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(Chest. 2001;120:1218-1225.)
© 2001 American College of Chest Physicians

Effects of Dobutamine on Critical Capillary PO2 and Lactic Acidosis Threshold in Patients With Cardiovascular Disease*

Akira Koike, MD; Kazuo Kobayashi, MD; Hiromasa Adachi, MD; Noritaka Shimizu, MD; Haruki Itoh, MD; Michiaki Hiroe, MD and Karlman Wasserman, MD, PhD, FCCP

* From The Cardiovascular Institute (Drs. Koike and Itoh), Tokyo; Hokushin General Hospital (Drs. Kobayashi and Adachi), Nagano; Second Department of Internal Medicine (Drs. Shimizu and Hiroe), Tokyo Medical and Dental University, Tokyo; and Division of Respiratory and Critical Care Physiology and Medicine (Dr. Wasserman), Harbor-UCLA Medical Center, Torrance, CA.

Correspondence to: Akira Koike, MD, The Cardiovascular Institute, 3–10, Roppongi 7-chome, Minato-ku, Tokyo 106-0032, Japan; e-mail: koike{at}cepp.ne.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Background: Muscle capillary PO2 has been found to reach a minimal value, ie, a critical capillary PO2, in the midrange of work capacity in patients with cardiovascular disease. However, it is not known if the critical capillary PO2 can be influenced by a change in blood flow response to exercise. This study was carried out to determine the effect of changing the blood flow response to exercise, using low-dose infusion of dobutamine, on muscle end-capillary PO2 (as approximated by femoral vein PO2), lactate concentration, oxygen uptake (O2), and the relation among these variables.

Methods: Eleven male patients with coronary artery disease performed an incremental exercise test on a cycle ergometer with and without continuous infusion of dobutamine, 6 µg/kg/min. Respiratory gas analysis was performed on a breath-by-breath basis; femoral vein blood was sampled every minute through a percutaneous catheter.

Results: Dobutamine increased resting O2 and O2 at the lactic acidosis threshold (LAT) but not peak O2. The femoral vein PO2 rapidly decreased toward a minimal value with increasing work rate (O2) irrespective of the infusion of dobutamine. After reaching its nadir (critical PO2), femoral vein lactate began to increase without further decrease in PO2. Infusion of dobutamine significantly increased femoral vein resting PO2 (27.4 ± 4.9 mm Hg vs 32.5 ± 3.8 mm Hg) and critical PO2 (20.5 ± 1.5 mm Hg vs 21.9 ± 1.7 mm Hg), but not the PO2 at peak O2 (22.1 ± 3.3 mm Hg vs 22.0 ± 2.9 mm Hg).

Conclusions: Infusion of dobutamine was found to raise the critical PO2 and LAT but not peak O2. These findings suggest that some of the acute increase in blood flow induced by dobutamine infusion benefits exercising muscle by increasing capillary PO2, thereby delaying the onset of lactic acidosis.

Key Words: dobutamine • lactate • oxygen uptake • PO2


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Considerable controversy surrounds the relation between the oxygen supply to the exercising muscle and the increase in blood lactate concentration during exercise.1 2 3 In 1994, we reported that muscle capillary PO2 reached a minimal value, ie, a critical capillary PO2, in the midrange of the work capacity in patients with cardiovascular disease,4 as had also been reported for normal subjects.5 Thereafter, PO2 remained stable or even increased with increasing work rate in these patients.4 In this study, we also found that lactate concentration increased only after reaching the critical capillary PO2.

Oxygen uptake (O2) at the lactic acidosis threshold (LAT) describes the maximum amount of oxygen consumption that can be sustained during prolonged exercise without a lactic acidosis.3 4 In contrast, the maximal O2 (O2max) is a measure of the peak capacity to consume oxygen and is dependent on the maximum ability to release oxygen from the blood to the muscles and the maximum ability of the muscles to consume it. Thus, it is conceivable that an inotropic drug might improve the sustainable work capacity by increasing delivery of oxygen to the muscle capillary bed, thereby delaying the exercise lactic acidosis to a higher work level without increasing O2max.

Dobutamine infusion is known to acutely increase cardiac output by improving coronary blood flow, decreasing left ventricular end-diastolic pressure, and enhancing cardiac contractility.6 7 Dobutamine infusion also increases muscle blood flow (m) during exercise.8 Thus, the capillary PO2 might be raised by infusion of dobutamine. This would facilitate the oxygen diffusion from the capillary to the mitochondria of muscle cell, thereby delaying the LAT.

In the present study, we aimed to determine the effect of changing the blood flow response to exercise, using low-dose infusion of dobutamine, on muscle end-capillary PO2 (as approximated by femoral venous PO2), lactate concentration, O2 at the LAT, peak O2, and the relation among these variables.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Study Patients
We enrolled 11 male patients with coronary artery disease at Hokushin General Hospital (Table 1 ). In these patients, the presence of peripheral artery disease was denied by the medical history and physical examination. No patient had a myocardial infarction within 1 month preceding enrollment in the study. Excluded from the study were patients with effort angina and those with severe ventricular arrhythmia. At the time of the study, all patients were in clinically stable condition and in sinus rhythm. The patients were all sedentary and not involved in any special exercise training programs before the study. In 10 patients, percutaneous coronary intervention was performed at least 3 months before the study. In the remaining one patient (patient 10 in Table 1 ), intracoronary thrombolysis was performed at the onset of myocardial infarction. Medical therapy included nitrates in 11 patients, calcium antagonists in 8 patients, diuretics in 2 patients, and angiotensin-converting enzyme inhibitors in 1 patient. The nature and purpose of the study, as well as the risks involved, were explained to each patient, and written informed consent was obtained prior to enrollment. The study was approved by the institutional committee on human research.


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  		Table 1. Physical Characteristics, Cardiac Diagnoses, and Angiographic Findings in Each Patient*

 
Exercise Protocol
An upright, electromagnetically braked cycle ergometer (WLP-400; Lode; Groningen, Holland) was used for the exercise testing. Subjects performed symptom-limited incremental exercise tests consisting of cycling at 20 W and 60 revolutions per minute for 3 min, and then progressively increasing work rate at 1 W every 6 s (10 W/min), both with IV infusion of dobutamine and without it. Both tests were performed on the same day with a rest interval of approximately 90 min between tests. The order of the two tests was switched by turns according to the entry order of the subjects. Heart rate was continuously monitored using a Case II Stress System (Marquette Medical Systems; Milwaukee, WI). Cuff BP was determined every minute during exercise tests with an automatic indirect manometer (STBP-680; Collin Denshi; Aichi, Japan).9 Perceived dyspnea at the end of exercise was rated in terms of the Borg scale.10

Infusion of Dobutamine
Dobutamine was administered IV, starting at 2 µg/kg/min. The dosage was increased by 2 µg/kg/min every 2 min until it reached 6 µg/kg/min. Exercise testing under dobutamine infusion was started 10 min after attaining continuous infusion of 6 µg/kg/min. A dosage of 6 µg/kg/min was maintained until the end of exercise testing.

Measurements of Blood Gases and Lactate
Femoral vein blood was obtained at rest, at 3 min of 20-W cycling, and every 1 min during the incremental period from a 16-gauge polyvinyl chloride catheter. The catheter was inserted in advance into the femoral vein 2 to 3 cm below the inguinal ligament and advanced approximately 7 cm proximally. Blood gases were analyzed using a blood gas system (ABL 520; Radiometer Medical A/S; Copenhagen, Denmark) for measurements of pH, bicarbonate, PO2, PCO2, and oxygen saturation (SO2). Lactate concentration was measured using an enzymatic method.11 Critical PO2 was defined as the lowest PO2 during exercise at which femoral vein lactate started to increase, as shown for typical subjects in Figure 1 .



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  		Figure 1. Relation between femoral vein lactate and PO2 during exercise with (+) and without (-) infusion of dobutamine (DOB) in two patients with coronary artery disease (patient 1 and patient 7 in Table 1 ). Arrows indicate the lowest PO2 at which femoral vein lactate started to increase.

 
Respiratory Gas Analysis
Gas exchange variables were measured on a breath-by-breath basis throughout the exercise periods using an AE-280 Respiromonitor (Minato Medical Science; Osaka, Japan), as previously described.12 13 This device consists of a hot-wire flowmeter, oxygen and carbon dioxide gas analyzers (zirconium-element-based oxygen analyzer and infrared carbon dioxide analyzer), and a microcomputer. Gas was sampled through a filter by a suction pump through the gas analyzers at a rate of 220 mL/min. The system was calibrated before each study.

O2 and carbon dioxide output were corrected to standard conditions; average values, determined by interpolation, were calculated every 10 s. Peak O2 was defined as the highest O2 attained during the exercise test. O2 at the LAT was determined noninvasively by respiratory gas analysis using the V-slope method,14 15 without knowledge of testing condition.

Statistical Analysis
Data are reported as mean ± SD. Differences in the variables between the test with dobutamine and that without dobutamine were analyzed by paired t tests. The significance level was p < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
The end point of exercise testing was dyspnea or leg fatigue in all subjects, irrespective of the infusion of dobutamine. The Borg scale6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 obtained at the end of exercise was 16.2 ± 2.0 for the test without dobutamine and was slightly but significantly increased to 16.8 ± 1.9 for the test with dobutamine (p = 0.02). There were no adverse effects of dobutamine on symptoms, hemodynamics, or ECG changes at rest and during exercise.

Effects of Dobutamine on Hemodynamic Variables
Heart rates both at rest and peak exercise were significantly increased by dobutamine (Table 2 ). Systolic BP at rest tended to be higher (136.6 ± 15.6 mm Hg vs 148.9 ± 20.5 mm Hg, p = 0.09), and diastolic BP at rest tended to be lower (81.3 ± 11.4 mm Hg vs 74.1 ± 12.4 mm Hg, p = 0.06) for the test with dobutamine (Table 2) . Thus, pulse pressure at rest was significantly increased by dobutamine (55.3 ± 14.8 mm Hg vs 74.8 ± 16.5 mm Hg, p < 0.001). However, the effect of dobutamine on the change in pulse pressure at peak exercise was not statistically significant.


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  		Table 2. Heart Rate, BP, and O2 at Rest and During Exercise in 11 Patients With Coronary Artery Disease*

 
Effects of Dobutamine on Femoral Vein PO2 and Lactate
There was no significant difference in the resting femoral vein lactate level between the tests with and without dobutamine (Table 2) . Femoral vein lactate level did not change appreciably until PO2 reached the minimal value (critical PO2) for both tests, as shown in Figure 1 for typical subjects. Thereafter, it dramatically increased with no further decrease in femoral vein PO2. After PO2 reached the minimal value, femoral vein lactate level increased without appreciable change in PO2 in six subjects (patients 1, 3, 4, 5, 6, and 9 in Table 1 ). In contrast, PO2 increased after reaching the minimal value in the remaining five subjects, as shown for patient 7 in Figure 1 .

When relating femoral vein PO2 to O2 (Fig 2 ), the lowest PO2 usually occurred not at peak O2 but in the midrange of increasing O2. As shown for patient 7, the femoral vein PO2 often increased after reaching its lowest value, despite increasing O2. While the PO2 was displaced upward with dobutamine, the pattern of the femoral vein PO2 vs O2 (Fig 2) and lactate vs PO2 (Fig 1) was distinctive for each subject and not altered by the infusion of dobutamine.



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  		Figure 2. Relation between femoral vein PO2 and O2 during exercise with (+) and without (-) infusion of dobutamine in two patients with coronary artery disease (patient 1 and patient 7 in Table 1 ). See Figure 1 legend for definition of abbreviation.

 
The average critical PO2 was significantly increased from 20.5 ± 1.5 to 21.9 ± 1.7 mm Hg during dobutamine infusion (p = 0.010; Fig 3 ). Also, infusion of dobutamine significantly increased resting femoral vein PO2 (27.4 ± 4.9 mm Hg vs 32.5 ± 3.8 mm Hg, p < 0.001), as well as the resting SO2 (49.4 ± 10.2% vs 61.5 ± 6.6%, p < 0.001), reflecting increase in leg blood flow. Thus, infusion of dobutamine shifted the plot of femoral vein lactate against PO2 toward the right by raising resting and critical PO2 (Fig 1) .



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  		Figure 3. Femoral vein PO2 at rest (left panel), at critical capillary PO2 level during exercise (middle panel), and at peak exercise (right panel). Large open circles represent mean values. The p values were determined by paired t test. DOB(-) = studies without dobutamine; DOB(+) = studies with dobutamine. NS = not significant.

 
Effects of Dobutamine on O2 and Exercise Capacity
The maximal work rate was 105.9 ± 20.5 W for the test without dobutamine and 106.7 ± 22.9 W for the test with dobutamine, showing no significant difference (Table 2) . Also, there was no difference in peak O2 between the two tests. However, dobutamine significantly increased resting O2 (p < 0.01). The LAT, which was determined noninvasively by respiratory gas analysis, was significantly increased from 13.6 ± 1.8 to 14.6 ± 1.7 mL/min/kg by infusion of dobutamine (p = 0.008; Fig 4 ).



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  		Figure 4. LAT determined by gas exchange analysis and peak O2. Large open circles represent mean values. The p values were determined by paired t test. See Figure 3 legend for definitions of abbreviations.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
In the present study, we have again shown that femoral vein PO2 in response to increasing work rate has its lowest value in the midrange of exercise tolerance and not at O2max. This should coincide with the O2 at which end-capillary PO2 reaches its lowest level. Since increasing O2 does not result in a further decrease in PO2, this PO2 would represent the critical capillary PO2. Interestingly, the plot of femoral vein lactate against PO2 during exercise was shifted rightward by infusion of low-dose dobutamine, resulting in an increase in the critical PO2. We have also found that infusion of dobutamine significantly increased O2 both at rest and at the LAT. The small increase in O2 at rest might have been due, in part, to the increase in resting myocardial work accompanying the increase in heart rate. The increase in LAT with dobutamine suggests that the increase in blood flow resulted in better perfusion of metabolically active muscle. This is consistent with the concept that the O2 above the LAT is diffusion dependent (O2 increasing without decreasing capillary PO2), as previously shown by Koike et al.16

Relation Between PO2 and O2
From Fick’s law of diffusion, the mass transfer of a substance, such as oxygen, is directly proportional to the partial pressure difference between the high pressure point in the capillary (Pc) to the low pressure point in the mitochondria (Pm) and the surface area (A) [degree of capillary hyperemia], and inversely related to the diffusion distance (L) [capillary to mitochondria].16 Thus, O2 can be described by the following equation:

O2 = k x A/L x (Pc - Pm), where k is the diffusion coefficient for oxygen, a function of the diffusibility and solubility of oxygen in the tissue substance. Therefore, an intervention that raises muscle capillary PO2 of the exercising muscles can be expected to increase the muscle O2 if O2 were diffusion limited.16

Concept of Critical Capillary PO2
As found in our previous report,4 femoral vein PO2 decreased with increasing work rate until it achieved a minimal value (critical PO2), irrespective of dobutamine infusion. Then femoral vein PO2 remained constant or increased, but did not significantly decrease further despite the increasing metabolic rate. Since the blood flow to the exercising muscle is much larger than that to the other tissues of the lower extremities during exercise, femoral vein PO2 must approximate the end-capillary PO2 of the exercising muscle. Thus, its failure to decrease further, and the subsequent increase in lactate concentration, suggest that the minimal femoral vein PO2 reflects the critical capillary PO2.

Mechanisms of an Increase in PO2 During Exercise
We found that femoral vein PO2 increased after reaching the minimal value in 5 of 11 patients irrespective of dobutamine infusion, a finding similar to that noted in our previous study.4 The increase in PO2 is due to an increase in femoral venous oxygen content, not due to a rightward shift in the oxyhemoglobin dissociation curve. Since arterial oxygen content during exercise would not be increasing under the conditions of this study, the increase in femoral vein PO2 at work rates above those at which the critical PO2 is reached may be the result of increased blood flow relative to the increase in O2.

An explanation for the increase in femoral vein PO2 above the critical level as work rate increases in almost half of our patients is that these patients might have uneven m relative to muscle oxygen consumption (O2m) relationships. With increasing oxygen requirement, it would be necessary to increase blood flow. But as the oxygen requirement increased, the low m/O2m muscle units would contribute less blood to the venous effluent flow than the blood flow to the high m/O2m units. Thus as O2 increases during exercise, heterogeneity in m/O2m ratios should result in an increase in femoral venous PO2 because of the progressively greater contribution of the high m/O2m ratio muscle units to the overall m. Simultaneously, lactate would be released from the low m/O2m muscle units, causing femoral vein lactate to increase despite increasing femoral PO2 (Fig 1) .

Effects of Dobutamine on m and Femoral Vein PO2
Although we did not measure m, it has already been confirmed by Wilson et al8 that low-dose infusion of dobutamine increases leg blood flow during exercise. In their study, dobutamine was administered IV during exercise until the maximum (SE) dose of 8.2 ± 2.5 µg/kg/min (range, 2.5 to 10 µg/kg/min) in patients with chronic heart failure. Dobutamine increased the peak cardiac output from 6.5 ± 0.9 to 7.4 ± 0.7 L/min (p < 0.01) and peak leg blood flow from 1.7 ± 0.3 to 2.1 ± 0.3 L/min (p < 0.05). In the present study, we employed a similar method for the infusion of dobutamine. We found that the dobutamine infusion significantly increased resting heart rate, pulse pressure, O2 and femoral vein PO2 and SO2, providing evidence that the rate of dobutamine infused in our study was sufficient to increase leg blood flow at least during submaximal exercise, as noted in the study by Wilson et al.8

Effects of Dobutamine on Exercise Capacity
In the present study, infusion of dobutamine significantly increased O2 at the LAT. Although this result suggests that the blood flow to the exercising muscle was increased by dobutamine at this submaximal level, O2, work rate, and femoral vein PO2 at peak exercise were not changed by infusion of dobutamine. Dobutamine infusion resulted in an increased heart rate (131.8 ± 19.8/min vs 146.5 ± 18.9/min) and reduced oxygen pulse (10.6 ± 2.4 mL/min/beat vs 9.7 ± 2.1 mL/min/beat) at peak exercise. Heart rate at peak exercise in the present study was considerably higher than in the patients studied by Wilson et al,8 in which it was 121 ± 6/min for the control exercise and 126 ± 5/min for the test with dobutamine. Because oxygen pulse is the product of stroke volume times the arterial/mixed venous oxygen difference, the reduced oxygen pulse at maximal exercise for the test with dobutamine may reflect a reduced arteriovenous oxygen difference, since it is unlikely that stroke volume would decrease with dobutamine. Femoral vein PO2 at peak exercise was not increased by dobutamine, but the mixed venous PO2 may increase, thereby decreasing arteriovenous oxygen difference if the increase in blood flow across the total circulation with dobutamine was primarily nonnutrient blood flow. Thus, in the present study, dobutamine might not have increased m at or near peak exercise, although it did improve m during submaximal exercise. The LAT O2, which is the sustainable O2, has been shown to be oxygen-transport dependent.17 Consequently, an improvement in oxygen transport during submaximal exercise could delay the onset of the exercise lactic acidosis.

Study Limitation
In the present study, blood was obtained from a catheter inserted into the femoral vein 2 to 3 cm below the inguinal ligament and advanced 7 cm proximally. This site of sampling might have influenced the femoral vein PO2. However, the blood flow to the exercising muscle is much larger than that to the other tissues of the lower extremities during exercise. In 1994, Agusti et al18 examined whether the tip of the femoral vein catheter used for sampling femoral venous PO2 is contaminated by skin or saphenous vein blood during leg cycling exercise. They compared femoral vein PO2 sampled from two catheters that were inserted into the femoral vein (7 cm distally and 5 cm proximally) in humans. They found negligible contributions to blood gas values from nonexercising tissues during exercise over the 12-cm distance. Therefore, we believe that femoral vein PO2 measured in the present study approximates the end-capillary PO2 of the exercising muscle.

Impairment of exercise capacity in our subjects was relatively mild, as compared to those of Wilson et al,8 because the coronary artery disease of most subjects had already been treated by percutaneous coronary intervention before the study. Whether dobutamine would also increase the critical PO2 and LAT in patients with impaired left ventricular function remains to be shown. It is also of interest to determine the effect of dobutamine on the LAT and critical PO2 in subjects without significant cardiovascular disease.

Clinical Implications
The LAT was increased by 8.1% by infusion of dobutamine. This would be sufficient to increase the sustainable work rate by about 7 W. From our experience,19 20 an improvement in LAT usually averages 8 to 10% in patients with cardiovascular disease responding to effective therapy.

One of the unique findings of the present study is that submaximal physiology was improved by infusion of dobutamine without changing variables at peak exercise. It is generally assumed that parameters of maximal exercise capacity are correlated with those during submaximal exercise. However, this is not always the case in cardiac patients. In 1994, we discovered that the speed of the increase in O2 kinetics during mild-intensity exercise was slower in patients with decreased left ventricular ejection fraction as compared to those with preserved ejection fraction, while there was no difference in peak exercise capacity.12 Cardiac patients are rarely exposed to maximal exercise during daily life. Thus, in terms of their quality of life and level of daily activity, circulatory improvements during submaximal exercise might be more beneficial than those during maximal exercise.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Our present findings suggest that some of the acute increase in blood flow induced by dobutamine infusion benefits exercising muscle by increasing capillary PO2, thereby delaying the onset of lactic acidosis.


   Acknowledgements
 
We thank Toshihiko Takamoto, MD, of Hokushin General Hospital.


   Footnotes
 
Abbreviations: LAT = lactic acidosis threshold; m = muscle blood flow; SO2 = oxygen saturation; O2 = oxygen uptake; O2m = muscle oxygen consumption; O2max = maximal oxygen uptake

Supported in part by a Grant-in-Aid for Scientific Research From the Ministry of Education, Science, and Culture of Japan, and by the Research Grant for Cardiovascular Diseases From the Ministry of Health and Welfare.

Received for publication September 26, 2000. Accepted for publication April 6, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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