Dobutamine

Background: Muscle capillary P[O.sub.2] has been found to reach a minimal value, ie, a critical capillary P[O.sub.2], in the midrange of work capacity in patients with cardiovascular disease. However, it is not known if the critical capillary P[O.sub.2] 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 P[O.sub.2] (as approximated by femoral vein P[O.sub.2]), lactate concentration, oxygen uptake (V[O.sub.2]), 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 [micro]g/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 V[O.sub.2] and V[O.sub.2] at the lactic acidosis threshold (LAT) but not peak V[O.sub.2]. The femoral vein P[O.sub.2] rapidly decreased toward a minimal value with increasing work rate (V[O.sub.2]) irrespective of the infusion of dobutamine. After reaching its nadir (critical P[O.sub.2]), femoral vein lactate began to increase without further decrease in P[O.sub.2]. Infusion of dobutamine significantly increased femoral vein resting P[O.sub.2] (27.4 [+ or -] 4.9 mm Hg vs 32.5 [+ or -] 3.8 mm Hg) and critical P[O.sub.2] (20.5 [+ or -] 1.5 mm Hg vs 21.9 [+ or -] 1.7 mm Hg), but not the P[O.sub.2] at peak V[O.sub.2] (22.1 [+ or -] 3.3 mm Hg vs 22.0 [+ or -] 2.9 mm Hg).

Conclusions: Infusion of dobutamine was found to raise the critical P[O.sub.2] and LAT but not peak V[O.sub.2]. These findings suggest that some of the acute increase in blood flow induced by dobutamine infusion benefits exercising muscle by increasing capillary P[O.sub.2], thereby delaying the onset of lactic acidosis. (CHEST 2001; 120:1218-1225)

Key words: dobutamine; lactate; oxygen uptake; P[O.sub.2]

Abbreviations: LAT = lactic acidosis threshold; Qm = muscle blood flow; S[O.sub.2] = oxygen saturation; V[O.sub.2] = oxygen uptake; V[O.sub.2]m = muscle oxygen consumption; V[O.sub.2]max = maximal oxygen uptake

Considerable controversy surrounds the relation between the oxygen supply to the exercising muscle and the increase in blood lactate concentration during exercise. (1-3) In 1994, we reported that muscle capillary P[O.sub.2] reached a minimal value, ie, a critical capillary P[O.sub.2], in the midrange of the work capacity in patients with cardiovascular disease, (4) as had also been reported for normal subjects. (5) Thereafter, P[O.sub.2] 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 P[O.sub.2].

Oxygen uptake (V[O.sub.2]) 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 V[O.sub.2] (V[O.sub.2]max) 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 V[O.sub.2]max.

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 (Qm) during exercise, (8) Thus, the capillary P[O.sub.2] 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 P[O.sub.2] (as approximated by femoral venous P[O.sub.2]), lactate concentration, V[O.sub.2] at the LAT, peak V[O.sub.2], and the relation among these variables.

MATERIALS AND METHODS

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.

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 [micro]g/kg/min. The dosage was increased by 2 [micro]g/kg/min every 2 min until it reached 6 [micro]g/kg/min. Exercise testing under dobutamine infusion was started 10 min after attaining continuous infusion of 6 [micro]g/kg/min. A dosage of 6 [micro]g/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, P[O.sub.2], PC[O.sub.2], and oxygen saturation (S[O.sub.2]). Lactate concentration was measured using an enzymatic method. (11) Critical P[O.sub.2] was defined as the lowest P[O.sub.2] during exercise at which femoral vein lactate started to increase, as shown for typical subjects in Figure 1.

[FIGURE 1 OMITTED]

Respiratory Gas Analysis

Gas exchange variables were measured on a breath-by-breath basis throughout the exercise periods using an AE-280 Respiremonitor (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.

V[O.sub.2] and carbon dioxide output were corrected to standard conditions; average values, determined by interpolation, were calculated every 10 s. Peak V[O.sub.2] was defined as the highest V[O.sub.2] attained during the exercise test. V[O.sub.2] 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 [+ or -] 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

The end point of exercise testing was dyspnea or leg fatigue in all subjects, irrespective of the infusion of dobutamine. The Borg scale (6-20) obtained at the end of exercise was 16.2 [+ or -] 2.0 for the test without dobutamine and was slightly but significantly increased to 16.8 [+ or -] 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 [+ or -]+ 15.6 mm Hg vs 148.9 [+ or -] 20.5 mm Hg, p = 0.09), and diastolic BP at rest tended to be lower (81.3 [+ or -] 11.4 mm Hg vs 74.1 [+ or -] 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 [+ or -] 14.8 mm Hg vs 74.8 [+ or -] 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.

Effects of Dobutamine on Femoral Vein P[O.sub.2] 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 P[O.sub.2] reached the minimal value (critical P[O.sub.2]) for both tests, as shown in Figure 1 for typical subjects. Thereafter, it dramatically increased with no further decrease in femoral vein P[O.sub.2]. After P[O.sub.2] reached the minimal value, femoral vein lactate level increased without appreciable change in P[O.sub.2] in six subjects (patients 1, 3, 4, 5, 6, and 9 in Table 1). In contrast, P[O.sub.2] increased after reaching the minimal value in the remaining five subjects, as shown for patient 7 in Figure 1.

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

[FIGURE 2 OMITTED]

The average critical P[O.sub.2] was significantly increased from 20.5 [+ or -] 1.5 to 21.9 [+ or -] 1.7 mm Hg during dobutamine infusion (p = 0.010; Fig 3). Also, infusion of dobutamine significantly increased resting femoral vein P[O.sub.2] (27.4 [+ or -] 4.9 mm Hg vs 32.5 [+ or -] 3.8 Into Hg, p < 0.001), as well as the resting S[O.sub.2] (49.4 [+ or -]+ 10.2% vs 61.5 [+ or -] 6.6%, p < 0.001), reflecting increase in leg blood flow. Thus, infusion of dobutamine shifted the plot of femoral vein lactate against Pos. toward the right by raising resting and critical P[O.sub.2] (Fig 1).

[FIGURE 3 OMITTED]

Effects of Dobutamine on V[O.sub.2] and Exercise Capacity

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

[FIGURE 4 OMITTED]

DISCUSSION

In the present study, we have again shown that femoral vein P[O.sub.2] in response to increasing work rate has its lowest value in the midrange of exercise tolerance and not at V[O.sub.2]max. This should coincide with the V[O.sub.2] at which end-capillary P[O.sub.2] reaches its lowest level. Since increasing V[O.sub.2] does not result in a further decrease in P[O.sub.2], this P[O.sub.2] would represent the critical capillary P[O.sub.2]. Interestingly, the plot of femoral vein lactate against P[O.sub.2] during exercise was shifted rightward by infusion of low-dose dobutamine, resulting in an increase in the critical P[O.sub.2]. We have also found that infusion of dobutamine significantly increased V[O.sub.2] both at rest and at the LAT. The small increase in V[O.sub.2] 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 V[O.sub.2] above the LAT is diffusion dependent (V[O.sub.2] increasing without decreasing capillary P[O.sub.2]), as previously shown by Koike et al. (16)

Relation Between P[O.sub.2] and V[O.sub.2]

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, V[O.sub.2] can be described by the following equation:

V[O.sub.2] = 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 P[O.sub.2] of the exercising muscles can be expected to increase the muscle V[O.sub.2] if V[O.sub.2] were diffusion limited. (16)

Concept of Critical Capillary P[O.sub.2]

As found in our previous report, (4) femoral vein P[O.sub.2] decreased with increasing work rate until it achieved a minimal value (critical P[O.sub.2]), irrespective of dobutamine infusion. Then femoral vein P[O.sub.2] 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 P[O.sub.2] must approximate the end-capillary P[O.sub.2] of the exercising muscle. Thus, its failure to decrease further, and the subsequent increase in lactate concentration, suggest that the minimal femoral vein P[O.sub.2] reflects the critical capillary P[O.sub.2].

Mechanisms of an Increase in P[O.sub.2] During Exercise

We found that femoral vein P[O.sub.2] 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 P[O.sub.2] 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 P[O.sub.2] at work rates above those at which the critical P[O.sub.2] is reached may be the result of increased blood flow relative to the increase in V[O.sub.2].

An explanation for the increase in femoral vein P[O.sub.2] above the critical level as work rate increases in almost half of our patients is that these patients might have uneven Qm relative to muscle oxygen consumption (V[O.sub.2]m) relationships. With increasing oxygen requirement, it would be necessary to increase blood flow. But as the oxygen requirement increased, the low Qm/V[O.sub.2]m muscle units would contribute less blood to the venous effluent flow than the blood flow to the high Qm/V[O.sub.2]m units. Thus as V[O.sub.2] increases during exercise, heterogeneity in Qm/ V[O.sub.2]m ratios should result in an increase in femoral venous P[O.sub.2] because of the progressively greater contribution of the high Qm/V[O.sub.2]m ratio muscle units to the overall Qm. Simultaneously, lactate would be released from the low Qm/V[O.sub.2]m muscle units, causing femoral vein lactate to increase despite increasing femoral P[O.sub.2] (Fig 1).

Effects of Dobutamine on Qm and Femoral Vein P[O.sub.2]

Although we did not measure Qm, it has already been confirmed by Wilson et al (8) 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 [+ or -] 2.5 [micro]g/kg/min (range, 2.5 to 10 [micro]g/kg/min) in patients with chronic heart failure. Dobutamine increased the peak cardiac output from 6.5 [+ or -] 0.9 to 7.4 [+ or -] 0.7 L/min (p < 0.01) and peak leg blood flow from 1.7 [+ or -] 0.3 to 2.1 [+ or -] 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, V[O.sub.2] and femoral vein P[O.sub.2] and S[O.sub.2], 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 V[O.sub.2] at the LAT. Although this result suggests that the blood flow to the exercising muscle was increased by dobutamine at this submaximal level, V[O.sub.2], work rate, and femoral vein P[O.sub.2] at peak exercise were not changed by infusion of dobutamine. Dobutamine infusion resulted in an increased heart rate (131.8 [+ or -] 19.8/min vs 146.5 [+ or -] 18.9/min) and reduced oxygen pulse (10.6 [+ or -] 2.4 mL/min/beat vs 9.7 [+ or -] 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 [+ or -] 6/min for the control exercise and 126 [+ or -] 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 P[O.sub.2] at peak exercise was not increased by dobutamine, but the mixed venous P[O.sub.2] may increase, thereby decreasing arteriovenous oxygen difference if the increase in blood flow across the total circulation with dobutamine was primarily non-nutrient blood flow. Thus, in the present study, dobutamine might not have increased Qm at or near peak exercise, although it did improve Qm during submaximal exercise. The LAT V[O.sub.2], which is the sustainable V[O.sub.2], 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 P[O.sub.2]. 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 al (18) examined whether the tip of the femoral vein catheter used for sampling femoral venous P[O.sub.2] is contaminated by skin or saphenous vein blood during leg cycling exercise. They compared femoral vein P[O.sub.2] 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 P[O.sub.2] measured in the present study approximates the end-capillary P[O.sub.2] 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 P[O.sub.2] 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 P[O.sub.2] 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 ease in cardiac patients. In 1994, we discovered that the speed of the increase in V[O.sub.2] 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

Our present findings suggest that some of the acute increase in blood flow induced by dobutamine infusion benefits exercising muscle by increasing capillary P[O.sub.2], thereby delaying the onset of lactic acidosis.

ACKNOWLEDGMENT: We thank Toshihiko Takamoto, MD, of Hokushin General Hospital.

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* 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. 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.

Manuscript received September 26, 2000; revision accepted April 6, 2001.

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

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