Author + information
- Received July 24, 1997
- Revision received October 7, 1997
- Accepted October 30, 1997
- Published online February 1, 1998.
- Beatrijs Bartelds MDA,
- Jan-Willem C Gratama, MD, PhDA,
- Koos J Meuzelaar, MDA,
- Michiel Dalinghaus, MD, PhDA,
- Jan H KoersA,
- Willem F Heikens, MDA,
- Willem G Zijlstra, MD, PhDA and
- Jaap R.G Kuipers, MD, PhDA,* ()
- ↵*Dr. Jaap R. G. Kuipers, Beatrix Children’s Hospital, Division of Pediatric Cardiology, University Hospital, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Objectives. We sought to study the effects of catecholamines on myocardial oxygen consumption (V̇o2), regional blood flows and total body V̇o2in lambs with circulatory congestion.
Background. Catecholamines are often used to support cardiovascular function in children with circulatory congestion because they increase contractility as well as heart rate. However, these changes increase myocardial oxygen demand and thus can lead to a mismatch between myocardial oxygen supply and demand. Catecholamines can also change regional blood flows and V̇o2unfavorably.
Methods. We infused isoproterenol (0.1 μg/kg body weight per min) and dopamine (10 μg/kg per min) and measured myocardial and total body V̇o2and regional blood flows in chronically instrumented 7-week old lambs with and without a left to right shunt.
Results. Isoproterenol increased myocardial V̇o2, parallel to the increase in heart rate. However, myocardial blood flow and, consequently, oxygen supply also increased. This increase outweighed the increase in myocardial V̇o2, so that myocardial oxygen extraction decreased. Isoproterenol did not change blood flow distribution. Isoproterenol increased total body V̇o2; however, systemic oxygen supply increased even more, so that oxygen extraction decreased and mixed venous oxygen saturation increased. In contrast, dopamine had no or little effect on myocardial V̇o2or blood flow distribution.
Conclusions. We conclude that the catecholamines isoproterenol and dopamine do not lead to a mismatch between myocardial oxygen supply and demand, nor do they change blood flow distribution unfavorably in 7-week old lambs with a left to right shunt. We demonstrated that isoproterenol is superior to dopamine, because it shifts the balance between oxygen supply and consumption toward supply so that systemic oxygen extraction reserve increases.
Catecholamines are often used in the management of cardiovascular dysfunction in children and adults because they increase contractility. However, some of the catecholamines increase heart rate as well, which can especially be useful in neonates, because their ability to increase cardiac output is predominantly determined by heart rate and, to a lesser extent, by preload, afterload and contractility . In a previous study we demonstrated that in lambs with an aortopulmonary left to right shunt, isoproterenol increased systemic blood flow more than dopamine did, because isoproterenol increased heart rate . We also demonstrated that dobutamine evoked a similar hemodynamic response to that of isoproterenol, although less marked. However, because no information was obtained about how these catecholamines would affect myocardial oxygen consumption (V̇o2), blood flow distribution and total body V̇o2, the results of that study were not conclusive with regard to using any of these catecholamines at an early age.
Myocardial V̇o2is expected to increase because catecholamines increase myocardial contractility and the oxygen requirement for basal cellular processes ; specifically, isoproterenol increases heart rate, which is a major determinant of myocardial V̇o2. However, myocardial V̇o2in lambs with an aortopulmonary shunt at rest is already twice as high as that in control lambs . To achieve this higher myocardial V̇o2, the lambs with a shunt have a coronary blood flow twice that of control lambs, because myocardial oxygen extraction under control and different experimental conditions is large and fairly constant. For the same reason, a further increase in myocardial V̇o2during infusion of catecholamines has to lead to a further increase in coronary blood flow, otherwise a mismatch between myocardial oxygen supply and demand occurs.
Changes in blood flow distribution can counterbalance the beneficial increase in systemic blood flow and thus oxygen supply. Isoproterenol is known to increase musculoskeletal blood flow . Dopamine, in contrast, increases systemic blood flow to a lesser extent than isoproterenol, but is known to increase renal blood flow in adults . Whether this is also true in children is questionable because this effect seems to be age dependent . Furthermore, an increase in total body V̇o2can counterbalance the beneficial increase in systemic blood flow and thus oxygen supply. An increase in V̇o2can be expected not only because of the expected increase in myocardial V̇o2, but also because of the calorigenic effect of catecholamines .
The aim of this study was to determine whether isoproterenol or dopamine leads to a mismatch between myocardial oxygen supply and demand, and whether either leads to unfavorable changes in blood flow distribution and V̇o2. Therefore, we measured myocardial V̇o2, regional blood flows and total body V̇o2in chronically instrumented 7-week old lambs with and without an aortopulmonary left to right shunt during infusion of isoproterenol or dopamine.
We studied a total of 32 lambs of mixed breed and ages ranging from 35 to 56 days. They were divided into two groups: 16 lambs with and 16 lambs without an aortopulmonary left to right shunt. The lambs were studied a mean (±SD) of 12 ± 3 days (range 5 to 19) after the operation. Some of the lambs have been used for other studies as well, with at least 1 day of rest in between. Until the day of the study the lambs remained with their mothers. Surgical and experimental procedures were approved by the Animal Research Committee of the University of Groningen.
1.1 Surgical Procedures
Surgical preparation, catheter care and antibiotic administration were performed as described previously . In brief, after induction of halothane anesthesia, we performed a left thoracotomy in the third or fourth intercostal space and sutured a Goretex conduit (inner diameter [ID] 6 mm; W.L. Gore and Associates, Inc.) between the descending aorta and the main pulmonary artery, at the level of the fibrotic string of the ductus arteriosus. Precalibrated electromagnetic flow transducers (ID 10 to 15 mm; Skalar Medical, Delft, The Netherlands) were placed around the aorta just above the coronary arteries and around the pulmonary artery proximal to the conduit. Polyvinyl catheters (ID 1.0 mm, outer diameter 1.5 mm) were placed in the ascending aorta, pulmonary artery, right ventricle, left and right atria and coronary sinus. An 8F polyvinyl catheter was placed in the left pleural cavity for chest drainage. The lambs that served as controls were instrumented in the same way, except for the conduit, the flow transducer around the aorta and the right ventricular catheter. The chest wall was closed in layers and the catheters, chest tube and flow transducer cable(s) were led through a subdermal tunnel to a cloth pouch that was sewn to the left flank of the lamb.
1.2 Experimental Protocol
Measurements were started at least 5 days after the operation. The lambs were allowed to eat until 2 h before the measurements. At that time they were weighed and placed in a canvas sling that supported them in the upright position. Ambient temperature was maintained at 22 to 23°C during the experiments . Data were collected only when the lambs were calm and resting. Systemic and pulmonary blood flows and aortic, pulmonary arterial and left and right atrial pressures were measured at 5-min intervals for 30 min. At 15 and 30 min, blood samples (0.7 ml) were withdrawn with a dry, heparinized syringe from the aortic, coronary sinus and mixed venous catheters. The mixed venous catheter was the right ventricular one for the lambs with shunts and the pulmonary arterial one for the control lambs. Oxygen saturation was determined in all samples; hemoglobin concentration, pH, partial pressure of carbon dioxide (Pco2), partial pressure of oxygen (Po2) and plasma HCO3−concentration were measured only in the blood samples from the aorta and the coronary sinus. After taking measurements for 30 min, microspheres labeled with either Ce-141, Cr-51, Ru-103, Sn-113 or Nb-95 (NEN-Trac, Dupont Company, Biotechnology Systems) were injected into the left atrium while a reference sample was withdrawn with a pump (Harvard Apparatus Company) from the aorta into a preweighed, heparinized syringe for 1.25 min at a rate of 6 ml/min .
After the baseline measurements we infused either 0.1 μg/kg body weight per min of isoproterenol or 10 μg/kg per min of dopamine for 20 min, while pressures and flows were measured every 5 min. Blood samples were withdrawn at 10 and 20 min after the start of the infusion. At the end of the infusion period, we injected microspheres labeled with an isotope other than the one used for baseline measurements. After the reference sample had been withdrawn, the infusion was stopped. Eight lambs with shunt as well as control lambs were infused with isoproterenol and another eight lambs with shunt as well as control lambs were infused with dopamine.
1.3 Measurements and Calculations
All pressures were measured with Gould P23ID pressure transducers (Spectromed Inc.) referenced to zero atmospheric pressure obtained at the mid-chest position. The precalibrated electromagnetic flow transducers were connected to Skalar MDL flow meters. Because the aortic flow transducer was applied around the aorta above the coronary arteries, it measured left ventricular output minus coronary blood flow. Therefore, we calculated total left ventricular output in lambs with shunt by adding coronary blood flow measured with the microspheres to aortic blood flow measured with the flow transducer . Heart rate was obtained from the aortic blood pressure or blood flow signal.
All variables were recorded on an Elema Mingograf 800 ink-jet recorder (Siemens-Elema, AB, Solna, Sweden). Blood gas tensions and pH were measured with an ABL 330 bloodgas analyzer (Radiometer A/S, Copenhagen, Denmark). Oxygen saturation was measured with a Radiometer OSM-2 hemoximeter. Hemoglobin concentration was determined with the methemoglobincyanide method . Left to right shunt flow was calculated as pulmonary minus systemic blood flow. Left to right shunt fraction was calculated as left to right shunt flow divided by pulmonary blood flow. Systemic, pulmonary and coronary vascular resistances were calculated according to standard equations. Total and effective stroke volumes were calculated by dividing pulmonary and systemic blood flow, respectively, by heart rate. Blood oxygen concentration was calculated as the product of oxygen saturation, hemoglobin concentration and a hemoglobin binding capacity of 1.36 ml/g. Total body V̇o2was calculated by multiplying the arterial and mixed venous oxygen concentration difference by systemic blood flow. Myocardial V̇o2was calculated by multiplying the aortic and coronary sinus oxygen concentration difference by blood flow to the left ventricular free wall.
Regional and myocardial blood flows were determined with the radionuclide-labeled microspheres injected in random order. After the second study the lambs were killed with an overdose of pentobarbital intravenously, and the heart, kidneys, brain, gastrointestinal organs, liver and spleen were removed separately, cleaned and weighed. The heart was reweighed after 4 to 7 days of fixation in 8% formalin and cleared of its pericardium, great vessels, epicardial fat and chordae. The septum and ventricular free walls were separated from the rest of the heart. All parts were subsequently weighed with an accuracy of 1 mg and corrected for the weight change caused by fixation. Radioactivity was determined in a Beckman 9000 gamma counter (Beckmann Instruments Inc.). Organ blood flows were calculated from the radioactivity counts in the tissue samples and arterial reference sample with the aid of a computer program . The flows are expressed in ml/min per 100 g wet weight. Adequate mixing of the microspheres in each lamb was confirmed by ascertaining that the blood flow per 100 g of tissue to the cerebral hemispheres, and also to the kidneys, did not differ by more than 10% . Organ vascular resistance was calculated by dividing organ perfusion pressure by organ blood flow.
1.4 Statistical Analysis
Results are expressed as the mean value ± SD, except in the figures, where we used the mean value ± SEM for graphic purposes. We studied eight lambs in each group. However, we obtained data for myocardial V̇o2and pH of the coronary sinus from five lambs during dopamine infusion in the control group and from seven lambs during dopamine and isoproterenol infusion in the shunt group. We applied the Student ttest for paired samples to test the response to infusion in each of the four groups (isoproterenol and dopamine infusion into lambs with shunt and control lambs). Two-way analysis of variance was used to test for differences in baseline values and for differences in response to infusion in lambs with shunt and control lambs in the two infusion groups . To test for differences in response, we used the difference between the baseline and infusion values. A p value <0.05 was considered significant. If the interaction between the groups was significant, we applied unpaired ttests with the Bonferroni correction for the multiple ttest . This was necessary with heart rate, aortic pressure and Po2at baseline. Because there were no other differences between the isoproterenol and dopamine groups at baseline, we pooled these data in the tables.
On the day of the study there were no significant differences in age (mean [±SD] 46 ± 5 vs. 47 ± 5 days) or weight (13.2 ± 3.0 vs. 11.8 ± 2.6 kg) between lambs with shunt and control lambs.
The left to right shunt led to significant hemodynamic differences between the lambs with shunt and control lambs (Table 1), which were similar to those previously reported from our laboratory . Briefly, pulmonary and coronary blood flows in the lambs with shunt were more than twice as high as those in the control lambs. Despite a substantial runoff of left ventricular output to the pulmonary circulation, the lambs with shunt were able to maintain their systemic blood flow at the same level as the control lambs. This was accomplished by a higher heart rate and left ventricular stroke volume in lambs with shunt compared with control lambs. The left to right shunt also led to significant increases in pulmonary arterial and right and left atrial pressures. Systemic, pulmonary and coronary vascular resistances were all lower in lambs with shunt than in control lambs. The changes in hemodynamic responses led to an increase in myocardial V̇o2, as well as in myocardial oxygen supply, in the lambs with shunt (Fig. 1). In the lambs with shunt, aortic pH and Pco2were significantly different from those in the control lambs, probably as a result of pulmonary venous congestion (Table 2). The differences in hemoglobin concentration and aortic oxygen concentration did not reach statistical significance.
Although systemic blood flow was not different between the two groups, there were some striking differences in regional blood flow. Coronary blood flow in the lambs with shunt was increased, not only because of the increase in heart weight, but was increased per 100 g tissue as well (Fig. 2). Kidney blood flow per 100 g tissue was lower in the lambs with shunt than in the control lambs, but the kidneys of the lambs with shunt weighed more (85.6 ± 24.7 vs. 64.7 ± 14.8 g, p < 0.05), so that blood flow to the kidneys was the same in lambs with shunt and control lambs. Blood flow to the diaphragm per 100 g tissue was higher in the lambs with shunt than in the control lambs. Blood flow to the brain was higher and to the splanchnic organs lower in the isoproterenol group than in the dopamine group, but was the same in lambs with shunt and control lambs.
The hemodynamic responses to infusion of isoproterenol and dopamine were similar to those reported previously from our laboratory . In summary,isoproterenol increased systemic blood flow more than dopamine did (Table 1), because of the increase in heart rate. Isoproterenol decreased left ventricular stroke volume in control lambs but not in lambs with shunt. In contrast, dopamine increased left ventricular stroke volume in both lambs with shunt and control lambs. Because pulmonary blood flow increased parallel to systemic blood flow, blood flow through the shunt did not change in any of the groups, whereas shunt flow as a percentage of left ventricular output decreased, more during isoproterenol than during dopamine infusion (Table 1).
2.3 Myocardial V̇o2
Neither isoproterenol nor dopamine led to a mismatch between myocardial oxygen supply and demand. Isoproterenol did increase myocardial V̇o2(Fig. 1) as a consequence of the increase in heart rate, because myocardial V̇o2per beat did not change (Table 2). However, isoproterenol increased myocardial oxygen supply even more than it did myocardial V̇o2, so that myocardial oxygen extraction decreased in the lambs with shunt (Fig. 1, Table 2). These changes led to an increase in oxygen saturation of the coronary sinus (Fig. 1).
Dopamine slightly but significant increased myocardial V̇o2and myocardial oxygen supply in the control lambs. However, these changes were less marked than those during isoproterenol infusion and did not lead to changes in coronary sinus oxygen saturation. Dopamine decreased the pH of the coronary sinus, but decreased the aortic pH as well. There were no differences between the lambs with shunt and control lambs in response to infusion.
2.4 Blood flow Distribution
Neither of the two catecholamines caused major changes in blood flow distribution. Although isoproterenol increased blood flow to the heart (Fig. 2), this change paralleled the increase in systemic blood flow because blood flow to the heart expressed as percentage of systemic blood flow did not change. Renal and brain blood flows did not change during isoproterenol infusion (Fig. 2). Splanchnic blood flow increased in the control lambs only.
Dopamine also increased blood flow to the heart, although less so than with isoproterenol. Dopamine increased renal blood flow significantly. However, renal blood flow expressed as percentage of systemic blood flow, as well as renal vascular resistance, did not change (Table 3). Dopamine increased brain blood flow in the lambs with shunt. There were no differences between the lambs with shunt and control lambs in response to infusion.
2.5 Total Body V̇o2
Although isoproterenol increased total body V̇o2in the lambs with shunt, it increased systemic oxygen supply even more (Fig. 3), so that systemic oxygen extraction decreased (Table 2). Systemic oxygen supply increased primarily because of the increase in systemic blood flow. In addition, oxygen concentration also increased slightly (Table 2). These changes led to an increase in the mixed venous oxygen saturation (Fig. 3). The control lambs showed the same response, except for total body V̇o2, which did not change significantly.
Dopamine did not change total body V̇o2. It slightly increased systemic oxygen supply, but significantly less so than with isoproterenol. Systemic oxygen extraction decreased slightly, but these changes did not lead to an increase in mixed venous oxygen saturation. Arterial pH and Po2decreased and Pco2and plasma HCO3−concentration increased significantly (Table 2) during dopamine infusion.
In the present study we have shown that in 7-week old lambs with an aortopulmonary left to right shunt, infusion of isoproterenol or dopamine does not lead to a mismatch between myocardial oxygen supply and demand, and that these catecholamines do not change blood flow distribution unfavorably. Furthermore, we have shown that isoproterenol shifts the balance between oxygen supply and V̇o2in favor of the oxygen supply, so that the mixed venous oxygen saturation increases.
3.1 Effects of Isoproterenol
Based on our results, we conclude that there were no signs of a mismatch between myocardial oxygen supply and demand. Although in the lambs with shunt isoproterenol increased myocardial V̇o2almost twofold, myocardial oxygen supply increased even more, so that myocardial oxygen extraction decreased. These changes led to an increase in oxygen saturation of the coronary sinus in the lambs with shunt (Fig. 1) during isoproterenol infusion. Furthermore, the pH of the coronary sinus did not change during isoproterenol infusion (Table 2). These results indicate that the increase in myocardial oxygen supply during isoproterenol infusion is sufficient to meet the increase in myocardial oxygen demand. This is further substantiated by a previous study from our laboratory in which we demonstrated that there was no net lactate production by the myocardium during infusion of isoproterenol into lambs with shunt and control lambs . In contrast to the lambs with shunt, myocardial oxygen extraction did not change in the control lambs. Because myocardial oxygen supply increased equally in lambs with shunt and control lambs (Fig. 1), the difference must be due to a relatively smaller increase in myocardial V̇o2in the lambs with shunt compared with the control lambs. Myocardial V̇o2increased because of the increase in heart rate, as myocardial V̇o2per beat did not change (Table 2). Apparently, the expected increase in myocardial V̇o2due to an increase in myocardial contractility and in the oxygen requirement for basal cellular processes was offset by a decrease in filling pressure and a decrease in end-diastolic volume, both of which result in a decrease in wall stress, another determinant of myocardial V̇o2.
Heart rate, and thereby myocardial V̇o2, increased less in the lambs with shunt than in the control lambs during infusion of isoproterenol, as a result of the higher baseline heart rate the lambs with shunt have. Despite the smaller increase in heart rate in the lambs with shunt compared with the control lambs during infusion of isoproterenol, systemic blood flow increased equally in the lambs with shunt and the control lambs. The equal increase in systemic blood flow is due to the fact that left ventricular stroke volume did not change in the lambs with shunt, but decreased in the control lambs. The difference in response in stroke volume can be explained by the differences in preload between the lambs with shunt and control lambs. Although left atrial pressure, our indicator for preload, decreased in lambs with shunt and control lambs, it remained considerably higher in the lambs with shunt during the infusion period (Table 1). As visualized in the Frank-Starling curve, the preload of the lambs with shunt remained within the flat part of the curve, whereas the preload of the control lambs decreased along the ascending limb. Therefore, left ventricular stroke volume is maintained in the lambs with shunt but not in the control lambs.
Apart from its chronotropic and inotropic effects, isoproterenol also decreased the systemic vascular resistance (Table 1). This effect may be especially beneficial in children who are unable to achieve a further increase in heart rate or who have impaired myocardial function.
The increase in systemic blood flow achieved during isoproterenol and dopamine infusion was directed toward the systemic circulation rather than toward the pulmonary circulation, as blood flow through the aortopulmonary shunt did not change. In contrast to shunt blood flow, the shunt ratio decreased (Table 1). These data again demonstrate that in patients with cardiac shunts, the use of actual blood flows is preferred over the use of shunt ratios .
3.2 Effects of Dopamine
Dopamine hardly affected myocardial V̇o2or hemodynamic data. Although dopamine slightly increased systemic blood flow through an increase in left ventricular stroke volume, this effect was negligible as compared with the increase in systemic blood flow during isoproterenol infusion. This was expected, because in young children the ability to increase cardiac output is predominantly determined by heart rate . The reason why dopamine is often used clinically is that it has been reported to increase renal blood flow . This study does not provide evidence for a specific dopaminergic increase in renal blood flow. Although dopamine increased renal blood flow in both lambs with shunt and control lambs, renal blood flow as a percentage of systemic blood flow and renal vascular resistance did not change. Dopamine, at the dose we used (10 μg/min per kg), slightly but significantly increased systemic vascular resistance in the control lambs (Table 1). Thus, in this group the specific renal vasodilative effect of dopamine was probably counteracted by an alpha-adrenergic vasoconstriction. However, in the lambs with shunt, dopamine decreased systemic vascular resistance, so this effect cannot explain the lack of a specific dopaminergic increase in renal blood flow. Our results are in accordance with those of a study by Driscoll et al. in young healthy puppies. In contrast to these studies, Girardin et al. reported an increase in renal blood flow in children during dopamine infusion (5 μg/min per kg), which persisted when the concomitant increase in cardiac output was abolished by beta-blockade. However, Girardin et al. studied patients with ages ranging from 1.5 to 15 years (mean [±SD] 7 ± 5). This wide range of ages might be responsible for the differences in effect as compared with our study, because the dopaminergic increase in renal blood flow is said to be age dependent .
Dopamine increased aortic Pco2and decreased aortic Po2and oxygen saturation. These adverse effects of dopamine on blood gas tensions have been reported previously [20–23]. They can be explained by hypoxia, hypoventilation or changes in the ventilation-perfusion ratio. Hypoxia is obviously not the case in our study. Hypoventilation, due to decreased activity of the peripheral chemoreceptors , is not likely to explain the changes in blood gas tensions for several reasons. Welsh et al. reported that the observed decrease in arterial Po2in response to dopamine infusion was larger than expected based on the degree of hypoventilation. Abdul-Rasool et al. reported a decrease in arterial Po2in patients in whom the ventilatory settings remained unchanged. Furthermore, in our study blood flow to the diaphragm, an indicator of respiratory work, did not change during dopamine infusion. That leaves changes in ventilation-perfusion ratio, which can be due to either an increase in pulmonary vascular resistance [23, 25]or an increase in intrapulmonary shunting . In our study pulmonary vascular resistance did not increase during dopamine infusion, which is also proved by the fact that shunt blood flow did not change. Thus, the observed changes in blood gas tensions are most likely to be due to intrapulmonary shunting, a possibility that can only be checked by pulmonary venous oxygen saturation measurements, which unfortunately we did not make. In our study the decrease in arterial oxygenation during dopamine infusion did not lead to a decrease in arterial oxygen concentration as the hemoglobin concentration increased (Table 2). Nevertheless, the adverse effects of dopamine on arterial oxygenation should be taken into account when considering the administration of this drug to support cardiovascular function.
3.3 Blood Flow Distribution and Total Body V̇o2
Neither of the catecholamines affected blood flow distribution unfavorably. Although both catecholamines increased coronary blood flow, this increase can never account for the increase in systemic blood flow, because coronary blood flow expressed as a percentage of systemic blood flow (about 8% in the lambs with shunt) did not change. Because isoproterenol did not change cerebral, renal or splanchnic blood flow, blood flow to the carcass will have been increased. In the lambs with shunt there was no need for an increase in blood flow, because blood flow to the vital organs at rest (except for the heart) was the same in the lambs with shunt and in the control lambs. It remains unclear how isoproterenol affects blood flow distribution when blood flow to the vital organs is jeopardized. Unfortunately, the lambs with shunt in whom that happened died before a proper study could be done. Despite the fact that systemic blood flow was the same in the lambs with shunt and the control lambs, we think our model is a good model to study circulatory congestion as a consequence of a left to right shunt. This is because these lambs with shunt showed classic symptoms of circulatory congestion : tachycardia, increased atrial pressures, hepatomegaly (37% increase in liver weight compared with control animals), respiratory distress (as deduced from a 71% increase in diaphragmatic blood flow and from the differences in blood gases and pH) and increased atrial natriuretic factor.
The increase in total body V̇o2during isoproterenol infusion in the lambs with shunt cannot be explained by the increase in myocardial V̇o2, because total body V̇o2minus myocardial V̇o2also increased. The increase in total body V̇o2may be due to the calorigenic effect of catecholamines , which is a peripheral beta-receptor stimulation of metabolism, inducing an increase in lipolysis in fat tissue and an increase in lipid oxidation . This explanation is supported by the observed changes in pH and HCO3−after isoproterenol infusion. Both an increase in arterial concentration of free fatty acids due to peripheral lipolysis and an increase in ketone body production due to increased lipid oxidation may have added to the small metabolic acidosis observed during isoproterenol infusion . In our study dopamine did not increase total body V̇o2. In contrast to our results, Abdul-Rasool et al. reported an increased total body V̇o2during dopamine infusion. However, in that study measurements were made after the dogs had been infused with 5 μg/kg per min for 30 min and with 10 μg/kg per min for 30 min, whereas we measured during a 20-min infusion period of 10 μg/kg per min only. It could be that the difference in the total amount of dopamine given explains the difference in results. Nevertheless, the increase in total body V̇o2does not impair the circulatory reserve of the lambs with shunt. This is because V̇o2expressed as percentage of maximal V̇o2, which is ∼24 ml oxygen/min per kg in lambs with shunt , is 25% under baseline conditions and only 33% during isoproterenol infusion. In contrast, the increase in oxygen supply outweighed the increase in V̇o2in the lambs with shunt and the control lambs during isoproterenol but not during dopamine infusion. These changes led to an increase in mixed venous oxygen saturation during infusion of isoproterenol and thus to an increased systemic oxygen extraction reserve. This effect is beneficial as long as it is not due to the opening up of peripheral arteriovenous shunts, thereby jeopardizing the oxygen delivery to the peripheral tissues. To rule out this possibility, we have taken aliquot samples of muscular tissue in four of our lambs with shunt. In these lambs we measured a significant increase in muscular blood flow during isoproterenol infusion—8.4 ± 3.2 to 13.7 ± 3.8 ml/min per 100 g. This is due to increased entrapment of microspheres, 15 μm in diameter, into the vascular bed, and thus rules out the possibility of arteriovenous shunting.
We demonstrated that infusion of isoproterenol or dopamine in 7-week old lambs with an aortopulmonary left to right shunt does not lead to a mismatch between myocardial oxygen supply and demand, and that these catecholamines do not change blood flow distribution unfavorably. Furthermore, we demonstrated that isoproterenol is superior to dopamine in supporting the cardiovascular function in young lambs with an aortopulmonary shunt, because it shifts the balance between oxygen supply and V̇o2in favor of the oxygen supply so that the mixed venous oxygen saturation increases and thus systemic oxygen extraction reserve increases.
We thank Alie Gerding and Janny Takens for their technical assistance during the experiments.
☆ This study was supported by the Jan Kornelis de Cock Foundation, Groningen and by The Netherlands Heart Foundation (Grant 85.089), The Hague.
This study was presented in part at the Annual Scientific Session of the Society for Pediatric Research, Anaheim, California, May 1990.
- inner diameter
- partial pressure of carbon dioxide
- partial pressure of oxygen
- oxygen consumption
- Received July 24, 1997.
- Revision received October 7, 1997.
- Accepted October 30, 1997.
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