Vol. 88, Issue 6, 2107-2115, June 2000
Cerebral and intestinal perfusion and metabolism in
normocythemic hyperviscous hypoxic newborn pigs
Marshall
Goldstein,
Virender K.
Rehan,
William
Oh, and
Barbara
S.
Stonestreet
Department of Pediatrics, Women and Infants' Hospital of Rhode
Island, Brown University School of Medicine, Providence, Rhode
Island 02905
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ABSTRACT |
We studied the effects of hypoxia on cerebral cortical
and intestinal perfusion and metabolism in normocythemic hyperviscous newborn pigs. Seven pigs were made hyperviscous by an
injection of cryoprecipitate, increasing viscosity from 5.8 ± 0.9 to
9.0 ± 1.2 (SD) cycles/s. Six normoviscous pigs received
0.9% NaCl. Reducing the inspired O2 decreased the arterial
O2 content (CaO2) from 9.5 ± 1.6 to 3.6 ± 1.3 ml O2/100 ml. Increases
in brain and decreases in gastrointestinal blood flow at the lower
CaO2 values were similar between the
groups. During hypoxia, blood flow to stomach, distal intestinal
mucosa, and large intestines was lower (
50, 23, and
28%, respectively) in the hyperviscous than normoviscous group.
At the lower CaO2 values, cerebral
cortical vascular resistance decreased in both groups and intestinal
vascular resistance increased (+257%) in the hyperviscous but not in
the normoviscous group. During hypoxia, systemic oxygen delivery
decreased, extraction increased, and uptake did not change; cerebral
cortical O2 delivery, extraction, and uptake did not
change; and intestinal O2 delivery decreased, extraction
increased, and uptake did not change in both groups. Our study
demonstrated that 1) during hypoxia, increases in systemic
O2 extraction compensated for decreases in delivery and
systemic uptake did not change; vasodilation sustained cerebral cortical O2 delivery and preserved metabolism; increases in
intestinal oxygen extraction offset decreases in delivery and uptake
was preserved; and 2) nonpolycythemic hyperviscosity did not
have a major influence on cardiovascular or metabolic responses to hypoxia, except for modest effects on intestinal resistance and perfusion to certain gastrointestinal regions. We conclude that, under
normocythemic conditions, a moderate increase in viscosity does not
have a major impact on hemodynamic or metabolic adjustments to hypoxia
in newborn pigs.
brain; gastrointestinal tract; hyperviscosity; polycythemia; metabolism; hemodynamic response
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INTRODUCTION |
HYPOXIA IN UTERO and/or at birth predisposes newborn
infants to increases in blood volume and red blood cell mass (28, 35, 41). Fetal hypoxia stimulates erythropoietin and,
consequently, red blood cell production (35, 38). These
changes can result in polycythemia and hyperviscosity. The increased
red blood cell mass represents a compensatory response to increase
fetal oxygen-carrying capacity and oxygen content. This response
offsets decreases in arterial oxygen tension during fetal hypoxia (35,
38). However, after birth the expanded red blood cell mass may not be
necessary to increase oxygen-carrying capacity. Consequently,
polycythemic hyperviscosity may represent a pathophysiological state.
Polycythemic hyperviscosity has been shown to reduce brain and
gastrointestinal perfusion (12, 18, 26, 32). During polycythemic
hyperviscosity, arterial oxygen content and viscosity are both
increased (18). Each of these factors may contribute to the reductions
in brain and gastrointestinal perfusion (10, 12, 13, 18-20, 26,
32).
During hypoxia, the fetus and neonate compensate by vasodilation with
increased perfusion and shunting of blood toward higher priority
organs, such as the brain, heart, and adrenal glands (7, 8, 25, 31,
37). Regional oxygen metabolism is maintained by increases in perfusion
and/or increases in oxygen extraction (2, 20, 25, 33). Although the
changes in regional perfusion during hypoxia have been studied
extensively in the fetus and newborn animals, there is less information
regarding compensatory mechanisms of regional oxygen metabolism,
particularly in more than one regional vasculature in the same
nonanesthetized young animals (5, 11, 36). During hypoxia, higher
priority organs, such as the brain and heart, preserve oxygen
metabolism by increases in perfusion (20, 31), whereas lower priority organs, such as the gastrointestinal tract, preserve metabolism by
increases in oxygen extraction (8, 25, 36). After prolonged intervals
of severe hypoxia, compensatory mechanisms may not be sufficient to
maintain aerobic oxygen metabolism (8, 31).
It is apparent that polycythemia and hyperviscosity often develop as a
result of fetal hypoxia and that hyperviscosity and hypoxia often occur
in newborn infants. Although both hyperviscosity and hypoxia have
important effects on perfusion and metabolism, information is not
available regarding the effects of isolated hyperviscosity on regional
perfusion and metabolism in hypoxic newborn animals.
Although polycythemic hyperviscosity is more common, ~1% of newborn
infants have been reported to have hyperviscosity without polycythemia
(34, 40). Decreased red blood cell deformability and elevated
concentrations of plasma proteins, such as fibrinogen, account for
hyperviscosity without polycythemia (3, 14). In this form of
hyperviscosity, arterial oxygen content is not increased.
In the present study, we examined the effects of nonpolycythemic
hyperviscosity on systemic and regional perfusion and metabolism in
hypoxic newborn pigs. We hypothesized that hyperviscosity limits compensatory responses to graded hypoxia in newborn pigs. To study this, we examined perfusion and metabolism in a higher priority organ,
the brain, and a lower priority organ, the gastrointestinal tract, to
evaluate regional responses to hypoxia in hyperviscous newborn pigs. We
produced isolated hyperviscosity by infusing concentrated
cryoprecipitate into newborn pigs and then exposed them to graded
hypoxia. We selected levels of hypoxia that simulated moderate and
severe reductions in systemic oxygenation commonly encountered in human
newborn infants. In addition, we examined the effects of hyperviscosity
and hypoxia on cerebral cortical glucose, lactate, and
-hydroxybutyrate metabolism to determine the adequacy of
compensatory cerebral cortical metabolic responses to these conditions.
Lactate and -hydroxybutyrate were evaluated because these
alternative substrates may be used by the brain under anaerobic conditions.
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MATERIALS AND METHODS |
Animals.
The study was approved by the Institutional Animal Care and Use
Committees of Women and Infants' Hospital of Rhode Island and Rhode
Island Hospital. Thirteen 2- to 4-day-old pigs were obtained from a
local hog breeder. The pigs weighed 1.3 ± 0.19 (SD) kg at the time of
the experiments.
Animal preparation.
Eighteen hours before the study, each pig received 70% nitrous oxide
and 30% oxygen administered via a head hood and 0.1% lidocaine local
anesthesia for surgical placement of catheters. Polyvinyl catheters
were placed under sterile conditions into 1) the left ventricle
via the left carotid artery for radionuclide-labeled microsphere
injection, 2) the midthoracic aorta via the right femoral
artery for radionuclide-labeled microsphere reference sample withdrawal
and arterial blood sampling, 3) the abdominal aorta via the
left femoral artery for blood pressure and heart rate recording,
4) the right atrium via a femoral vein for cryoprecipitate or
0.9% sodium chloride administration and blood sampling, 5) the
superior sagittal sinus for cerebral cortical efferent blood sampling,
and 6) the portal vein via a common umbilical vein for venous
oxygen content values. Previous work from our laboratory has shown that
use of the carotid artery to catheterize the left ventricle for
radionuclide-labeled microsphere administration does not alter brain
blood flow during control conditions, asphyxia or hypotension in
newborn pigs (22).
Postoperatively, the pigs received parenteral ampicillin (100 mg/kg),
kanamycin (5 mg/kg), and 5% dextrose in water (10 ml/kg). Catheters were filled with a heparin solution (100 U/ml) and secured to
the flank. After recovery from anesthesia, the pigs were gavage fed (30 ml/kg) with an artificial pig milk preparation (Land-O-Lakes, Minneapolis, MN) every 3 h, until 8 h before the study. The pigs remained warm and were freely mobile during the overnight recovery and
throughout the study.
Study groups.
The newborn pigs were randomly assigned to hyperviscous (n = 7)
and normoviscous (n = 6) groups.
Experimental protocol.
On the morning of study, the pigs were weighed, and a rectal
temperature probe was placed. The pigs were then placed in a darkened
study chamber with ports for the catheters, temperature probe, and
tubing to administer the study gas mixture. Although the pigs were
allowed to sleep or remain awake during the studies, the majority of
the pigs were awake during the studies.
Each study measurement consisted of arterial pH; blood gases;
hematocrit; rectal temperature; fibrinogen concentration; whole blood
viscosity; mean arterial, superior sagittal sinus, portal, and central
venous pressures; arterial, superior sagittal sinus, portal and right
atrial oxygen content values; and arterial and sagittal sinus plasma
glucose, whole blood lactate, and -hydroxybutyrate concentrations. Total and regional brain and
gastrointestinal blood flow and cardiac output were measured with
radionuclide-labeled microspheres.
After baseline determinations (study time = 0 min), the group
designated hyperviscous was given 5 ml/kg of concentrated
cryoprecipitate intravenously over 10 min and the normoviscous group an
equal volume of 0.9% sodium chloride, which was the vehicle for the cryoprecipitate. Repeat measurements were made 180 min after
cryoprecipitate or 0.9% sodium chloride administration. Thereafter,
graded hypoxia was induced by allowing the pig to breathe a variable
oxygen concentration with a mixture of 5% carbon dioxide and
85-87% nitrogen to achieve a fractional inspired oxygen
concentration of 8-10%. The gas mixture was
adjusted to maintain normocapnia during graded hypoxia. A third
measurement was obtained after exposure to hypoxia for 20 min, or 200 min after cryoprecipitate or 0.9% sodium chloride had been
administered, and a fourth or final measurement after 40 min of
exposure to hypoxia, or 220 min after cryoprecipitate or 0.9% sodium
chloride had been given. Blood losses due to study sampling were
replaced with packed red blood cells from another piglet. At the end of
the study, the piglet was killed with an intravenous injection of
thiopental sodium (200 mg/kg; Animal Health, St. Joseph, MO).
At necropsy, catheter placement was confirmed, and the brain and
gastrointestinal tract were removed and weighed. The brain and
gastrointestinal tract were fixed in 10% Formalin. After fixation, the
brain was divided into the cerebral cortex, cerebellum, and brain stem.
The gastrointestinal tract was divided into the stomach and small and
large intestines. The small intestines were further divided into
proximal and distal mucosa-submucosa and muscularis-serosa as
previously described (4, 27).
Analytic methods.
Concentrated cryoprecipitate was prepared 24 h before study. A total of
5 units of cryoprecipitate were pooled and centrifuged at 5,000 g for 5 min to increase the fibrinogen concentration (13). The
cryoprecipitate was frozen at 18°C and then thawed to
4°C on the morning of study. For the purpose of our study, hyperviscosity was defined as whole blood viscosity values 
2 SD above
the mean in newborn pigs (13, 34, 40).
Total and regional brain and gastrointestinal blow flow and cardiac
output were determined as previously described (2, 17, 21, 22, 24).
Microspheres (15 ± 5 µm in diameter) labeled with one of the six
randomly assigned radionuclides (46Sc, S1Cr,
57Co, 95Nb, 103Ru, or
113Sn; New England Nuclear, Boston, MA) were administered.
Approximately 9 × 105 microspheres, suspended and
continuously agitated in 2 ml of 10% dextran and 0.01% Tween 80, were
injected over 45 s via the left ventricle catheter, which was then
flushed with 2 ml of 0.9% sodium chloride. Reference blood samples
were collected for 2 min from the thoracic aorta beginning 15 s before
microsphere injection at the rate of 1.03 ml/min with a
constant-withdrawal pump (model 940, Harvard Apparatus, Millis, MA).
Previous work in our laboratory has demonstrated the validity of the
aortic reference-sample catheter for determination of brain blood flow in newborn pigs (21).
Sections of brain, the remaining organs, and carcass were incinerated
separately at 275°F for 96 h, and the carbonized tissue was packed
in glass vials to a height of 1 cm. Fixed samples of mucosa-submucosa
and muscularis-serosa were prepared as previously described (4, 27).
Radioactivity of blood, carbonized, and fixed tissue samples was
determined in a gamma well counter (sample changer model 1185, Tracor
Analytic, Elk Grove Village, IL) interfaced to a pulse-height analyzer
(model 4203, Canberra Industries, Meriden, CT). Blood flow was
determined by using the least squares method of analysis with the
following equation: blood flow = [(tissue counts/min)/(reference
blood counts/min)] × (rate of withdrawal of reference
blood) (17). All tissue samples contained sufficient microspheres to
ensure blood flow accuracy to within ±5% (17). The absence of ductus
arteriosus shunting was confirmed by documenting that pulmonary blood
flow was equivalent to bronchial blood flow, e.g., 1-2% of the
cardiac output.
Arterial blood gases and pH were measured on a Corning 175 blood-gas
analyzer (Corning Scientific, Medford, MA) and corrected for body
temperature. The rectal temperature of the pig was measured at each
study determination. Oxygen content values were measured in duplicate
on a Lex-O2-Con (Lexington Instruments, Waltham, MA).
Hematocrits were measured by a microhematocrit method. Heart rate and
mean arterial blood pressure were continuously monitored by using a
Hewlett-Packard transducer (model 1280, Lexington, MA) and recorded on
a Hewlett-Packard Polygraph (model 7754 A series, Waltham, MA). Heart
rate was calculated from the arterial blood pressure tracing and
represented a mean of nine determinations at each study time.
Plasma glucose concentrations were measured with a glucose analyzer
(model 23A, Yellow Springs Instruments, Yellow Springs, OH). Plasma
glucose concentrations were converted to whole blood concentrations by
using individual hematocrit values. Whole blood lactate and
-hydroxybutyrate were measured in duplicate by enzymatic analysis as
previously described (16, 39). Plasma fibrinogen concentration was
determined in duplicate by a coagulation assay (Ortho Diagnostic
Systems, Raritan, NJ) adapted from the method of Clauss (6). Whole
blood viscosity was determined on duplicate 0.5-ml heparinized samples
at a shear rate of 11.25/s on a Wells-Brookfield microviscometer LVT-CP
at a constant 37°C temperature (Brookfield Engineering
Laboratories, Stoughton, MA). Samples were analyzed immediately to minimize red blood cell settling.
Calculations and statistical analysis.
Cardiac output was calculated by summing blood flow to the
organs and carcass. Vascular resistance
(mmHg · ml
1 · 100 g · min or
mmHg · ml1 · kg · min)
was calculated as the mean arterial minus venous pressures (e.g.,
sagittal sinus, portal venous, or right atrial) divided by blood flow
to the appropriate region (e.g., cerebrum, intestines, or whole
body). Oxygen delivery (ml
O2 · 100 g1 · min1 or ml
O2 · kg1 · min1)
was calculated as arterial oxygen content values times blood flow.
Oxygen uptake (ml O2 · 100 g1 · min1 or ml
O2 · kg1 · min1)
was calculated as arterial minus the appropriate venous oxygen content
value (e.g., sagittal sinus, portal venous, or right atrial) times
blood flow to the appropriate region (e.g., cerebral cortex, gastrointestinal tract, or whole body) (2, 24, 36). Oxygen extraction
was calculated as oxygen uptake divided by delivery. Portal venous
oxygen content has been shown to accurately represent mesenteric venous
oxygen content values (27). Similar formulas were used for cerebral
cortical glucose metabolism (24). Although the above equations are most
accurately applied to substrates with unidirectional flux such as
oxygen, the same equations were used to quantify cerebral cortical
lactate and -hydroxybutyrate flux (2).
All results are expressed as means ± SD. Serial measurements were
compared between the two groups by two-factor ANOVA for repeated
measures. If a significant difference was found by ANOVA, the two
groups were further compared by the Bonferroni-corrected two-group
Student's t-test. To further describe and enhance
statistically significant findings, additional analyses were performed.
Changes within each group were analyzed separately by using ANOVA for repeated measures. If significant differences were found by ANOVA, Newman-Keuls post hoc testing was used to detect significant
differences among study periods. ANOVAs for repeated measures were also
performed on brain, gastrointestinal, and systemic perfusion and oxygen metabolism within each group. When a significant difference was detected, pairwise regional comparisons were made by ANOVA. P < 0.05 was considered statistically significant.
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RESULTS |
After induction of graded hypoxia, the decreases in arterial oxygen
content and tension were similar between the study groups (Table
1). The arterial carbon
dioxide tension remained within the normocapnic range in both groups,
despite small reductions in carbon dioxide tension during
hypoxia. Arterial pH decreased slightly at the end of the
study in the hyperviscous group. Hematocrit values did not change in
either group. After cryoprecipitate administration, fibrinogen
concentration increased by 1.4-fold and whole blood viscosity by
1.6-fold, and they remained elevated until end of the study.
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Table 1.
Arterial oxygen content, blood-gas, pH, hematocrit, fibrinogen
concentration, and viscosity values by study group
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Baseline cardiac output and total brain and gastrointestinal tract
blood flow were similar between the groups (Fig.
1, Table 2).
During hypoxia, cardiac output did not increase significantly (Table
2). The increases in brain and decreases in gastrointestinal blood flow
at the lower arterial oxygen content values were similar between the
groups (Fig. 1). The increases in blood flow to the cerebrum,
cerebellum, and brain stem also did not differ between groups (Table
3). Blood flow to the stomach was lower in
the hyperviscous than in the normoviscous group during the final
hypoxic measurement. Blood flow to the proximal intestinal mucosa
decreased in both groups, and that to the distal intestinal mucosa
decreased in the hyperviscous but not in the normoviscous group and was lower in the hyperviscous than normoviscous group at the final hypoxic
measurement. Blood flow to the proximal and distal muscularis did not
change during the study. The patterns of change in the proximal and
distal mucosa differed (ANOVA: interactions, P < 0.05) from
those of the proximal and distal muscularis over the study periods in
both groups. Blood flow to the large intestines decreased
in the hyperviscous but not in the normoviscous group and was lower in
the hyperviscous than the normoviscous group during the final hypoxic
determination.
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Fig. 1.
Blood flow to total brain (A) and intestinal tract (B)
plotted against study time at baseline (0 min) and at 180, 200, and 220 min in hyperviscous (n = 7) and normoviscous (n = 6)
groups. Values are means ± SD. * P < 0.05 vs. baseline.
+ P < 0.05 vs. 180 min.  ANOVA:
interactions, P < 0.05 vs. brain blood flow in
hyperviscous group over time. § ANOVA: interactions, P < 0.05 vs. brain blood flow in normoviscous group over
time.
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Table 2.
Mean arterial blood pressure, heart rate, cardiac output, and total
peripheral vascular resistance values by study group
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Total peripheral vascular resistance did not change in either group
during hypoxia (Table 2). Cerebral cortical vascular resistance
decreased at the lower arterial oxygen content values in both groups,
and intestinal resistance increased in the hyperviscous but not in the
normoviscous group (Fig. 2).
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Fig. 2.
Cerebral cortical (A) and intestinal (B) vascular
resistance values plotted against study time at baseline (0 min) and at
180, 200, and 220 min in hyperviscous (n = 7) and normoviscous
(n = 6) groups. Values are means ± SD.
* P < 0.05 vs. baseline. + P < 0.05 vs. 180 min.  P < 0.05 vs. 200 min.
ANOVA: interactions, P < 0.05 vs. cerebral cortical
vascular resistance in hyperviscous group over time. § ANOVA:
interactions, P < 0.05 vs. cerebral cortical vascular
resistance in normoviscous group over time.
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Systemic oxygen delivery decreased, extraction increased, and uptake
did not change in both groups at the lower arterial oxygen content
values (Table 4). Cerebral cortical oxygen
delivery did not change in either group, and intestinal delivery
decreased in both groups at the lower arterial oxygen content values
(Fig. 3). The patterns of change in
cerebral cortical oxygen delivery differed from intestinal delivery in
both groups (ANOVA: interactions, P < 0.05). Cerebral
cortical oxygen extraction did not change during hypoxia in either
group, and intestinal extraction increased in both groups (Fig.
4). The pattern of change in cerebral
cortical oxygen extraction differed from intestinal extraction in both groups (ANOVA: interactions, P < 0.05). Cerebral cortical and intestinal oxygen uptake did not change at the lower arterial oxygen
content values in either group (Fig. 5).
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Fig. 3.
Cerebral cortical (A) and intestinal (B) oxygen
delivery plotted against study time at baseline (0 min) and at 180, 200, and 220 min in hyperviscous (n = 7) and normoviscous
(n = 6) groups. Values are means ± SD. * P < 0.05 vs. baseline. + P < 0.05 vs. 180 min.
ANOVA: interactions, P < 0.05 vs. cerebral cortical
oxygen delivery in hyperviscous group over time. § ANOVA:
interactions, P < 0.05 vs. cerebral cortical oxygen delivery
in normoviscous group over time.
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Fig. 4.
Cerebral cortical (A) and intestinal (B) oxygen
extraction plotted against study time at baseline (0 min) and at 180, 200, and 220 min in hyperviscous (n = 7) and normoviscous
(n = 6) groups. Values are means ± SD. * P < 0.05 vs. baseline. + P < 0.05 vs. 180 min.
ANOVA: interactions, P < 0.05 vs. cerebral cortical
oxygen extraction in hyperviscous group over time. § ANOVA:
interactions, P < 0.05 vs. cerebral cortical oxygen
extraction in normoviscous group over time.
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Fig. 5.
Cerebral cortical (A) and intestinal (B) oxygen uptake
plotted against study time at baseline (0 min) and at 180, 200, and 220 min in hyperviscous (n = 7) and normoviscous (n = 6)
groups. Values are mean ± SD.
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Glucose delivery to the cerebral cortex increased and extraction
decreased during the final hypoxic measurement in both groups (Table
5). Glucose uptake of the cerebrum
increased during the first hypoxic period in the hyperviscous group.
Cerebral lactate delivery increased in both groups during the final
hypoxic measurement, and extraction and flux did not change in either
group. -Hydroxybutyrate delivery increased in both groups during the
final study period, and extraction and flux did not change in either
group.
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DISCUSSION |
In this study, we examined the effects of nonpolycythemic
hyperviscosity on systemic and regional cardiovascular and metabolic responses in 2- to 4-day-old nonanesthetized hypoxic pigs. Our study
demonstrated the following: 1) during graded hypoxia, in awake
spontaneously breathing pigs, increases in systemic oxygen extraction
compensated for decreases in oxygen delivery such that systemic oxygen
uptake was maintained; cerebral cortical oxygen delivery was maintained
by vasodilation such that oxygen metabolism was preserved; increases in
intestinal oxygen extraction preserved intestinal oxygen uptake despite
vasoconstriction-related decreased oxygen delivery; and 2)
nonpolycythemic hyperviscosity in the range that we examined did not
appear to have a major influence on cardiovascular or metabolic
responses to hypoxia except for physiologically relevant increases in
gastrointestinal resistance and deceases in regional perfusion to
certain gastrointestinal areas, such as the stomach, distal intestinal
mucosa, and large intestines.
Although many studies have examined the effects of hypoxic hypoxia on
regional perfusion and metabolism of individual regional vasculatures,
limited information is available regarding the effects of hypoxia on
the regional perfusion and metabolism of multiple vascular beds within
the same young animal (5, 11, 36). We examined systemic, cerebral
cortical, and gastrointestinal circulation and metabolism
simultaneously in the same nonanesthetized spontaneously breathing
hypoxic newborn subject. The normoviscous group was enrolled to serve
as a comparison for the hyperviscous group and to confirm previously
reported cerebral cortical and gastrointestinal circulatory and
metabolic responses to hypoxia. In our awake newborn pigs, hypoxic
hypoxia resulted in 59 and 70% reductions in arterial oxygen tension
and in 45 and 62% reductions in arterial oxygen content 20 and 40 min
after the onset of hypoxia. These levels of hypoxia were selected to
simulate those commonly encountered in hypoxic human newborn infants
experiencing moderate and severe reductions in systemic oxygenation. It
was important to study nonanesthetized pigs because anesthetics are
known to influence cardiovascular regulation and microcirculatory
function and to account for variability in cardiovascular studies (1, 9, 23). The lack of effect of hypoxia on heart rate and mean arterial
blood pressure in our newborn pigs was most likely because the pigs
were not anesthetized.
The systemic and regional hemodynamic and metabolic responses to
hypoxia were similar to those of previous reports (7, 20, 25, 31).
Briefly, hypoxia was associated with the expected increases in
perfusion to all brain regions and decreases in perfusion to the total
gastrointestinal tract and the proximal intestinal mucosa. Similar to
the previous findings, the increase in regional brain perfusion was
greatest after exposure to the lower levels of systemic oxygenation,
and the decrease in intestinal perfusion was only apparent at the lower
levels of oxygenation (8, 20, 36, 37). The metabolic adjustments were
also consistent with previous reports (20, 25, 31, 36, 37). They
included maintenance of systemic oxygen uptake by increases in
extraction; maintenance of cerebral cortical oxygen uptake because
oxygen delivery was preserved by vasodilation; and maintenance of
intestinal oxygen uptake by increases in oxygen extraction, which
offset decreases in delivery resulting from decreases in arterial
oxygen content and blood flow. During the more severe hypoxic exposure, cerebral cortical delivery of glucose increased based on increased perfusion. Glucose uptake was maintained by increases in delivery. Cerebral cortical lactate delivery increased as a function of increased
substrate concentration and perfusion, and lactate flux did not change.
The lack of substantial changes in cerebral metabolism for oxygen,
glucose, and alternative substrates supports the contention that
aerobic cerebral cortical metabolism can be maintained, even when
systemic oxygenation is reduced by as much as 70%.
Similar to a previous report from our laboratory, cryoprecipitate
administration resulted in a 38% increase in fibrinogen concentration
(13). Fibrinogen is an anisometric plasma protein that increases whole
blood viscosity at low shear rates by promoting red blood cell
aggregation. In this and our previous report, we used a shear rate of
11.25/s, because in vitro viscosity has been shown to increase as
fibrinogen concentrations increase at this shear rate. This shear rate
also approximates those of small arterioles and venules (29). The 55%
increase in in vitro whole blood viscosity in our present study was
similar to our previous report and approximates that observed in human
newborns as hematocrit values increase from 40% to 55% (15). The
objective of our study was to isolate the effects of hyperviscosity
without increasing red blood cell mass. We achieved a moderate increase
in whole blood viscosity without concomitant changes in hematocrit or
normoxic arterial content values. The sustained elevation in in vitro
whole blood viscosity allowed comparisons of hemodynamic and metabolic
responses to hypoxia in hyperviscous and normoviscous normocythemic
newborn subjects.
Polycythemic hyperviscosity has been shown to result in reduced cardiac
output and brain and gastrointestinal perfusion (12, 18, 26, 32).
During polycythemic hyperviscosity, reductions in perfusion to the
brain are a result of the independent effects of increased red blood
cell mass and consequently arterial oxygen content and of increases in
viscosity (18, 20, 32). In general, the higher the viscosity the
greater the reduction in perfusion. In our study, the moderate increase
in whole blood viscosity did not appear to have a major influence on
systemic or regional circulatory or metabolic responses to moderate or
severe hypoxia. With regard to the hemodynamic adaptions to hypoxia,
the increase in total brain blood flow and decrease in gastrointestinal
blood flow were similar in the hyperviscous and normoviscous groups.
However, regional perfusion to the stomach, distal intestinal mucosa,
and large intestines was lower in the hyperviscous than in the
normoviscous group during exposure to severe hypoxia. These findings
suggest that, even during moderate hyperviscosity, there are minor, but physiologically relevant, abnormalities in the regional
gastrointestinal response to hypoxia. We cannot rule out the
possibility that these changes might have been accentuated if the
increase in viscosity had been greater or the exposure to hypoxia
longer or more severe.
The systemic and regional metabolic adjustments of the brain and
gastrointestinal tract to hypoxia were similar between the groups.
Similarly, the metabolic adjustments of the cerebral cortex to glucose,
lactate, and -hydroxybutyrate metabolism during hypoxia did not
differ between the groups.
Human newborn infants are often simultaneously exposed to
hyperviscosity and hypoxia. Interactions between these two conditions has been suggested but not previously explored (30). On the basis of
our findings, it is reassuring that a moderate increase in viscosity
does not appear to have major effects on hemodynamic and metabolic
adjustments to hypoxia in newborn subjects. However, newborn pigs have
lower hematocrit values at birth than do human newborns. Therefore, it
remains likely that, for equivalent changes in viscosity, human infants
might exhibit more severe pathophysiological changes than those we
observed in our newborn pigs.
In summary, systemic and regional brain and gastrointestinal
compensations to moderate and severe hypoxia are largely intact in
moderately hyperviscous normocythemic newborn pigs. However, we cannot
exclude the possibility that a more severe change in viscosity might
have impaired the adjustments to hypoxia.
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FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: B. S. Stonestreet, Women & Infants' Hospital of Rhode Island, 101 Dudley
St., Providence, RI 02905-2499 (E-mail:
bstonest{at}wihri.org).
Received 19 January 2000; accepted in final form 18 February 2000.
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