protocol was initiated (minute
0). Baseline data were collected from
minute 5 to minute
10. In the RSR-13-treated group (n = 9), RSR-13 (100-120 mg/kg
body wt) was dissolved in 0.45% saline (20 mg/ml) and given
intravenously from minute 10 to
minute 15. Additional RSR-13 was
continuously infused at 27-45
mg · h1 · kg1
iv from minute 10 to the end of the
study (minute 130). Controls (n = 9) received a similar volume of
0.45% saline without drug. Data were again collected 30 min later
(minutes 35-40), and hindlimb flow was then reduced at minute 40 to
90 ml · min1 · kg1.
Flow was further reduced in 10 ml · min1 · kg1
steps every 10 min, with data collected during the last 5 min of each
10-min period. We previously showed that hindlimb
O2, O2ER, and resistance reached a
steady state within 3 min of a change in flow (31). After the final
data collection at a flow of ~10
ml · min1 · kg1,
the hindlimb was reperfused at systemic pressure to document responsiveness of the MDO system. After confirmation of adequate anesthetic depth, the dogs were killed with an intravenous bolus of
concentrated KCl or by exsanguination.
Because of the anticoagulation with heparin, the abdominal, hindlimb,
and neck incisions oozed at variable rates, despite careful hemostasis
during surgery. To maintain a stable hematocrit and systemic
hemodynamics, frequent small volumes of packed RBCs and 6% dextran
were given as needed [total volume 31 ± 12 (SD) ml/kg].
NaHCO3 [0.7 ± 0.8 (SD)
meq/kg] was also given as needed to keep serum
HCO3 within a normal range. The
volume and amount of NaHCO3 given
did not differ between groups.
After each study, regression lines were fitted to the
delivery-independent and delivery-dependent portions of the
O2-O2 curve using a dual-line, least-squares method (25). The intercept of
these two lines defined the critical
O2,
i.e., the delivery at which
O2 decreased with any
further decline in
O2.
The critical O2ER was taken as the
ratio of O2 to
O2
at critical O2.
Statistics.
Significant differences within a group across time and between groups
were identified using a repeatedmeasures analysis of variance with
a protected Fisher's least significant difference test using
commercial software (SAS Institute, Cary, NC).
RESULTS
O2
were somewhat higher in RSR-13-treated dogs at baseline but decreased
by minute 40 to match controls, and
O2 never differed between
groups or across time. RSR-13 treatment was associated with a small but
significant decrease in mean arterial pressure that persisted across
time. Immediately after administration of RSR-13, mixed
venous PO2 increased significantly,
despite the concurrent decrease in cardiac index and
O2.
It then returned to baseline values, whereas mixed
venous PO2 in controls decreased
slightly but significantly with time. Arterial
O2 saturation (SaO2) decreased from 99 to
90-92% with RSR-13 administration and was unchanged
in controls. P50 increased
significantly after RSR-13 treatment (Table
2), and these changes were stable
throughout the ischemia protocol. The average increase in
P50 for all times after RSR-13
administration was 12.3 ± 4.7 (SD) Torr.
P50 in controls did not change
across time.
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O2
tended to be 1-3
ml · min1 · kg1
lower in RSR-13-treated than in control dogs at each time point (Fig.
1B). Hindlimb
O2 (Fig.
2A) and
O2ER (Fig.
2B) are therefore plotted as a
function of
O2
rather than time. There were no differences in baseline
O2 or in the pattern of
O2 decrease as
O2
became critical. Similarly, O2ER
increased at a comparable rate in both groups. Critical values
determined from individual O2o2
plots are listed in Table 3. Critical
O2
and the O2 at
critical
O2
did not differ between groups. Critical
O2ER in control and RSR-13-treated
dogs were also not significantly different
(P = 0.075), and peak
O2ER values were identical (87%). Venous PO2
(PvO2) values at all values of
O2
were significantly higher in the RSR-13-treated group than in controls,
although this difference narrowed below critical
O2
(Fig. 3). Hindlimb perfusion pressure
decreased with decreased
O2
in both groups (Fig.
4A) as
resistance showed little change (Fig.
4B). The acute effects of RSR-13 or
placebo on the above hindlimb parameters at baseline (constant) flow
are shown in Table 4. Hindlimb
O2 decreased with RSR-13 secondary to the decrease in
SaO2 (Table 1), and
O2ER increased. RSR-13
administration was also associated with a significant increase in
PvO2 and a slight increase in
O2. Perfusion pressure and
vascular resistance were not affected.
1 · kg1
every 10 min to a final value of ~10
ml · min1 · kg1.
Values are means ± SE. 
Significantly different from
control, P < 0.05.
O2,
A) and
O2 extraction ratio
[O2/O2
delivery
(O2),
B] as a function of
O2.
Data were grouped along x-axis into
similar
O2
bins. Data from sample 1 (predrug or
preplacebo) are not included. Values are means ± SE.
Significantly different from control,
P < 0.05.
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O2.
Data from sample 1 (predrug or
preplacebo) are not included. Arrow, critical
O2, which was the same in both groups. Values are means ± SE.
Significantly different from control,
P < 0.05.
O2.
Data from sample 1 (predrug or
preplacebo) are not included. Values are means ± SE.
Significantly different from control,
P < 0.05.
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O2 = 5.7 ± 0.4 ml · min1 · kg1,
PtiO2 = 22.0 ± 11.0 (SD) Torr, PvO2 = 19 ± 1 Torr. This occurred very close to derived
critical
O2
(5.7 ± 0.5 ml · min1 · kg1).
Despite a significant decrease in hindlimb
O2
immediately after RSR-13 treatment, mean
PtiO2 increased
from 35.5 ± 11.6 to 41.9 ± 19.0 (SD) Torr and
PvO2 increased from 47 ± 1 to 57 ± 3 (SE) Torr (Fig. 5). Similar to controls,
PtiO2 in
RSR-13-treated dogs did not significantly decrease compared with
baseline until sample 9. Calculated
critical
O2
in the RSR-13-treated group (5.6 ± 0.5 ml · min1 · kg1)
occurred between sample 8 [O2 = 6.4 ± 0.4 ml · min1 · kg1,
PvO2 = 30 ± 3 Torr,
PtiO2 = 31.9 ± 13.5 (SD) Torr] and sample 9 (O2 = 4.7 ± 0.2 ml · min1 · kg1,
PvO2 = 24 ± 2 Torr,
PtiO2 = 22.0 ± 12.1 Torr), so it is not possible to say what critical
PvO2 and
PtiO2
were, but they presumably would have been between the above values.
To compare
PtiO2 between
groups at similar
O2,
the mean values were replotted with
O2
binned into 2.5 ml · min1 · kg1
groups along the x-axis (Fig.
6).
PtiO2 was
6-11 Torr higher in RSR-13-treated dogs at
O2
above critical and was equal to control below critical
O2.
To more closely examine the development of relatively hypoxic
regions of muscle, the percentage of
PtiO2 values
<20 Torr was plotted as a function of
O2
(Fig. 7). Except for one of the
delivery bins above critical
O2,
the percent hits <20 Torr did not differ between groups,
indicating that the higher mean
PtiO2 in
RSR-13-treated dogs was due to an increased number of very
high values rather than the prevention of development of
low-PtiO2
areas.
O2
grouped into 2.5-Torr bins after placebo or RSR-13. Open symbols,
predrug data from sample 1. Arrow,
critical O2
determined from
O2-O2
plots, which did not differ between groups. Values are means ± SE.
Significantly different from control,
P < 0.05.
O2.
Arrow, critical
O2.
Values are means ± SE. Significantly different from control, P < 0.05.
DISCUSSION
Our hypothesis was that a rightward-shifted oxyhemoglobin dissociation
curve would raise mean capillary PO2
and thus increase the available pressure gradient to assist diffusion
of O2 into mitochondria as blood
flow was progressively limited. If the diffusion gradient was a
limiting factor, then the critical O2ER should have been raised in
the treated group. To prove that the rightward-shifted oxyhemoglobin
dissociation curve was effective, we measured muscle surface
PtiO2 at the
test site. We found that RSR-13 produced a stable and predictable shift
in the oxyhemoglobin dissociation curve of 12.3 ± 4.7 (SD) Torr, an
~40% increase. During breathing of 30-35%
O2, this shift caused
SaO2 to decrease to 90-92%, but
there were no physiologically significant adverse systemic effects.
Hindlimb muscle
PtiO2
significantly increased after RSR-13 administration, and at
O2
above critical it was 5-10 Torr higher than in controls. Still,
despite higher values of mean
PtiO2 and
PvO2 with RSR-13 even as
ischemia progressed, critical values of
O2,
O2, and
O2ER did not differ between groups.
For a given O2, Hb
concentration, and blood flow, end-capillary
PO2 is determined by
PaO2 and the Hb dissociation curve (Fig.
8). Hb in this study averaged ~11.9 g/dl
(Table 1). In controls a normal arteriovenous
O2 difference of 5 ml/dl
corresponds to a fall in vascular PO2
from 155 to 38 Torr. Increasing P50 by 12 Torr, as in the
RSR-13-treated group, predicts an end-capillary PO2 of ~53 Torr. Conversely,
increased Hb O2 affinity would
necessitate a lower end-capillary
PO2. Because capillary
PO2 sets the upper end of the
O2 gradient available for
diffusion, such shifts in the dissociation curve have been interpreted
as aiding (increased P50) or
impeding (decreased P50) tissue
oxygenation. Such a view is supported teleologically by the existence
of mechanisms such as the Bohr and temperature effects that decrease Hb
O2 affinity in working muscle and
by subjects with chronic hypoxia, who develop increased levels of RBC
2,3-DPG (20, 21). Still, the experimental evidence that Hb
O2 affinity may ever be the
rate-limiting factor in O2 is
scant.
Previous studies with altered P50 . Several early studies showed impaired O2 extraction in animals extensively transfused with stored blood, which was ascribed to RBC 2,3-DPG depletion and increased Hb O2 affinity (2, 38). However, Ross and Hlastala (24) later showed that the impaired O2 extraction was due to some unidentified effect of blood storage other than 2,3-DPG depletion, because animals with P50 decreased to similar levels by carbamylation of Hb had normal muscle O2 extraction when challenged with hypoxic hypoxia. Also, other studies in which Hb O2 affinity was increased by carbamylation (19, 26, 29) or with use of stroma-free Hb (33) showed no impact on exercise performance during systemic hypoxia (29), on
O2 during systemic hemorrhage
(26), or on critical
O2
of gracilis muscle (19) or liver (33) subjected to ischemia. In each
study, animals with low P50 were
able to lower PvO2 as needed to achieve venous O2 contents comparable to
subjects with normal P50. In some
studies, PvO2 fell to 
10 Torr.
In the few studies in which altering
P50 did appear to impact
O2 (4, 11, 18, 27), the
authors postulated other effects of their intervention that may have
been operative. Still, in one study without obvious confounding factors
(12), maximal O2
(O2 max) of dog
gastrocnemius muscle was 17% less when it was perfused with
low-P50 blood. Similarly, Woodson
et al. (37) saw a 24% decrease in
O2 of dog brains perfused
with carbamylated blood (P50 = 18 Torr) at normal flow rates. The apparent importance of
P50 in these two studies may be
related to the specific circumstance of relatively high
O2 demand in contracting muscle and brain and the short RBC transit time using normal flow (relative to
ischemic hypoxia models). We hoped that RSR-13, which provides a
dose-dependent increase in P50
without other confounding effects, would help clarify the importance of
Hb affinity during O2 supply limitation.
Diffusion limitation vs. heterogeneity.
We found higher values of
PtiO2 and
PvO2 with increased
P50, as predicted by Fig. 8. Yet,
critical O2ER in RSR-13-treated dogs (79.4 ± 1.3) was not statistically higher than in controls (74.0 ± 2.1, P = 0.075), despite
the theoretical benefits to diffusion of increased capillary
PO2 and more rapid
O2 unloading from Hb (9). Wagner
et al. (34) argued that
O2 max is limited by
diffusion constraints as capillary
PO2 falls below some critical value.
This is supported by the work of Hogan et al. (13) and Dodd et al. (7)
in canine gastrocnemius muscle, in which they showed small but
significant differences in
O2 max and
O2ER for ischemic hypoxia compared
with hypoxic hypoxia at identical
O2.
The higher O2ER in ischemic
hypoxia was attributed to the presumably higher capillary
PO2 than in hypoxic hypoxia.
Accordingly, an increased P50 and
capillary PO2 in our study should
have resulted in a higher critical
O2ER.
The above argument ignores the possible role of perfusion heterogeneity
in limitation of O2. Using
published capillary transit time distributions and an assumption of
100% extraction in perfused vessels (no diffusion limitation), Walley
(35) tested a model of perfusion heterogeneity and found that it
accurately predicted the O2ER
values in the literature. In another report from the laboratory of
Walley et al. (14), measured perfusion heterogeneity also accurately
predicted the difference in gut critical
O2ER values between healthy pigs
and an endotoxic group. They concluded that incomplete
O2 extraction can be almost
entirely ascribed to demand-delivery mismatching, with diffusion
limitation playing a relatively small role. Still, their
predicted values in each group exceeded the actual values, and they
speculated that diffusion limitation may well have been responsible for
the remaining inefficiency of extraction not accounted for by
mismatching of perfusion to O2
demand.
If the role of perfusion heterogeneity in determining
O2ER overshadows the role of
diffusion limitation, then altering Hb O2 affinity and capillary
PO2 would also be unlikely to impact
O2ER. That perfusion heterogeneity
does occur in skeletal muscle, even during exercise, is well documented
(16, 22). Also, in ischemic rat hearts, NADH fluorescence studies
showed patchy areas of severe hypoxia immediately adjacent to very well oxygenated areas (15, 30). In studies comparing different forms of
hypoxia (3, 10, 26), large differences in
PvO2 have been found at the same
critical
O2,
which again argues against a primary role for diffusion constraints as
the cause of decreased O2
during limited O2 supply.
Our
PtiO2
and PvO2 data are consistent with the
presence of significant perfusion heterogeneity.
PtiO2
reflects the balance between local
O2
delivery and demand. RSR-13 treatment increased the average
PtiO2
at higher blood flows. However, as ischemia progressed and more areas
were likely underperfused, mean
PtiO2 (and
O2) fell as in controls. The
relatively high PO2 values in the
presumably overperfused areas were apparently unable to maintain
O2 in the distant
hypoxic areas. Although the difference was relatively small
(~5-8 Torr), PvO2 in
RSR-13-treated dogs around critical
O2
was signficantly higher than in controls (Fig. 3). The
PvO2 values are flow weighted and
necessarily overrepresent any areas with better perfusion. This could
explain why PvO2 values below critical
remained higher in RSR-13-treated dogs, despite PtiO2 values
equivalent to controls. Also, decreased Hb affinity raises plasma
PO2 for a given
O2 content and amplifies the
effect of perfusion heterogeneity on end-organ
PvO2.
Hindlimb PvO2 was
4-7 Torr higher than
PtiO2 in the
RSR-13-treated group at the two lowest flows, but
PvO2 was similar to
PtiO2
in controls. It is unlikely that the between-group differences in
PvO2 at low O2
were due to any differences in the degree of heterogeneity, inasmuch as
critical and peak values of O2ER
did not differ between groups.
Convergence of dissociation curves.
Another explanation for our negative results can be inferred from Fig.
8. Although a 12-Torr shift in P50
dictates an ~15-Torr higher PvO2
during resting conditions, venous
O2 saturation values of
20-25% at the onset of supply limitation should be associated with PvO2 values only ~5 Torr higher
because the dissociation curves converge. This is confirmed by the
PvO2 data in Fig. 3. Consequently, there
may be insufficient difference between groups in Hb function at the
point in question, i.e., critical
O2. This is further supported by the fact that
PtiO2
below critical O2
did not differ between groups (Fig. 6).
The impact of small differences in unloading rate and capillary
PO2 on satisfying
O2 demand will also depend on
other factors important to diffusion, such as RBC transit time and
diffusion distance. At one extreme, i.e., stopped flow,
O2 extraction will eventually be
100% regardless of Hb affinity, initial
PO2, or diffusion distance. The
nature of our model, ischemic hypoxia with long transit times and low
O2 demand in paralyzed muscle, would minimize the impact of an increased
P50. Healthy skeletal muscle is
also quite vascular, with potentially short diffusion distances. In one
modeling study, Schumacker and Samsel (28) estimated that varying
P50 up to 18 Torr would have
little impact on critical
O2
during ischemia as long as modest capillary recruitment occurred with
diffusion distance <120 µm.
Conclusions.
RSR-13 is a new compound that can decrease Hb
O2 affinity without other adverse
effects. At the dose used,
P50 was increased ~12 Torr,
which decreased SaO2 to 90-92%
when PaO2 was kept at 150 Torr with
30-35% inspired O2 fraction.
At
O2
above critical, hindlimb muscle
PtiO2 was ~10
Torr higher than in controls. Still, RSR-13-treated dogs did no
better than controls at increasing O2 extraction during
hindlimb ischemia. Perfusion heterogeneity may explain the
lack of effect of RSR-13 on critical extraction values. Another
explanation is that a 12-Torr increase in
P50 represents too small a change
in capillary PO2 in healthy skeletal
muscle at critical
O2
to be detected by our methods because of the convergence of the
dissociation curves. A greater effect may be seen with a larger
increase in P50 or under
conditions more challenging to O2
diffusion, such as with anemia in which rapid RBC transit times
prevail, with increased tissue water (edema), which increases the
resistance to O2 diffusion, with
vascular microembolization and increased diffusion distance, or with
higher metabolic demands such as muscle near
O2 max.
ACKNOWLEDGEMENTS
We appreciate the loan of equipment from Abbott Laboratories, International Laboratories, and Siemens Elema.
FOOTNOTES
Address for reprint requests: S. E. Curtis, Dept. of Pediatrics, Children's Hospital of Alabama, 1600 7th Ave. South, Birmingham, AL 35203.
Received 29 October 1996; accepted in final form 9 July 1997.
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,
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