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J Appl Physiol 85: 874-882, 1998;
8750-7587/98 $5.00
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Vol. 85, Issue 3, 874-882, September 1998

Reductions in cardiac output in hypoxic young pigs: systemic and regional perfusion and oxygen metabolism

Barbara S. Stonestreet, Sylvia Santos Ocampo, and William Oh

Brown University School of Medicine, Providence 02912; and Department of Pediatrics, Women & Infants' Hospital of Rhode Island, Providence, Rhode Island 02905

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

We tested the hypotheses that, in hypoxic young pigs, reductions in cardiac output restrict systemic oxygen transport to a greater extent than does hypoxia alone and that compensatory responses to this restriction are more effective in higher than in lower priority vasculatures. To study this, 10- to 14-day-old instrumented awake hypoxic (arterial oxygen tension = 39 Torr) pigs were exposed to reduced venous return by inflation of a right atrial balloon-tipped catheter. Blood flow was measured with radionuclide-labeled microspheres, and oxygen metabolism was determined with arterial and venous oxygen contents from appropriate vessels. Hypoxia resulted in a reduction in oxygen tension; increases in cardiac output and perfusion to brain (72% over baseline), heart, adrenal glands, and liver without reductions to other organs except for the spleen; reductions in systemic and intestinal oxygen delivery; and increases in systemic and intestinal oxygen extraction without changes in systemic, cerebral, or intestinal oxygen uptake. During hypoxia, decreasing venous return was associated with increases in arterial lactic acid concentration and central venous pressure; attenuation of the hypoxia-related increase in cardiac output; sustained increases in brain (72% over baseline) and heart perfusion; reductions in lung (bronchial artery), pancreatic, renal, splenic, and intestinal (-50% below baseline) perfusion; decreases in systemic and gastrointestinal oxygen delivery; sustained increases in systemic and intestinal oxygen extraction; and decreases in intestinal oxygen uptake, without changes in cerebral oxygen metabolism. We conclude that when venous return to the heart is reduced in hypoxic young pigs, the hypoxia-related increase in cardiac output was attenuated and the relative reduction in cardiac output was associated with preserved cerebral oxygen uptake and compromised intestinal oxygen uptake. Regional responses to hypoxia combined with relative reductions in cardiac output differ from that of hypoxia alone, with the greatest effects on lower priority organs such as the gastrointestinal tract.

brain; gastrointestinal tract; hypoxia; lactate; oxygen metabolism

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

HYPOXIA AND HEMODYNAMIC ABNORMALITIES, including reductions in cardiac output, are observed in infants with cardiopulmonary disorders, such as persistent pulmonary hypertension, respiratory distress syndrome, meconium aspiration syndrome, diaphragmatic hernia, pulmonary hypoplasia, and congenital cardiac abnormalities. These abnormalities may be accentuated during therapeutic interventions, which may further complicate the hemodynamic stability of sick neonates. During high-frequency ventilation, elevated mean airway pressures can potentially impede venous return to the heart, lowering cardiac output in hypoxic subjects (1). When pulmonary compliance improves, this phenomenon may be accentuated. Reductions in cardiac output may account for the unexplained metabolic acidosis, which has been reported during high-frequency ventilation (1).

In adult and young animals, when systemic oxygen availability is limited by hypoxia, the point at which whole body oxygen consumption begins to decrease is termed the "critical level" of oxygen transport, after which tissue hypoxia, acidemia, and systemic lactic acidosis develop (5, 28). Although many studies have examined the effects of hypoxia on whole body oxygen consumption, few have simultaneously examined whole body and regional organ perfusion and oxygen metabolism, particularly in unanesthetized young subjects (3, 19).

It is well known that hypoxia is associated with a redistribution of cardiac output, in which higher priority organs, such as the brain, heart, and adrenal glands, receive a larger proportion of cardiac output than do lower priority organs, such as the gastrointestinal tract, kidneys, and muscle (4, 6). We and others also have observed variations in regional metabolic responses to decreases in systemic oxygen supply in newborn and young animals (2, 13). Regional vascular beds are known to vary in their compensatory responses to decreased oxygen delivery, e.g., in some, blood flow is increased, whereas, in others, oxygen extraction is augmented (26). During hypoxia, cerebral oxygen uptake is preserved because oxygen transport is maintained by cerebral hyperperfusion until exposure to severe hypoxia is prolonged (24). Hypoxia may also render the cerebral circulation pressure passive if systemic hypotension develops (32). In contrast, in lower priority organs, such as the gastrointestinal tract, oxygen uptake is preserved primarily by increases in oxygen extraction (15, 30).

A simple technique has been reported to examine the effects of selectively lowering cardiac output by impeding venous return to the heart in intact awake large animals (10). This technique has been used mainly to examine the effects of reduced cardiac output on systemic oxygen transport and lactate production (10). When systemic oxygen transport is reduced by moderate decreases in cardiac output, whole body oxygen extraction increases and oxygen consumption is maintained over a relatively wide range of changes in cardiac output (11). Similar to changes described above for hypoxia, when a critical level for systemic oxygen transport is reached, increases in extraction no longer compensate for decreased delivery, and consequently oxygen consumption decreases (11). Although this technique has been extensively used to determine changes in whole body oxygen metabolism, there is less information regarding the effects of reductions in cardiac output on regional oxygen metabolism, particularly in young unsedated subjects (13). Moreover, in adult rabbits, there is strong evidence to suggest that the response of oxygen consumption to the same total oxygen transport is dependent on whether there is a high- or low-flow state (16). Thus, taken together, these findings suggest that systemic and regional responses to hypoxia alone most likely differ from responses that occur when a hypoxic subject also experiences reductions in cardiac output.

Given the above considerations, hypoxia and selective reductions in cardiac output each independently compromise systemic oxygen transport, thereby potentially resulting in regional tissue hypoxia. Reductions in cardiac output in hypoxic subjects most likely affect regional oxygen metabolism to a greater extent than does hypoxia alone. Therefore, in this study, we tested the hypotheses that, in hypoxic young pigs, reductions in cardiac output restrict systemic oxygen transport to a greater extent than does hypoxia alone and that compensatory responses to this restriction are more effective in higher than in lower priority vasculatures. To test these hypotheses, we examined systemic and regional oxygen metabolism for vascular beds representing a high-priority organ, the brain, and a lower priority organ, the gastrointestinal tract. In addition, systemic lactate concentrations, regional blood flow, distribution of cardiac output, and cerebral glucose and lactate metabolism were measured to determine whether hypoxic compensatory responses were altered when cardiac output is reduced.

    MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Animals. This study was approved by the Institutional Animal Care and Use Committees of Women and Infants' Hospital of Rhode Island and Rhode Island Hospital. Eleven 10- to 14-day-old pigs were obtained from a local hog breeder. The pigs weighed 2.97 ± 1.15 (SE) kg.

Surgical preparation. Approximately 4 h before the study, each piglet received 70% nitrous oxide and 30% oxygen, and 1.0% lidocaine anesthesia for surgical placement of catheters. Polyvinyl catheters were inserted into the left ventricle via a brachial artery for radionuclide-labeled microsphere injection, into the thoracic aorta via a femoral artery for radionuclide-labeled microsphere reference sample withdrawal, into the upper abdominal aorta via a femoral artery for pressure monitoring and blood sampling, into the portal vein via the umbilical vein for pressure monitoring and blood sampling, and into the superior sagittal sinus for pressure monitoring and blood sampling. A balloon-tipped catheter was placed into the right atrium via the jugular vein for blood sampling and pressure monitoring and to reduce cardiac output as previously described in lambs (10). Placement of the left ventricular and right atrial catheters was confirmed by pressure tracings and inspection at autopsy. At completion of surgery, each pig received a 10 ml/kg infusion of 10% dextrose solution to prevent hypoglycemia during the study, and 100 mg/kg ampicillin and 5 mg/kg kanamycin were given intravenously. A 2% xylocaine gel was applied on all wounds. Before commencement of the study, each piglet was allowed a 2-h recovery period.

Experimental protocol. Each awake spontaneously breathing piglet was placed in a study chamber that contained side ports for the catheters, temperature probe, and tubing for supplemental oxygen and carbon dioxide. The deep rectal temperature was maintained between 38 and 39°C.

After recovery from surgery, the unanesthetized spontaneously breathing pigs were studied while they were resting quietly in the study chamber. Each study consisted of a series of four determinations. Thirty-five minutes before hypoxia, a normoxic baseline measurement was obtained. Hypoxia was induced by allowing the piglet to breathe variable concentrations of oxygen with 5% carbon dioxide and 88-92% nitrogen adjusted to achieve an arterial oxygen tension (PaO2) <40 Torr and an arterial carbon dioxide tension (PaCO2) similar to the piglet's own baseline value. The gas mixture was adjusted to maintain the blood gases in this predetermined range for the remainder of the study. After 45 min of sustained hypoxia, the second determination was obtained. Thereafter, the right atrial balloon-tipped catheter was inflated with 2 ml of 0.9 sodium chloride to reduce venous return to the right atrium. A third determination was made after 40 min of balloon inflation or at 75 min of study, and the final determination was made after 55 min of continued balloon inflation or at 100 min of study. In preliminary studies, we had attempted to inflate the balloon-tipped catheter in two stepwise increments (10), but this was not feasible in hypoxic pigs because they became hemodynamically unstable. Each measurement consisted of arterial pH; blood gases; hematocrit; mean arterial, superior sagittal sinus, portal, and central venous blood pressures; arterial, portal, and superior sagittal oxygen contents; and arterial and sagittal sinus plasma glucose and whole-blood lactate concentrations. Total and regional brain and gastrointestinal and regional systemic blood flows and cardiac outputs were measured by using radionuclide-labeled microspheres. Blood losses due to study sampling were replaced with packed red blood cells from another piglet of the same age. At the end of the study, the piglet was killed with an intravenous injection of thiamylal sodium (200 mg/kg; Animal Health, St. Joseph, MO).

At autopsy, catheter placement was confirmed, and the organs were removed and weighed. The organs were placed in 10% Formalin until subsequent carbonization. The brain and gastrointestinal tract were fixed in 10% Formalin. After fixation, the brain was dissected into the cerebrum, cerebellum, and brain stem. The gastrointestinal tract was divided into the stomach and the small and large intestines. The small intestines were further divided into mucosa and submucosa as previously described (23).

Although we did not use a sham-operated control group in this study, we previously have shown that brain blood flow and hemodynamic measurements do not change over a similar time frame in recovered sham-operated normoxic normocarbic pigs (14, 29). We also did not examine a timed hypoxic control group. However, we have previously shown sustained elevations in brain blood flow (7) and reductions in gastrointestinal blood flow (30) during exposure to hypoxia alone.

Analytic methods. Regional brain and gastrointestinal and systemic organ blood flows and cardiac outputs were determined by using previously described techniques (2, 4, 18, 23, 30). Microspheres (15 ± 5 µm in diameter) labeled with one of six randomly assigned radionuclides (46Sc, 51Cr, 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 by using 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 (20). Arterial and venous blood pressure and heart rates were continuously measured with pressure transducers (model 1280 C, Hewlett-Packard, Waltham, MA) and recorded on a polygraph (7754 A series, Hewlett-Packard).

Sections of brain, whole 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 were prepared as previously described (23). Radioactivity of blood and of carbonized and fixed tissue samples were 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 (18): blood flow = [(tissue counts/min)/(reference blood counts/min)] × (rate of withdrawal of reference blood). All tissue samples contained sufficient microspheres to ensure blood flow accuracy to within ±5% (18). The absence of ductus arteriosus shunting was confirmed by documenting that pulmonary blood flow was equivalent to bronchial blood flow, i.e., 1-2% of the cardiac output.

Arterial blood gases were measured by a Corning 175 blood-gas analyzer (Corning Scientific, Medford, MA) corrected for body temperature, oxygen contents were measured in duplicate on a Lex-O2-Con (Lexington Instruments, Waltham, MA), hematocrits were measured in duplicate by a microhematocrit method, and plasma glucose concentrations were measured in duplicate by a glucose oxidase method on a Yellow Springs Instruments glucose analyzer (model 23A, Yellow Springs Instruments, Yellow Springs, OH). Plasma glucose concentrations were converted to whole blood concentrations by using the individual hematocrit values. Whole blood lactate was measured in duplicate by enzymatic analysis (17).

Calculations and statistical analysis. Cardiac output was calculated by summing blood flow to the organs and carcass. Oxygen delivery (µmol · min-1 · 100 g-1 or µmol · min-1 · kg-1) was calculated as arterial oxygen content times blood flow; oxygen uptake (µmol · min-1 · 100 g-1 or µmol · min-1 · kg-1) was calculated as arterial minus the appropriate venous oxygen content (e.g., sagittal sinus, portal venous, or right atrial) times blood flow (e.g., cerebrum, gastrointestinal tract, and whole body) as previously described; and oxygen extraction was calculated as oxygen uptake divided by oxygen delivery. Calculation of intestinal oxygen metabolism by using portal venous oxygen content has been shown to accurately represent arterial mesenteric oxygen content (23). Similar formulas were used for cerebral glucose metabolism (22). Although the above equations are most accurately applied to substrates with unidirectional flux, such as oxygen, the same equations were used to quantify cerebral lactate influx and efflux (2).

ANOVA for repeated measures was used to examine for significant differences within the study group over time. If a significant difference was found by ANOVA, Newman-Keuls post hoc testing was used to detect statistically significant differences among the study periods. To further describe and enhance statistically significant region by time interactions, additional analysis were performed. Separate ANOVAs for repeated measures were performed on brain and gastrointestinal regions and on systemic, cerebral, and intestinal oxygen metabolism. When a significant difference was detected, pairwise regional comparisons were made by ANOVA. All data were expressed as means ± SE. P < 0.05 was considered statistically significant.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

After the induction of hypoxia, arterial oxygen content and PaO2 decreased as expected and remained at the same level when balloon inflation was added (Table 1). Arterial pH and base excess decreased significantly at the end of the study. Small but significant decreases in PaCO2 were observed after balloon inflation. Hematocrit values and whole-blood glucose concentrations did not change during the study. Whole-blood arterial lactate concentrations increased significantly after balloon inflation was added.

                              
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  		Table 1.   pH, arterial blood-gas, hematocrit, oxygen content, lactate, and glucose values during the study periods

Heart rate decreased at the end of the study compared with hypoxia alone (Table 2). Mean arterial blood pressure increased during hypoxia and returned to baseline when balloon inflation was added. Central venous pressure increased after the onset of balloon inflation. Sagittal sinus and portal venous pressures and stroke volume did not change significantly during the studies.

                              
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  		Table 2.   Hemodynamic values during the study periods

Cardiac output increased significantly from a baseline value of 255 ± 17 to 315 ± 20 ml · min-1 · kg-1 during hypoxia, and it decreased compared with hypoxia alone to 254 ± 20 and 228 ± 18 ml · min-1 · kg-1 at 40 and 55 min, respectively, after balloon inflation was added. Changes in regional perfusion are summarized in Tables 3 and 4. Blood flow to the cerebrum, cerebellum, and brain stem increased significantly during hypoxia and remained elevated when balloon inflation was added. In contrast, blood flow to the stomach, total small intestine, proximal and distal mucosa, and large intestines decreased significantly when balloon inflation was added, compared with baseline and hypoxia, and blood flow to the proximal and distal muscularis decreased with balloon inflation compared with hypoxia alone (Table 3). The patterns of change in the proximal and distal mucosa blood flow differed significantly from those of the proximal and distal muscularis, respectively, over the study periods (ANOVA: interactions, P < 0.05). Blood flow to the heart increased significantly during hypoxia and remained increased when balloon inflation was added; blood flow to the adrenal glands and liver increased significantly during hypoxia and did not differ from baseline after balloon inflation; blood flow to the lungs (bronchial artery), pancreas, and kidneys did not change during hypoxia and decreased significantly, compared with baseline and hypoxia alone, during hypoxia with balloon inflation; blood flow to the spleen decreased during hypoxia and decreased further with balloon inflation; and blood flow to the carcass decreased, compared with hypoxia alone, when balloon inflation was added (Table 4).

                              
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  		Table 3.   Regional brain and gastrointestinal blood flow during the study periods

                              
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  		Table 4.   Regional organ blood flow and percent distribution of cardiac output during the study periods

The percentage of cardiac output to the brain increased during hypoxia and remained elevated with balloon inflation; that to the heart increased during hypoxia with balloon inflation, and this increase was greater than with hypoxia alone during the last study period; that to the adrenal glands increased significantly during the final study period; that to the liver did not change; that to the lungs (bronchial artery) decreased during hypoxia and with balloon inflation; that to the pancreas decreased during hypoxia with balloon inflation; that to the kidneys and gastrointestinal tract decreased during hypoxia and decreased further when balloon inflation was added; that to the spleen decreased during hypoxia and with balloon inflation; and that to the carcass did not change (Table 4).

Systemic oxygen delivery decreased significantly after hypoxia and decreased further when balloon inflation was added (Fig. 1). Oxygen delivery to the cerebrum did not change, and oxygen delivery to the gastrointestinal tract decreased during hypoxia and decreased further when balloon inflation was added. The patterns of change in cerebral and intestinal oxygen delivery differed significantly from that of systemic delivery, and the pattern of change in intestinal oxygen delivery differed from that of cerebral oxygen delivery over the study periods (ANOVA: interactions, P < 0.05). Systemic oxygen extraction increased during hypoxia and remained elevated when balloon inflation was added (Fig. 2). Cerebral oxygen extraction did not change, and intestinal oxygen extraction increased during hypoxia and remained elevated when balloon inflation was added. The pattern of cerebral oxygen extraction differed from that of systemic and intestinal extraction over the study periods (ANOVA: interactions, P < 0.05). Systemic and cerebral oxygen uptakes did not change during the studies (Fig. 3). In contrast, intestinal oxygen uptake decreased during hypoxia with balloon inflation, compared with baseline and hypoxia alone. Cerebral oxygen uptake represented 2.7 ± 0.42% and intestinal uptake represented 8.4 ± 1.93% of total systemic basal uptake. Cerebral and intestinal uptake as a percentage of systemic uptake did not change during hypoxia or with balloon inflation added.


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  		Fig. 1.   Systemic, cerebral, and intestinal oxygen delivery plotted against study time at baseline (open bars), during hypoxia (hatched bars), and during hypoxia with balloon inflation added (solid bars). Values are means ± SE for 11 pigs. * P < 0.05 vs. baseline. + P < 0.05 vs. hypoxia (time = 45 min). ++ ANOVA: interactions, P < 0.05 vs. systemic oxygen delivery over time. § ANOVA: interactions, P < 0.05 vs. cerebrum over time.


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  		Fig. 2.   Systemic, cerebral, and intestinal oxygen extraction plotted against study time at baseline (open bars), during hypoxia (hatched bars), and during hypoxia with balloon inflation added (solid bars). Values are mean ± SE for 11 pigs. * P < 0.05 vs. baseline. ++ ANOVA: interactions, P < 0.05 vs. systemic oxygen extraction over time. § ANOVA: interactions, P < 0.05 vs. cerebrum over time.


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  		Fig. 3.   Systemic, cerebral, and intestinal oxygen uptake plotted against study time at baseline (open bars), during hypoxia (hatched bars), and during hypoxia with balloon inflation added (solid bars). Values are means ± SE for 11 pigs. * P < 0.05 vs. baseline. + P < 0.05 vs. hypoxia (time = 45 min).

Glucose delivery to the cerebrum increased during hypoxia and remained elevated when balloon inflation was added (Table 5). Cerebral glucose extraction and uptake did not change during the studies. Lactate delivery to the cerebrum increased significantly, compared with baseline and hypoxia alone, during hypoxia with balloon inflation added. Cerebral lactate extraction did not change during the studies, and lactate influx increased significantly at the end of the study.

                              
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  		Table 5.   Cerebral glucose and lactate metabolism during the study periods

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

In this study, we examined the effects of limiting venous return to the heart on systemic and regional cardiovascular and metabolic responses in 2-wk-old unanesthetized hypoxic pigs. Our study demonstrated the following: 1) when venous return was limited, the hypoxia-related increase in cardiac output was attenuated; 2) during hypoxia, the relative reductions in cardiac output were associated with preserved cerebral oxygen uptake and compromised intestinal oxygen uptake; 3) the former was mediated by sustained oxygen delivery, because of cerebral hyperperfusion, and the latter by decreased oxygen delivery, which was not adequately offset by increased intestinal oxygen extraction; and 4) regional responses to hypoxia combined with relative reductions in cardiac output differ from that of hypoxia alone, with greatest effects on lower priority organs such as the gastrointestinal tract.

In our awake spontaneously breathing young pigs, hypoxic hypoxia resulted in 42% reductions in arterial oxygen content and 56% reductions in PaO2, which remained at the same level when venous return to the heart was limited. This level of hypoxia was selected to simulate the moderate levels of hypoxia commonly encountered in infants with cardiopulmonary disorders. It was important to study nonanesthetized subjects because anesthetics are known to influence cardiovascular regulation and microcirculatory function and to account for variability in cardiovascular studies (9, 21). However, we cannot be certain that our pigs did not have an elevated basal sympathetic tone, which can also influence cardiovascular studies. The basal heart rate in our pigs was somewhat higher than that reported in chronically catheterized pigs [187 ± 28 (SD) beats/min] at 11 days of age (9). Although differences in basal heart rate are to be expected when chronically catheterized pigs are compared with animals studied 2 h after recovery from surgery, our mean values were within 1 SD of those previously reported (9). Nevertheless, we cannot rule out the possibility that changes in sympathetic tone in our awake spontaneously breathing pigs could have influenced the outcome of our studies. We attenuated the development of hypocapnia by adding supplemental carbon dioxide to the inspired gas mixture (8). The small significant decrease in PaCO2 after balloon inflation was probably not of major physiological importance and was far smaller than previously reported in spontaneously breathing subjects exposed to similar conditions (8).

Cardiac output was reduced in our hypoxic young pigs according to methods previously described in lambs (10, 11, 13). Right atrial balloon inflation was associated with an elevation in central venous pressure, confirming that venous return to the heart had decreased (12). When venous return was reduced, the hypoxia-related increase in mean arterial blood pressure was eliminated such that arterial blood pressure returned to values that were similar to baseline. Our findings are in contrast to similar studies in lambs, in which large reductions in blood pressure occurred immediately after balloon inflation (12). During hypoxia, decreased venous return to the heart attenuated the hypoxia-related increase in cardiac output. In preliminary studies in hypoxic young pigs, not included in this report, we had attempted to achieve larger reductions in cardiac output but found that the pigs became hemodynamically unstable. To avoid rapid cardiovascular changes that render the Fick equation inaccurate for calculation of systemic and regional metabolic changes (33), we did not attempt larger decreases in cardiac output. Therefore, in the present study, we were able to examine the specific effects of limiting venous return to the heart in normocapnic, normotensive hypoxic young subjects.

The systemic and regional hemodynamic and metabolic changes during hypoxia were similar to those in previous reports (5, 27, 28, 30). Briefly, they included increases in mean arterial blood pressure, cardiac output, and perfusion to brain, heart, adrenal glands, and liver (hepatic artery) without reductions to other organs except for the spleen; decreases in systemic and intestinal oxygen delivery; and increases in systemic and intestinal oxygen extraction without changes in systemic, cerebral, or intestinal oxygen uptake.

When relationships among cardiac output, regional blood flow, and fractional distribution of cardiac output are examined in the present study, five patterns emerge. Blood flow and the percentage of cardiac output were increased to the brain and heart, even though cardiac output was compromised during hypoxia. This confirms that, during hypoxia, vasodilation persists in these organs irrespective of changes in cardiac output (6, 7). In the second pattern, the increased blood flow during hypoxia returned to baseline when venous return was limited, although the percentage of cardiac output did not change. Thus hepatic and initially adrenal blood flow decreased passively in a fashion similar to the diminishing cardiac output. The third pattern was typified by such organs as lungs (bronchial artery), pancreas, kidneys, and gastrointestinal tract. In these organs, blood flow did not change during hypoxia and then was reduced to a greater degree than cardiac output, when venous return was decreased, such that the percentage of cardiac output distributed to these organs also decreased. In the fourth pattern, represented by the spleen, blood flow and the percentage of cardiac output decreased during hypoxia and the decrease in perfusion was accentuated when venous return was reduced. This suggests that the spleen was particularly sensitive to hypoxia and reductions in cardiac output. Finally, in the carcass, blood flow did not change until the final study determination, and the percentage of cardiac output to the carcass did not change. The pattern of blood flow distribution away from the gastrointestinal tract toward the brain and heart delineates the physiological milieu for our changes in systemic and regional oxygen metabolism, when cardiac output is reduced in young hypoxic pigs. It is important to emphasize that only one level of hypoxia was examined in this study. It remains possible that, if the reduction in oxygenation had been more severe, the patterns of response to decreased cardiac output during hypoxia would most likely have differed from those outlined above.

The hemodynamic findings outlined above deserve comparison with our previous work examining the effects of tension pneumothorax in hypoxic and hypercarbic ventilated newborn piglets (4). In that study, the effect of pneumothorax on reductions in cardiac output was the single most prominent hemodynamic change, suggesting that the changes were presumably similar to those when cardiac output was reduced by other means (4, 10). The increase in central venous pressure and decrease in cardiac output during hypoxia and hypercarbia with pneumothorax were greater than those in the present study (4). Although the relative changes in hemodynamic patterns were similar in the two studies, pneumothorax limited the hypoxic and hypercarbic-mediated increase in perfusion to brain and heart and accentuated reductions to the splanchnic organs and kidneys (4). On the basis of these findings, it is probable that more severe reductions in cardiac output during hypoxia might have restricted the hypoxia-related increased perfusion to the heart and brain and accentuated the decreases to such organs as the kidneys and gastrointestinal tract.

In adult dogs, systemic lactic acidosis has been reported to occur at a higher PaO2 when cardiac output was reduced than during hypoxia alone (28). Consistent with these findings in our young pigs, during hypoxia alone at an PaO2 of 39 Torr, arterial lactic acid concentrations were not significantly increased. However, when the hypoxia-related increase in cardiac output was attenuated at the same PaO2, arterial lactate concentrations increased significantly. Therefore, when cardiac output was reduced in our hypoxic young pigs, systemic lactic acidosis developed at a similar PaO2 to that reported for adult dogs, i.e., 40 Torr (28).

When cardiac output is reduced in normoxic lambs, an abrupt reduction in systemic oxygen consumption has been reported to coincide with increased systemic lactate production (11). In our young pigs, when cardiac output was reduced during hypoxia, systemic lactic acid increased, even though systemic oxygen consumption was not compromised. In low-flow states, systemic lactic acid accumulation had previously been attributed to increased lactate production by hypoxic tissues (11). However, it has become apparent that, when cardiac output is reduced by sepsis or by decreased venous return to the heart, lactic acid accumulation represents the sum total of increased regional production and/or increased or decreased utilization occurring simultaneously in different proportions in a variety of tissues (2, 11, 13, 28). Moreover, hypoxia and reductions in cardiac output result not only in decreased oxygen delivery to various tissues but also in a redistribution of blood flow such that decreased oxygen is delivered to some regions, whereas oxygen in excess of metabolic requirements may be delivered to other areas (28). Thus, in some areas, this might result in an increase in lactate production and in others decrease or increase uptake (2, 13, 19). Therefore, although we did not measure regional lactate flux except in the cerebrum, we speculate that, when cardiac output was reduced during hypoxia, increases in arterial lactate concentrations represent an imbalance between regional production and utilization (2, 13).

During hypoxia, when cardiac output was reduced, the effects on systemic and regional oxygen transport differed from that of hypoxia alone. When cardiac output was reduced, systemic and intestinal oxygen delivery decreased on the basis of reduced perfusion and oxygenation. In contrast, oxygen delivery to the cerebrum was maintained by hyperperfusion, and consequently cerebral oxygen uptake was preserved, similar to other reports (7, 24). Although the hypoxia-related increase in mean arterial blood pressure was attenuated when cardiac output was reduced, systemic hypotension did not develop in our young pigs. Therefore, cerebral oxygen extraction did not increase as has been reported during stresses in which the hypoxia-related cerebral hyperperfusion is attenuated by indomethacin (7) or during severe prolonged hypoxia in fetal sheep (24). Systemic oxygen uptake was maintained by increased oxygen extraction. In contrast, the increase in intestinal oxygen extraction was not sufficient to offset the decrease in delivery, and consequently intestinal oxygen uptake was compromised. Therefore, although the whole body and cerebrum were relatively tolerant to the combined pertubations, compensatory mechanisms were not sufficient to sustain oxygen metabolism to a lower priority organ such as the intestines, which were more vulnerable to the combined insults. It should be noted that we have not studied a timed hypoxic control group and cannot rule out the possibility that some of the observed changes in the distribution of cardiac output and acid-base status could have been related to the hypoxic exposure over time. Nevertheless, it is likely that the major reductions in intestinal perfusion and oxygen uptake occuring after the onset of balloon inflation were primarily related to decreased venous return to the heart in the hypoxic subjects.

During hypoxia, when cardiac output was reduced, although significant increases were observed in cerebral glucose delivery because of increased perfusion, glucose uptake was not altered. Increases in cerebral lactate delivery as a function of increases in perfusion and substrate concentrations were associated with lactate influx or uptake at the end of the study. Lactate crosses the blood-brain barrier, is oxidized by the brain, and at elevated concentrations can partially replace glucose as an oxidative substrate during hypoglycemia in fetal sheep (31). In addition, utilization of aerobic lactate as an energy substrate has recently been shown to enhance functional recovery after prolonged hypoxia in the hippocampus (25). Therefore, in our study it is likely, that at the elevated systemic lactate concentrations, the increase in lactate influx or uptake supplemented glucose as a substrate for cerebral metabolism.

In summary, when venous return to the heart was reduced in hypoxic young pigs, the hypoxia-related increase in cardiac output was attenuated, and these relative reductions in cardiac output were associated with preserved cerebral oxygen uptake and compromised intestinal oxygen uptake. Regional responses to hypoxia combined with relative reductions in cardiac output differ from those of hypoxia alone.

    ACKNOWLEDGEMENTS

We acknowledge the excellent technical assistance of Grazyna Sadowska, Lisa Boyle, Dennis Berard, and Catherine Yen and the excellent secretarial assistance of Betsey Mottershead.

    FOOTNOTES

Address for reprint requests: B. S. Stonestreet, Dept. of Pediatrics, Women & Infants' Hospital of Rhode Island, 101 Dudley St., Providence, RI 02905.

Received 11 December 1997; accepted in final form 21 April 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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