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Impaired skeletal muscle nutritive flow during exercise in patients with congestive heart failure: Role of cardiac pump dysfunction as determined by the effect of dobutamine
CONGESTIVE HEART FAILURE
Impaired Skeletal Muscle Nutritive Flow During Exercise in Patients with Congestive Heart Failure: Role of Cardiac Pump Dysfunctionas Determined by the Effect of Dobutamine JOHN R. WILSON, MD, JACK L. MARTIN, MD, and NANCY FERRARO, RN
The maximal exercise capacity of patients with congestive heart failure (CHF) is frequently reduced, partly because of inadequate skeletal muscle nutritlve flow. To investigate whether this altered muscle nutritive flow is a result of inability of the heart to increase cardiac output normally during exercise, the effect of dobutamine on systemic and leg blood flow and metabolism during maximal exercise was examined in 11 patients with CHF. At maximal exercise before dobutamine, all patients were limited by fatigue and had reduced maximal systemic oxygen uptake ( 11.9 f 1.1 ml/min/kg) ( f standard error of the mean), markedly elevated leg oxygen extraction (85 f 2%) and elevated femoral venous lactate (53 f 5 mg/dl), consistent with impaired nutritive flow to working muscle. Dobutamine increased the peak cardiac output from (8.5 f 0.9
to 7.4 f 0.7 liters/min, p
Patients with chronic congestive heart failure (CHF) are frequently limited during exercise even when they are asymptomatic at rest.1-3 This exertional intolerance is due at least in part to inadequate nutritive flow to working skeletal muscle, because patients with CHF are frequently limited by fatigue1p4 and, during exercise, characteristically have reduced cardiac output,1*4 reduced skeletal muscle blood fl0w,5-~ heightened limb oxygen extraction7T8 and early lactate release.l,gJO However, the cause of this impaired skeletal muscle nutritive flow is uncertain. Some investigators have speculated that nutritive flow is impaired because of an
inability of the heart to increase cardiac output normally during exercise. l Other investigators have suggested that impaired dilation of precapillary arterioles or sphincters within working skeletal muscle is the principal reason that nutritive flow is reduced.5J1 This study was undertaken to investigate the hypothesis that an inability of the heart to increase cardiac output normally during exercise is primarily responsible for impaired skeletal muscle nutritive flow in patients with CHF. Accordingly, we measured both systemic and leg blood flow and metabolism during upright maximal bicycle exercise in patients with CHF. We then repeated these studies after enhancement of cardiac function with dobutamine, a catecholamine that increases cardisc contractility by directly stimulating myocardial ,81 adrenoreceptors.12 We reasoned that if the hypothesis was accurate, dobutamine should produce an increase in leg blood flow associated with a commensurate increase in systemic and leg oxygen uptake and a reduction in arterial lactate concentration and leg lactate release.
(Am J Cardiol 1984;53:1308-1315)
From the Cardiovascular Section, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. This study was supported in part by Clinical Research Center Grant 5-MO1-RFtOOO4Oand a Young Investigator Grant from the National Institutes of Health, Bethesda, Maryland. Manuscript received October 19, 1983; revised manuscript received January 4,1984, accepted January 5, 1984. Address for reprints: John Ft. Wilson, MD, Cardiovascular Section, 943 West Gates, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. 1308
May 1. 1984
TABLE I
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Effects of Dobutamine on Systemic Hemodynamic and Metabolic Responses to Exercise PWP
BP (If&
(mYPm2in)
0s Extraction
Lactate
(%I
(mg/dU
(beazmin)
(mm Hg)
84 f 4 88 f 5 101 f 7
85 f 2 88 f 3 95 f 4
3.2 f 0.2 3.2 f 0.3 8.2 f 0.7
20 f 2 17f3 22 f 4
234 f 11 283 f 24 731 f 41
45 f 3 52 f 4 70 f 4
14.; i 20.6 f
121 f 6
101 f 4
6.5 f 0.9
29 f 3
829 f 97
79 f 3
33.8 f 2.2
14 f 2’
246 263 f 18 16 749 f 41
:z+ 61 f4+
24f2’ 24f2’
869 f 77 888 f 76’
72 f 2+ 73 f 2+
(mm Hg) Control
$$J Submaximal exercise Peak exercise
1.4 1.6
Dohutamine
Lying Bike Submaximal exercise’ Peak exercisef Maximal exercise
91 98 f 3’ 4’ 113f 5+ 126f 126f
5 5
83 89 f 4 97 f 2 103f3 103 f 3
7.4 f 0.7+ 7.4 f 0.7+
l
15.6 i 19.5 f
1.8 1.9
34.6 f 3.5 37.0 f 3.7
p <0.05 compared with control; + p
Methods Patients: Eleven patients, 8 men and 3 women with a mean age of 57 f 10 years (range 45 to 70), with chronic left ventricular (LV) dysfunction (mean ejection fraction 20 f 10% [f standard deviation]) were studied. All had exertional breathlessness or fatigue despite administration of digoxin and diuretics. None had peripheral edema, ascites, angina pectoris, intermittent claudication or reduced pulses in their legs at the time of study. Each patient had a reduced maximal 0s uptake (VOs max) below the expected normal range (average 11.9 f 3.5 ml/min/kg, range 5.3 to 15.4; normal >20).l-3J3-15 LV dysfunction was attributed to coronary artery disease in 7 patients and to idiopathic dilated cardiomyopathy in 4. Protocol: On the day before study, a trial maximal exercise test was performed to acquaint the patient with the exercise protocol. Exercise was performed on an upright mechanically braked bicycle ergometer (Monark) and begun at a work load of 20 W. Every 3 minutes, the work load was increased by 20 W to symptomatic maximum. All exercise tests were performed at least 4 hours after meals. The next morning, a Swan-Ganz catheter was inserted through an antecubital vein and positioned in the pulmonary artery. A short polyethylene catheter was inserted in a radial artery. A No. 5Fr thermodilution catheter was inserted percutaneously into a femoral vein and advanced 15 to 16 cm anterograde into the iliac vein. Thirty minutes after instrumentation, hemodynamic measurements were made and blood samples were obtained from the radial arterial and femoral venous catheters for oxygen saturation and lactate concentration. Femoral venous blood flow was measured in triplicate. Respiratory gases were measured with a Beckman metabolic cart equipped with 0s and COs analyzers and a turbine volume transducer. The patient then mounted the bicycle and was allowed to equilibrate for 5 minutes, after which all measurements were repeated. The patient then began to exercise. Respiratory gas and hemodymunic measurements were made continuously. During each 3-minute exercise stage, leg blood flow was measured every 30 seconds starting at 30 seconds and continuing for 2.5 minutes for a total of 5 measurements. Blood sampling was performed during the last 30 seconds of the stage. Leg flow was not measured during this period. After exercise was terminated, the patient was allowed to rest for 2 hours. Dobutamine was then administered intra-
venously, starting at 2.5 pglkglmin. The dose was increased by 2.5 pg/kg/min every 10 minutes until the cardiac output increased by more than 30% or until a peak dose of 10 pg/kg/min was achieved. The average final dobutamine dose was 8.2 f 2.5 /.tg/kg/min (range 2.5 to 10). The exercise protocol was then repeated. Measurements were made at identical exercise times as during control exercise and, when a patient exercised longer after dobutamine administration, also at the new maximal exercise level. The period between exercise tests was 2.5 hours. This period was believed to be adequate to assure full recovery from the first exercise test because hemodynamic and metabolic parameters returned to control levels by 2 hours. Previous observations have also documented the return of these variables to baseline levels within 2 hours.16J7 Metabolic responses to exercise tests before and 2 hours after nitrate administration are comparable,16 suggesting that 2 hours is also a sufficient time for metabolic responses to return to control levels; nitrates are primarily venodilators and should not affect oxygen delivery to muscle. We have also performed duplicate exercise tests 2.5 hours apart in 4 patients with CHF. Ventilatory, hemodynamic and metabolic responses to exercise were reproducible. Leg blood flow: Leg blood flow was determined as previously described.” In brief, femoral vein flow was measured using a 50-cm 5Fr thermodilution catheter with the thermistor at 2 cm and the injection port at 12 cm. Flow was determined using rapid injection of a 2.5-ml iced dextrose bolus injectate and a commercially available thermodilution computer (Elecath). Output curves were displayed on a strip-chart recorder to assure an exponential decay curve. Flow determined using this system correlated closely with known flow rates (0.2 to 6.0 liters/min, r = 0.99) when evaluated using a closed-loop system in which 37°C water was continuously circulated through 7-mm polyethylene tubing using a roller pump. The coefficient of variation of duplicate flow measurements made sequentially in patients during the same exercise test was 9 f 10% at rest and 16 f 1% during exercise (i standard deviation). This variation is partly due to normal phasic alterations in flow. Therefore, flow measurements were routinely made every 30 seconds after the first 30 seconds of an exercise stage. Measurements at any given stage were then averaged. In 4 patients, 2 exercise tests were performed 2.5 hours apart to evaluate the reproducibility of such averaged flow measurements. The coefficient of variation of repeated flow measurements was 16 f 10% (n = 14). Averaged group flow measurements made during the first and second exer-
1310
SKELETAL MUSCLE NUTRITIVE FLOW IN HEART FAILURE
Control:
_
Dab: ---
p=NS
SUPINE
BIKE
MAX SUBMAX EXERCISE
**:p<. 01
SUPINE
*:p<. **:ps
BIKE
MAX SUBMAX EXERCISE
05 01
cise periods were reproducible: resting (0.35 f 0.05 vs 0.34 f 0.03 liters/min), submaximal exercise (2.64 f 1.40 vs 2.52 f 1.06 liters/min) and maximal exercise (3.05 f 1.00 vs 3.00 f 1.24 liters/min). We previously demonstrated a close correlation between leg flow measured using this technique and systemic VOz.17 The measured leg flow levels observed in this study are comparable to leg flow measurements reported with other methods.18-20 The validity of using the thermodilution technique to measure leg flow during upright bicycle exercise has also been confirmed by other investigators.20 Measured variables: Hemoglobin concentration was measured by Coulter Counter; hemoglobin oxygen saturation was measured with a cooximeter (Instrumentation Laboratories) precalibrated with human blood. Blood O2 content was calculated as the product of hemoglobin, 1.34 ml 02/g hemoglobin, and the percent 02 saturation. Oxygen extraction was calculated as the ratio of the arteriovenous 02 difference and arterial 02 content. Cardiac output was calculated from the Fick principle as VOJsystemic arteriovenous 02 difference. Leg vascular resistance was calculated as (arterial pressure - femoral venous pressure)/leg flow. Leg 02 consumption was calculated as the product of femoral flow and the arteriovenous 02 difference across the leg. Blood for lactate determination was deproteinized with cold perchloric acid and assayed with a spectrophotometric technique.21 Normal values at rest for this technique in our laboratory are 3 to 12 mg/dl. Leg lactate release was calculated as leg flow - (femoral venous arterial lactate concentration). Leg flow and leg 02 and lactate data were not obtained simultaneously. Therefore, calculation of leg VOz and lactate release assumes that leg flow remained relatively constant during exercise. In support of this assumption, we observed that flow increases abruptly with the onset of exercise and stabilizes within 30 to 45 seconds. Statistical methods: Values are presented as mean f standard error of the mean. Differences between measurements at rest, submaximal exercise and maximal exercise were compared by the paired Student t test.22 In only 6 patients were measurements made during submaximal exercise. In 2 of these 6 patients, multiple measurements were made during submaximal exercise. These measurements were averaged before analyzing the effect of dobutamine on submaximal exercise measurements. A value of <0.05 was considered significant.
Results The effects of dobutamine on systemic and regional parameters are summarized in Tables I and II and illustrated in Figures 1 to 4. The control and postdobutamine data illustrated in the figures were obtained at identical work times. In 2 patients, leg blood flow measurements were not obtained because of technical difficulties.
Control systemic hemodynamic and metabolic measurements (Fig. 1 and 2): At supine rest, cardiac output
SUPINE
BIKE
MAX SUBMAX EXERCISE
FIGURE 1. Effect of dobutamine (Dob) on mean blood pressure (BP), cardiac output (CO) and pulmonary wedge pressure (PWP) responses to exercise. The apparent lack of increase in CO from submaximal to maximal exercise is due to inclusion of submaximal data from only 6 patients, not to a plateauing of the CO response. Significant differences between control and dobutamine data are noted by asterisks. NS = not significant.
was 3.2 f
0.2 liters/min,
pulmonary wedge 02 extraction 45 f 3%, consistent with LV pump dysfunction. When the bicycle was mounted, cardiac output remained unchanged whereas pulmonary wedge pressure decreased slightly to 17 f 3 mm Hg. Patients exercised an average of 5.5 f 0.8 minutes (range 3 to 9), stopping due to fatigue at a maximum VO, of 829 f 97 ml/min. Exercise increased cardiac output to 6.5 f 0.9 liters/min, pulmonary wedge pres-
pressure 20 f 2 mm Hg and systemic
May I.1984
TABLE II
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Effect of Dobulamine on Leg Hemodynamic and Metabolic ReSpOnSeSt0 Exercise Leg Flow (I/min)
Leg i/O* (ml/min)
Leg
Leg 02
Resistance (units)
Extraction (“/)
Femoral Lactate (mgldt)
AV Lactate Difference (mgjdt)
Leg Lactate Release (mglmin)
Control /j”,” Submaximal exercise Peak exercise
0.25 f 0.03 0.26 0.05 1.60 f 0.31 1.72 f 0.26
28.1 19.5 f 2.4 4.6 204.4 f 30.0 234.0 f 32.7
297 f 36 310 17 62f 12 53 f 7
65 f 3 47 81 f2 85 f 2
15.3’%‘1.7 29.3 f 3.4 52.6 f 4.5
1.3’%‘0.9 8.8 f 1.8 19.1 f 3.2
4f2 104 f 29 248 f 39
16.9.j.2.0 27.2 f 2.0 47.9 f 4.3’ 52.6 f 5.4
1.9’i.o.s 7.7 f 1.5 13.3 f 1.9+ 15.7 f 2.7’
4f2 140 f 46 275 f 53 275 f 94
Dobutamine Lying Bike Submaximal exercise’ Peak exerciset Maximal exercise
0.41 0.33 2.00 2.06 2.01
f f f f f
0.07’ 0.07 0.36’ 0.28’ 0.70‘
22.5 27.7 239.0 264.2 265.9
f f f f f
5.1 6.1 39.9 31.8’ 30.1
235 f 250 f 42 f 36 f 3865’
41 37+ 7 5+
30 f 3+ 51*5+ ‘8;: 2 $ 81 f
I+
p <0.05 compared with control; + p
sure to 29 f 3 mm Hg, systemic 02 extraction to 79 f 3% and arterial lactate concentration to 34 f 2 mg/dl. Effect of dobutamine on systemic 02 transport (Fig. 1 and 2): At supine rest, dobutamine increased cardiac output from 3.2 f 0.2 to 4.8 f 0.3 liters/min (p
patients; the mean arteriovenous lactate difference was 1.3 f 0.9 mg/dl. With exercise, leg flow increased progressively to a peak flow of 1.72 f 0.26 liters/min whereas leg resistance decreased to 53 f 7 units. Leg VOs increased to 234 f 33 ml/min, mediated by both the increase in flow and the increase in leg 02 extraction to 85 f 2%. Femoral venous lactate increased from 15 f 2 to 53 f 5 mg/dl, whereas leg lactate release increased from 4 f 2 to 248 f 39 mg/min, indicating increased anaerobic metabolic activity in the leg. Effect of dobutamine on leg flow and metabolism (Fig. 3 and 4): Administration of dobutamine increased the supine resting leg flow from 0.25 f 0.03 to 0.41 f 0.07 liters/min (p <0.05), whereas leg 0s extraction decreased from 47 f 3 to 30 f 3% (p
1312
SKELETAL MUSCLE NUTRITIVE FLOW IN HEART FAILURE
Control: Dab:
-
Control:
---
Dab:
1
_
---
J l
l:pc.
05
*---
0 SUPINE
BIKE
SUBMAX
SUPINE
MAX
BIKE
SUBMAX
MAX
EXERCISE
EXERCISE
500
100
l:p<. 05 +*:p<. 01
400
75
50
;/
p” **
2*
/
/
/
/ t*
2 / / **
300
-\ l * \
\ \ 100
25 BIKE
f --i
200
l
0 SUPINE
**:p<. 01
SUffUAX
\
I__
SUPiNE
MAX
BIKE
kic-z+& **
SUBMAX
MAX
EXERCISE
EXERCISE
80
5-O
40
60 p =NS 30
20
10
0 SUPINE
BIKE
SUBMAX
MAX
EXERCISE
FIGURE 2. Effect of dobutamine (Dob) on systemic oxygen uptake (\iO,), systemic oxygen extraction and arterial lactate. Significant differences between control and dobutamine data are noted by asterisks. NS = not significant.
SUP/NE
BIKE
MAX SUBMAX EXERCISE
FIGURE 3. Effect of dobutamine (Dob) on leg flow, leg resistance and the percentage of cardiac output delivered to the leg. Significant differences between controt and dobutamine data are noted by astertsks. NS = not significant.
May 1. 1984
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
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100
Control: Oob:
---
$?
75
l
/-
-
B 2 $
/
50
5 /
/ /
/
2 5 rp<.
.i.T ,k ’
l
*
/ **
/ / f** /
F
25
/
-3
**:p<.01
**
05
i;.;-i R SUPINE
BIKE
/ / P/ *
SUPZNE
BIKE
MAX SUEUAX EXERCISE
BIKE
SUBMAX MAX EXERCISE
T
*:pc. 05
SUPINE
SUBMAX MIX EXERCISE
BIKE
SUBMAX MAX EXERCISE
p=NS
SUPZNE
FIGURE 4. Effect of dobutamine (Dob) on leg oxygen uptake (\j02). leg oxygen extraction, leg lactate release and femoral venous lactate. Significant differences between control and dobutamine data are noted by asterisks. NS = not significant.
18 f 3% of total cardiac output. This proportion did not change with mounting the bicycle. Leg flow increased to 58 f 3% of the cardiac output at peak exercise, consistent with redistribution of flow to the leg during exercise. Administration of dobutamine did not significantly alter the proportion of flow to the legs. Discussion We have investigated the hypothesis that an inability of the heart to increase cardiac output normally during exercise is responsible for impaired skeletal muscle nutritive flow in patients with chronic CHF. Leg blood flow and leg 0s extraction were used as indexes of skeletal muscle perfusion, because flow to nonmuscular tissue makes up only a small portion of leg flow during exercise.23 Femoral venous lactate concentration was used to assess nutritional flow to working muscle. Previous studies have demonstrated that a reduction in nutritional flow to working muscle causes increased lactate production.24-2s Our results suggest that skeletal muscle nutritive flow is impaired during exercise in patients with chronic CHF. In addition, improving cardiac output during
exercise with dobutamine does not reverse or improve this flow impairment. During control exercise, metabolic changes developed in all patients, suggesting impaired nutritive flow to working muscle. Specifically, patients were limited by fatigue at markedly reduced maximal oxygen uptakes of 11.9 f 1.2 ml/min/kg. In normal subjects of comparable age, maximal oxygen uptake normally exceeds 20 to 25 ml/min/kg.1-“J3-15 Peak leg 02 extraction was markedly increased at 85 f 2%. In normal subjects performing similar levels of exercise, leg 02 extraction is usually less than 70%.7*27-2gMoreover, termination of exercise was associated with femoral venous lactate concentrations of 53 f 5 mg/dl and arterial lactate levels of 34 f 2 mg/dl, indicating increased anaerobic activity in muscle. In normal subjects, femoral venous and arterial lactate levels do not reach these levels until a work load above 125 W and an oxygen uptake of 15 to 20 ml/min/kg is achieved.10J4t2g,30 Similar regional metabolic abnormalities during exercise in patients with heart failure have been reported previously.l,7-'0,17,31
Administration of dobutamine significantly improved cardiac output and reduced pulmonary wedge pressure
1314
SKELETAL MUSCLE NUTRITIVE FLOW IN HEART FAILURE
during exercise, indicating improved cardiac performance. In addition, dobutamine improved femoral vein flow during exercise, indicating an increase in leg flow and suggesting an increase in total skeletal muscle flow. Despite these improvements in both cardiac output and leg flow, we observed little evidence that skeletal muscle nutritive flow was significantly changed. Specifically, maximal exercise duration was not improved. Systemic VOs and arterial lactate concentrations were also not significantly different from control exercise values when compared at identical exercise loads and times. The amount of lactate released from the leg was unchanged, marked leg lactate release still developing early in exercise. Femoral venous lactate decreased slightly, but this decrease was most likely due to a dilutional effect rather than to less lactate production by muscle. Finally, leg 02 extraction was reduced by dobutamine throughout exercise, consistent with the increase in leg flow primarily being due to an increase in nonnutritive flow. The only evidence of a significant improvement in skeletal muscle nutritive flow was a small but significant increase in leg VOz when measured at the same peak work load as that during control exercise. However, because systemic VOz did not change at the same time, this increase in leg VOz must involve a decrease in 02 uptake by nonexercising tissue, which seems unlikely. It is more likely that leg VOz did not increase and that the apparent change in VOz was due to technical factors. Specifically, femoral venous effluent samples may not necessarily assess venous drainage from the same total muscle mass contributing to the leg flow measurement. This could occur if, for example, the sampling port is close to a sizable vein draining into the femoral or iliac vein. In addition, flow measurements represent the average of measurements made over 3 minutes, whereas 02 extraction is measured only once every 3 minutes. Finally, substantial phasic alterations in leg flow normally occur during exercise, making it possible for modest quantitative errors in leg flow to occur. These 3 factors together potentially could result in modest errors in calculated leg 02 uptake. Dobutamine administration also was associated with a small increase in maximal VOz. This increase was made significant by 2 patients exercising longer with dobutamine but at the expense of substantially higher maximal arterial lactate levels than those during control exercise. In both cases, systemic VOz and lactate levels were similar to control exercise levels when compared at comparable work loads. This finding suggests that both patients had increased VOz levels because of increased motivation during the second exercise test rather than improved skeletal muscle nutritive flow. During maximal exercise in normal, well-motivated subjects, VOz typically reaches a definite plateau beyond which further increments in work load produce no further increments in VOz. In our experience and in that of other investigators, 32 few patients with heart failure reach a definite VOz plateau during maximal exercise, although a relative plateauing of VOz often occurs. Therefore, a patient can have a slight increase in maximal VO2 during a repeat exercise test because of
increased motivation. However, unless muscle flow is improved, this increase in maximal VOs will be accompanied by an increase in blood lactate concentration. Our findings are consistent with a recent report by Maskin et al,33 in which they examined the effect of dobutamine on systemic hemodynamic and metabolic responses to exercise in 8 patients with heart failure. Dobutamine increased the maximum cardiac index from 2.7 to 3.2 liters/min/m2 and the maximal 902 from 8.5 to 9.1 ml/min/kg. However, the average exercise duration and maximal arterial lactate levels were unchanged. Only 1 patient had an increase in VOz max of more than 1.0 ml/min/kg and did so only at the expense of an 11.6 mg/dl increase in maximal lactate concentration. Therefore, these investigators speculated that dobutamine does not improve blood flow to working skeletal muscle. However, they did not directly measure leg flow or metabolism. The failure of dobutamine to improve leg metabolism in our patients suggests that impaired skeletal muscle nutritive flow in CHF is not due simply to an inability of the heart to increase cardiac output normally during exercise. Indeed, our observation that leg metabolism did not change despite heightened leg flow suggests the presence of a defect within muscle which prevented the increased flow from being delivered to or utilized by ischemic working muscle. This defect could be intrinsic to muscle or, far less likely, be due to dobutamine. Dobutamine causes /3z adrenoreceptor stimulation,3P36 an effect that could alter flow distribution in muscle.37 However, such stimulation usually does not occur until doses exceed 10 ~g/kg/min.lzf4 Moreover, such stimulation is thought to improve, rather than worsen, nutritive flo~.~~ Therefore, our findings are most consistent with the presence of an intrinsic defect in skeletal muscle that interferes with nutritive flow delivery or utilization, or both. Studies by Zelis et a15p6also suggest the presence of such a defect. Specifically, they observed that forearm blood flow and O2 uptake were both depressed during forearm exercise in patients with heart failure. Because the small increases in flow required by forearm exercise should be attainable even by patients with substantial cardiac dysfunction, these investigators proposed that cardiac dysfunction is probably not the cause of impaired skeletal muscle nutritive flow in heart failure.5 These investigators also documented impaired arteriolar vasodilation in skeletal muscle in patients with heart failure and suggested that this abnormality may be one reason for impaired skeletal muscle nutritive flow.11 The presence of such peripheral abnormalities could preclude the use of inotropic agents in the treatment of exertional fatigue in patients with CHF. If these abnormalities are not reversed by augmenting cardiac pump function, the administration of inotropic agents may serve no useful function as far as exercising muscle is concerned. However, our data do not indicate that cardiac pump dysfunction is unimportant. Cardiac pump dysfunction is presumably ultimately responsible for the abnormalities that impair muscle nutritive flow.
May 1. 1984
Therefore, chronic administration of inotropic agents may reverse these abnormalities and, thereby, improve skeletal muscle nutritive flow and exertional fatigue. References 1. Weber KT, Kinasewitz GT, Janicki JS, Fishman AP. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 1982;65:1218-1223. 2. Franciosa JA, Ziesche S, When M. Functional capacity of patients with chronic left ventricular failure. Relationship of bicycle exercise performance to clinical and hemodynamic characterization. Am J Med 1979;67:460466. 3. Patterson JA, Naughton J, Pletras RJ, Gunnar RY. Treadmill exercise in assessment of the functional capacity of patients with cardiac disease. Am J Cardiol 1972;30:757-762. 4. WINon JR, Ferraro N. Exercise intolerance in patients with chronic left heart failure: relation to oxygen transport and ventilatory abnormalities. Am J Cardiol 1983;51:1358-1363. Zells R, Long&et J, Capone RJ, Mason DT. A comparison of regional blood 5. flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 197450: 137-143. 6. Longhurst J, Gffford W, Zelis R. Impaired forearm oxygen consumption during static exercise in patients with congestive heart failure. Circulation 1976;54:477-480. 7. Donald KW, Wormald PN, Taylor SH, Bishop JM. Changes in the oxygen content of femoral venous blood and leg blood flow during leg exercise in relation to cardiac output response. Clin Sci 1957;16:587-591. 8. LeJemtel TH, Maekln CS, Chadwick 8, Sfnoway L. Near maximal oxygen extraction by exercising muscles in patients with severe heart failure: a limitation to benefits of physical training (abstr). J Am Coll Cardiol 1983; 1:662. 9. Huckabee WE, Judson WE. The role of anaerobic metabolism in the performance of mild muscular work. I. Relationship to oxygen consumption and cardiac output and the effect of congestive heart failure. J Clin Invest 1958:37:1577-1592. 10. Donaid KW, Gloeter J, Harris EA, Reeves J, Harris P. The production of lactic acid during exercise in normal subjects and in patients with rheumatic heart disease. Am Heart J 1961:62:494-510. Il. Zells R, Nellls SH, Lonahurst J; Lee G, Mason DT. Abnormalities in the regional circulations accompanying congestive heart failure. Prog Cardiovasc Dis 1975:18:181-199. 12. SoMenMick EH, Frtstunan WH, LeJerntei TH. Dobutamine: a new synthetic cardioactive sympathetic amine. N Engl J Med 1979;300:17-22. 13. Bruce RA, Kusuml F, Hoerher D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J 1973;85:546-562. 14. Aetrahd I. Aerobic work capacity in men and women with special reference to age. Acta Physiol Stand 1960;49:suppl 169:1-92. 15. Sidney KH, Shephard RJ. Maximum and submaximum exercise tests in men and women in the seventh. eiohth and ninth decades of life. J Aool Physiol 1977;43:280-287
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16. Moskowitz RM, Kinney EL, Zelis RF. Hemodynamic and metabolic responses to upright exercise in patients with congestive heart failure. Chest 1979;76:640-646. 17. Wilson JR, Martln JL, Ferraro N, Weber KT. Effect of hydralazine on perfusion and metabolism in the leg during upright bicycle exercise in patients with heart failure. Circulation 1983:68:425-432. 16. Jorfeldt L, Wahren J. Leg blood flow during exercise in man. Clin Sci 1971;41:459-473. 19. Garu V, Hlavova A, Fmnek A, Linhart J, Prerovsky I. Measurement of blood flow in the femoral artery in man at rest and during exercise by local thermodilution. Circulation 1964;30:86-89. 20. Jorfektt L, Jublin-Dannfeft A, Pernow B, Wassen E. Determination of human leg blood flow: a thermodilution technique based on femoral venous bolus injection. Clin Sci Mol Med 1968;54:517-523. 21. Henry JR. Clinical Chemistry, Principles and Technics. New York: Harper 8 Row, 1968:655. 22. Snedecor GW, Cochran WG. Statistical Methods. Ames, IA: Iowa State University Press, 1967. 23. Roweil LB. Human cardiovascular adiustments to exercise and thermal stress. Physiol Rev 1974;54:75-159. ’ 24. Horstman DH, Gieser M, Deiehurtt J. Effects of altering 0s delivery on VO, of isolated, working muscle. Am J Physiol 1976;230:327-334. 25. Walker PM,, idstrom J, Schersten T, Bylund-Felienius A. Metabolic response in different muscle types to reduced blood flow during exercise in oerfused rat hindlimb. Clin Sci 1982:63:293-299. 26. PentOw B, Saftln B, Wahren J, Cron&trand R, Ekestrom S. Leg blood flow and muscle metabolism in occlusive arterial disease of the legbefore and after reconstructive suroerv. Clin Sci Mol Med 1975:49:265-275. 27. Pirnay F, Lamy M,, DuJa;di; J, Deroanne R, Petit JM. Analysis of femoral venous blood durrng maximal muscular exercise. J Appl Physiol 1972; 33:289-292. 26. Doll E, Keul J, Malwald C. Oxygen tension and acid-base equilibration in venous blood of working muscle. Am J Physiol 1968;215:23-29. 29. Cobb LA, Smfth PH, Lwai S, Short FA. External iliac vein flow: its response to exercise and relation to lactate oroduction. J ADDI 1969:26: *. Phvsiol I 606-610. 30. ksekutzB Jr, Rodahi K. Respiratory quotient during exercise. J Appl Physiol 1961:16:606-610, 31. Hood’ WB Jr, Krasnow N,.Rolett EL, Yurchak PM, Gorlin R. Anaerobic metabolism of the exercrsrng leg in man. Clin Sci 1965;28:175-189. 32. Matsumura N, Nishljlma H, Kojlma S, Hashlmoto F, Minaml Y, Yasuda H. Determination of anaerobic threshold for assessment of functional state in patients with chronic heart failure. Circulation 1983;68:360-367. 33. Maekln CS. Forman R. Sonnanbiick EH. Frishman WH. LeJemtei TH. Failure of dobutamine to increase exerci& capacity despite hemodynamic improvement in severe chronic heart failure. Am J Cardiol 1983;51: 177-182. 34. Roble NW, Nutter DO, Moody C, McNay JL. In vivo analysis of adrenergic receptor activity of dobutamine. Circ Res 1974:34:663-671. 35. Sheehan RM, Rehkin EM. Influence of adrenergic drugs on blood-tissue diffusion. Pharmacologist 1965;7:178. 36. Lundvall J, Jarhutt J. Beta-adrenergic dilator component of the sympathetic vascular response in skeletal muscle. Acta Physiol Stand 1978;96: 180-192. 37. Hlrvonen L, Korobkin M, Sonnenschein RR, Wright DL. Depression of contractile force of skeletal muscle by intra-arterial vasodilator drugs. Circ Res 1964;19:525-535.
Impaired Skeletal Muscle Nutritive Flow During Exercise in Patients with Congestive Heart Failure: Role of Cardiac Pump Dysfunctionas Determined by the Effect of Dobutamine JOHN R. WILSON, MD, JACK L. MARTIN, MD, and NANCY FERRARO, RN
The maximal exercise capacity of patients with congestive heart failure (CHF) is frequently reduced, partly because of inadequate skeletal muscle nutritlve flow. To investigate whether this altered muscle nutritive flow is a result of inability of the heart to increase cardiac output normally during exercise, the effect of dobutamine on systemic and leg blood flow and metabolism during maximal exercise was examined in 11 patients with CHF. At maximal exercise before dobutamine, all patients were limited by fatigue and had reduced maximal systemic oxygen uptake ( 11.9 f 1.1 ml/min/kg) ( f standard error of the mean), markedly elevated leg oxygen extraction (85 f 2%) and elevated femoral venous lactate (53 f 5 mg/dl), consistent with impaired nutritive flow to working muscle. Dobutamine increased the peak cardiac output from (8.5 f 0.9
to 7.4 f 0.7 liters/min, p
Patients with chronic congestive heart failure (CHF) are frequently limited during exercise even when they are asymptomatic at rest.1-3 This exertional intolerance is due at least in part to inadequate nutritive flow to working skeletal muscle, because patients with CHF are frequently limited by fatigue1p4 and, during exercise, characteristically have reduced cardiac output,1*4 reduced skeletal muscle blood fl0w,5-~ heightened limb oxygen extraction7T8 and early lactate release.l,gJO However, the cause of this impaired skeletal muscle nutritive flow is uncertain. Some investigators have speculated that nutritive flow is impaired because of an
inability of the heart to increase cardiac output normally during exercise. l Other investigators have suggested that impaired dilation of precapillary arterioles or sphincters within working skeletal muscle is the principal reason that nutritive flow is reduced.5J1 This study was undertaken to investigate the hypothesis that an inability of the heart to increase cardiac output normally during exercise is primarily responsible for impaired skeletal muscle nutritive flow in patients with CHF. Accordingly, we measured both systemic and leg blood flow and metabolism during upright maximal bicycle exercise in patients with CHF. We then repeated these studies after enhancement of cardiac function with dobutamine, a catecholamine that increases cardisc contractility by directly stimulating myocardial ,81 adrenoreceptors.12 We reasoned that if the hypothesis was accurate, dobutamine should produce an increase in leg blood flow associated with a commensurate increase in systemic and leg oxygen uptake and a reduction in arterial lactate concentration and leg lactate release.
(Am J Cardiol 1984;53:1308-1315)
From the Cardiovascular Section, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. This study was supported in part by Clinical Research Center Grant 5-MO1-RFtOOO4Oand a Young Investigator Grant from the National Institutes of Health, Bethesda, Maryland. Manuscript received October 19, 1983; revised manuscript received January 4,1984, accepted January 5, 1984. Address for reprints: John Ft. Wilson, MD, Cardiovascular Section, 943 West Gates, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. 1308
May 1. 1984
TABLE I
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Effects of Dobutamine on Systemic Hemodynamic and Metabolic Responses to Exercise PWP
BP (If&
(mYPm2in)
0s Extraction
Lactate
(%I
(mg/dU
(beazmin)
(mm Hg)
84 f 4 88 f 5 101 f 7
85 f 2 88 f 3 95 f 4
3.2 f 0.2 3.2 f 0.3 8.2 f 0.7
20 f 2 17f3 22 f 4
234 f 11 283 f 24 731 f 41
45 f 3 52 f 4 70 f 4
14.; i 20.6 f
121 f 6
101 f 4
6.5 f 0.9
29 f 3
829 f 97
79 f 3
33.8 f 2.2
14 f 2’
246 263 f 18 16 749 f 41
:z+ 61 f4+
24f2’ 24f2’
869 f 77 888 f 76’
72 f 2+ 73 f 2+
(mm Hg) Control
$$J Submaximal exercise Peak exercise
1.4 1.6
Dohutamine
Lying Bike Submaximal exercise’ Peak exercisef Maximal exercise
91 98 f 3’ 4’ 113f 5+ 126f 126f
5 5
83 89 f 4 97 f 2 103f3 103 f 3
7.4 f 0.7+ 7.4 f 0.7+
l
15.6 i 19.5 f
1.8 1.9
34.6 f 3.5 37.0 f 3.7
p <0.05 compared with control; + p
Methods Patients: Eleven patients, 8 men and 3 women with a mean age of 57 f 10 years (range 45 to 70), with chronic left ventricular (LV) dysfunction (mean ejection fraction 20 f 10% [f standard deviation]) were studied. All had exertional breathlessness or fatigue despite administration of digoxin and diuretics. None had peripheral edema, ascites, angina pectoris, intermittent claudication or reduced pulses in their legs at the time of study. Each patient had a reduced maximal 0s uptake (VOs max) below the expected normal range (average 11.9 f 3.5 ml/min/kg, range 5.3 to 15.4; normal >20).l-3J3-15 LV dysfunction was attributed to coronary artery disease in 7 patients and to idiopathic dilated cardiomyopathy in 4. Protocol: On the day before study, a trial maximal exercise test was performed to acquaint the patient with the exercise protocol. Exercise was performed on an upright mechanically braked bicycle ergometer (Monark) and begun at a work load of 20 W. Every 3 minutes, the work load was increased by 20 W to symptomatic maximum. All exercise tests were performed at least 4 hours after meals. The next morning, a Swan-Ganz catheter was inserted through an antecubital vein and positioned in the pulmonary artery. A short polyethylene catheter was inserted in a radial artery. A No. 5Fr thermodilution catheter was inserted percutaneously into a femoral vein and advanced 15 to 16 cm anterograde into the iliac vein. Thirty minutes after instrumentation, hemodynamic measurements were made and blood samples were obtained from the radial arterial and femoral venous catheters for oxygen saturation and lactate concentration. Femoral venous blood flow was measured in triplicate. Respiratory gases were measured with a Beckman metabolic cart equipped with 0s and COs analyzers and a turbine volume transducer. The patient then mounted the bicycle and was allowed to equilibrate for 5 minutes, after which all measurements were repeated. The patient then began to exercise. Respiratory gas and hemodymunic measurements were made continuously. During each 3-minute exercise stage, leg blood flow was measured every 30 seconds starting at 30 seconds and continuing for 2.5 minutes for a total of 5 measurements. Blood sampling was performed during the last 30 seconds of the stage. Leg flow was not measured during this period. After exercise was terminated, the patient was allowed to rest for 2 hours. Dobutamine was then administered intra-
venously, starting at 2.5 pglkglmin. The dose was increased by 2.5 pg/kg/min every 10 minutes until the cardiac output increased by more than 30% or until a peak dose of 10 pg/kg/min was achieved. The average final dobutamine dose was 8.2 f 2.5 /.tg/kg/min (range 2.5 to 10). The exercise protocol was then repeated. Measurements were made at identical exercise times as during control exercise and, when a patient exercised longer after dobutamine administration, also at the new maximal exercise level. The period between exercise tests was 2.5 hours. This period was believed to be adequate to assure full recovery from the first exercise test because hemodynamic and metabolic parameters returned to control levels by 2 hours. Previous observations have also documented the return of these variables to baseline levels within 2 hours.16J7 Metabolic responses to exercise tests before and 2 hours after nitrate administration are comparable,16 suggesting that 2 hours is also a sufficient time for metabolic responses to return to control levels; nitrates are primarily venodilators and should not affect oxygen delivery to muscle. We have also performed duplicate exercise tests 2.5 hours apart in 4 patients with CHF. Ventilatory, hemodynamic and metabolic responses to exercise were reproducible. Leg blood flow: Leg blood flow was determined as previously described.” In brief, femoral vein flow was measured using a 50-cm 5Fr thermodilution catheter with the thermistor at 2 cm and the injection port at 12 cm. Flow was determined using rapid injection of a 2.5-ml iced dextrose bolus injectate and a commercially available thermodilution computer (Elecath). Output curves were displayed on a strip-chart recorder to assure an exponential decay curve. Flow determined using this system correlated closely with known flow rates (0.2 to 6.0 liters/min, r = 0.99) when evaluated using a closed-loop system in which 37°C water was continuously circulated through 7-mm polyethylene tubing using a roller pump. The coefficient of variation of duplicate flow measurements made sequentially in patients during the same exercise test was 9 f 10% at rest and 16 f 1% during exercise (i standard deviation). This variation is partly due to normal phasic alterations in flow. Therefore, flow measurements were routinely made every 30 seconds after the first 30 seconds of an exercise stage. Measurements at any given stage were then averaged. In 4 patients, 2 exercise tests were performed 2.5 hours apart to evaluate the reproducibility of such averaged flow measurements. The coefficient of variation of repeated flow measurements was 16 f 10% (n = 14). Averaged group flow measurements made during the first and second exer-
1310
SKELETAL MUSCLE NUTRITIVE FLOW IN HEART FAILURE
Control:
_
Dab: ---
p=NS
SUPINE
BIKE
MAX SUBMAX EXERCISE
**:p<. 01
SUPINE
*:p<. **:ps
BIKE
MAX SUBMAX EXERCISE
05 01
cise periods were reproducible: resting (0.35 f 0.05 vs 0.34 f 0.03 liters/min), submaximal exercise (2.64 f 1.40 vs 2.52 f 1.06 liters/min) and maximal exercise (3.05 f 1.00 vs 3.00 f 1.24 liters/min). We previously demonstrated a close correlation between leg flow measured using this technique and systemic VOz.17 The measured leg flow levels observed in this study are comparable to leg flow measurements reported with other methods.18-20 The validity of using the thermodilution technique to measure leg flow during upright bicycle exercise has also been confirmed by other investigators.20 Measured variables: Hemoglobin concentration was measured by Coulter Counter; hemoglobin oxygen saturation was measured with a cooximeter (Instrumentation Laboratories) precalibrated with human blood. Blood O2 content was calculated as the product of hemoglobin, 1.34 ml 02/g hemoglobin, and the percent 02 saturation. Oxygen extraction was calculated as the ratio of the arteriovenous 02 difference and arterial 02 content. Cardiac output was calculated from the Fick principle as VOJsystemic arteriovenous 02 difference. Leg vascular resistance was calculated as (arterial pressure - femoral venous pressure)/leg flow. Leg 02 consumption was calculated as the product of femoral flow and the arteriovenous 02 difference across the leg. Blood for lactate determination was deproteinized with cold perchloric acid and assayed with a spectrophotometric technique.21 Normal values at rest for this technique in our laboratory are 3 to 12 mg/dl. Leg lactate release was calculated as leg flow - (femoral venous arterial lactate concentration). Leg flow and leg 02 and lactate data were not obtained simultaneously. Therefore, calculation of leg VOz and lactate release assumes that leg flow remained relatively constant during exercise. In support of this assumption, we observed that flow increases abruptly with the onset of exercise and stabilizes within 30 to 45 seconds. Statistical methods: Values are presented as mean f standard error of the mean. Differences between measurements at rest, submaximal exercise and maximal exercise were compared by the paired Student t test.22 In only 6 patients were measurements made during submaximal exercise. In 2 of these 6 patients, multiple measurements were made during submaximal exercise. These measurements were averaged before analyzing the effect of dobutamine on submaximal exercise measurements. A value of <0.05 was considered significant.
Results The effects of dobutamine on systemic and regional parameters are summarized in Tables I and II and illustrated in Figures 1 to 4. The control and postdobutamine data illustrated in the figures were obtained at identical work times. In 2 patients, leg blood flow measurements were not obtained because of technical difficulties.
Control systemic hemodynamic and metabolic measurements (Fig. 1 and 2): At supine rest, cardiac output
SUPINE
BIKE
MAX SUBMAX EXERCISE
FIGURE 1. Effect of dobutamine (Dob) on mean blood pressure (BP), cardiac output (CO) and pulmonary wedge pressure (PWP) responses to exercise. The apparent lack of increase in CO from submaximal to maximal exercise is due to inclusion of submaximal data from only 6 patients, not to a plateauing of the CO response. Significant differences between control and dobutamine data are noted by asterisks. NS = not significant.
was 3.2 f
0.2 liters/min,
pulmonary wedge 02 extraction 45 f 3%, consistent with LV pump dysfunction. When the bicycle was mounted, cardiac output remained unchanged whereas pulmonary wedge pressure decreased slightly to 17 f 3 mm Hg. Patients exercised an average of 5.5 f 0.8 minutes (range 3 to 9), stopping due to fatigue at a maximum VO, of 829 f 97 ml/min. Exercise increased cardiac output to 6.5 f 0.9 liters/min, pulmonary wedge pres-
pressure 20 f 2 mm Hg and systemic
May I.1984
TABLE II
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Effect of Dobulamine on Leg Hemodynamic and Metabolic ReSpOnSeSt0 Exercise Leg Flow (I/min)
Leg i/O* (ml/min)
Leg
Leg 02
Resistance (units)
Extraction (“/)
Femoral Lactate (mgldt)
AV Lactate Difference (mgjdt)
Leg Lactate Release (mglmin)
Control /j”,” Submaximal exercise Peak exercise
0.25 f 0.03 0.26 0.05 1.60 f 0.31 1.72 f 0.26
28.1 19.5 f 2.4 4.6 204.4 f 30.0 234.0 f 32.7
297 f 36 310 17 62f 12 53 f 7
65 f 3 47 81 f2 85 f 2
15.3’%‘1.7 29.3 f 3.4 52.6 f 4.5
1.3’%‘0.9 8.8 f 1.8 19.1 f 3.2
4f2 104 f 29 248 f 39
16.9.j.2.0 27.2 f 2.0 47.9 f 4.3’ 52.6 f 5.4
1.9’i.o.s 7.7 f 1.5 13.3 f 1.9+ 15.7 f 2.7’
4f2 140 f 46 275 f 53 275 f 94
Dobutamine Lying Bike Submaximal exercise’ Peak exerciset Maximal exercise
0.41 0.33 2.00 2.06 2.01
f f f f f
0.07’ 0.07 0.36’ 0.28’ 0.70‘
22.5 27.7 239.0 264.2 265.9
f f f f f
5.1 6.1 39.9 31.8’ 30.1
235 f 250 f 42 f 36 f 3865’
41 37+ 7 5+
30 f 3+ 51*5+ ‘8;: 2 $ 81 f
I+
p <0.05 compared with control; + p
sure to 29 f 3 mm Hg, systemic 02 extraction to 79 f 3% and arterial lactate concentration to 34 f 2 mg/dl. Effect of dobutamine on systemic 02 transport (Fig. 1 and 2): At supine rest, dobutamine increased cardiac output from 3.2 f 0.2 to 4.8 f 0.3 liters/min (p
patients; the mean arteriovenous lactate difference was 1.3 f 0.9 mg/dl. With exercise, leg flow increased progressively to a peak flow of 1.72 f 0.26 liters/min whereas leg resistance decreased to 53 f 7 units. Leg VOs increased to 234 f 33 ml/min, mediated by both the increase in flow and the increase in leg 02 extraction to 85 f 2%. Femoral venous lactate increased from 15 f 2 to 53 f 5 mg/dl, whereas leg lactate release increased from 4 f 2 to 248 f 39 mg/min, indicating increased anaerobic metabolic activity in the leg. Effect of dobutamine on leg flow and metabolism (Fig. 3 and 4): Administration of dobutamine increased the supine resting leg flow from 0.25 f 0.03 to 0.41 f 0.07 liters/min (p <0.05), whereas leg 0s extraction decreased from 47 f 3 to 30 f 3% (p
1312
SKELETAL MUSCLE NUTRITIVE FLOW IN HEART FAILURE
Control: Dab:
-
Control:
---
Dab:
1
_
---
J l
l:pc.
05
*---
0 SUPINE
BIKE
SUBMAX
SUPINE
MAX
BIKE
SUBMAX
MAX
EXERCISE
EXERCISE
500
100
l:p<. 05 +*:p<. 01
400
75
50
;/
p” **
2*
/
/
/
/ t*
2 / / **
300
-\ l * \
\ \ 100
25 BIKE
f --i
200
l
0 SUPINE
**:p<. 01
SUffUAX
\
I__
SUPiNE
MAX
BIKE
kic-z+& **
SUBMAX
MAX
EXERCISE
EXERCISE
80
5-O
40
60 p =NS 30
20
10
0 SUPINE
BIKE
SUBMAX
MAX
EXERCISE
FIGURE 2. Effect of dobutamine (Dob) on systemic oxygen uptake (\iO,), systemic oxygen extraction and arterial lactate. Significant differences between control and dobutamine data are noted by asterisks. NS = not significant.
SUP/NE
BIKE
MAX SUBMAX EXERCISE
FIGURE 3. Effect of dobutamine (Dob) on leg flow, leg resistance and the percentage of cardiac output delivered to the leg. Significant differences between controt and dobutamine data are noted by astertsks. NS = not significant.
May 1. 1984
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
1313
100
Control: Oob:
---
$?
75
l
/-
-
B 2 $
/
50
5 /
/ /
/
2 5 rp<.
.i.T ,k ’
l
*
/ **
/ / f** /
F
25
/
-3
**:p<.01
**
05
i;.;-i R SUPINE
BIKE
/ / P/ *
SUPZNE
BIKE
MAX SUEUAX EXERCISE
BIKE
SUBMAX MAX EXERCISE
T
*:pc. 05
SUPINE
SUBMAX MIX EXERCISE
BIKE
SUBMAX MAX EXERCISE
p=NS
SUPZNE
FIGURE 4. Effect of dobutamine (Dob) on leg oxygen uptake (\j02). leg oxygen extraction, leg lactate release and femoral venous lactate. Significant differences between control and dobutamine data are noted by asterisks. NS = not significant.
18 f 3% of total cardiac output. This proportion did not change with mounting the bicycle. Leg flow increased to 58 f 3% of the cardiac output at peak exercise, consistent with redistribution of flow to the leg during exercise. Administration of dobutamine did not significantly alter the proportion of flow to the legs. Discussion We have investigated the hypothesis that an inability of the heart to increase cardiac output normally during exercise is responsible for impaired skeletal muscle nutritive flow in patients with chronic CHF. Leg blood flow and leg 0s extraction were used as indexes of skeletal muscle perfusion, because flow to nonmuscular tissue makes up only a small portion of leg flow during exercise.23 Femoral venous lactate concentration was used to assess nutritional flow to working muscle. Previous studies have demonstrated that a reduction in nutritional flow to working muscle causes increased lactate production.24-2s Our results suggest that skeletal muscle nutritive flow is impaired during exercise in patients with chronic CHF. In addition, improving cardiac output during
exercise with dobutamine does not reverse or improve this flow impairment. During control exercise, metabolic changes developed in all patients, suggesting impaired nutritive flow to working muscle. Specifically, patients were limited by fatigue at markedly reduced maximal oxygen uptakes of 11.9 f 1.2 ml/min/kg. In normal subjects of comparable age, maximal oxygen uptake normally exceeds 20 to 25 ml/min/kg.1-“J3-15 Peak leg 02 extraction was markedly increased at 85 f 2%. In normal subjects performing similar levels of exercise, leg 02 extraction is usually less than 70%.7*27-2gMoreover, termination of exercise was associated with femoral venous lactate concentrations of 53 f 5 mg/dl and arterial lactate levels of 34 f 2 mg/dl, indicating increased anaerobic activity in muscle. In normal subjects, femoral venous and arterial lactate levels do not reach these levels until a work load above 125 W and an oxygen uptake of 15 to 20 ml/min/kg is achieved.10J4t2g,30 Similar regional metabolic abnormalities during exercise in patients with heart failure have been reported previously.l,7-'0,17,31
Administration of dobutamine significantly improved cardiac output and reduced pulmonary wedge pressure
1314
SKELETAL MUSCLE NUTRITIVE FLOW IN HEART FAILURE
during exercise, indicating improved cardiac performance. In addition, dobutamine improved femoral vein flow during exercise, indicating an increase in leg flow and suggesting an increase in total skeletal muscle flow. Despite these improvements in both cardiac output and leg flow, we observed little evidence that skeletal muscle nutritive flow was significantly changed. Specifically, maximal exercise duration was not improved. Systemic VOs and arterial lactate concentrations were also not significantly different from control exercise values when compared at identical exercise loads and times. The amount of lactate released from the leg was unchanged, marked leg lactate release still developing early in exercise. Femoral venous lactate decreased slightly, but this decrease was most likely due to a dilutional effect rather than to less lactate production by muscle. Finally, leg 02 extraction was reduced by dobutamine throughout exercise, consistent with the increase in leg flow primarily being due to an increase in nonnutritive flow. The only evidence of a significant improvement in skeletal muscle nutritive flow was a small but significant increase in leg VOz when measured at the same peak work load as that during control exercise. However, because systemic VOz did not change at the same time, this increase in leg VOz must involve a decrease in 02 uptake by nonexercising tissue, which seems unlikely. It is more likely that leg VOz did not increase and that the apparent change in VOz was due to technical factors. Specifically, femoral venous effluent samples may not necessarily assess venous drainage from the same total muscle mass contributing to the leg flow measurement. This could occur if, for example, the sampling port is close to a sizable vein draining into the femoral or iliac vein. In addition, flow measurements represent the average of measurements made over 3 minutes, whereas 02 extraction is measured only once every 3 minutes. Finally, substantial phasic alterations in leg flow normally occur during exercise, making it possible for modest quantitative errors in leg flow to occur. These 3 factors together potentially could result in modest errors in calculated leg 02 uptake. Dobutamine administration also was associated with a small increase in maximal VOz. This increase was made significant by 2 patients exercising longer with dobutamine but at the expense of substantially higher maximal arterial lactate levels than those during control exercise. In both cases, systemic VOz and lactate levels were similar to control exercise levels when compared at comparable work loads. This finding suggests that both patients had increased VOz levels because of increased motivation during the second exercise test rather than improved skeletal muscle nutritive flow. During maximal exercise in normal, well-motivated subjects, VOz typically reaches a definite plateau beyond which further increments in work load produce no further increments in VOz. In our experience and in that of other investigators, 32 few patients with heart failure reach a definite VOz plateau during maximal exercise, although a relative plateauing of VOz often occurs. Therefore, a patient can have a slight increase in maximal VO2 during a repeat exercise test because of
increased motivation. However, unless muscle flow is improved, this increase in maximal VOs will be accompanied by an increase in blood lactate concentration. Our findings are consistent with a recent report by Maskin et al,33 in which they examined the effect of dobutamine on systemic hemodynamic and metabolic responses to exercise in 8 patients with heart failure. Dobutamine increased the maximum cardiac index from 2.7 to 3.2 liters/min/m2 and the maximal 902 from 8.5 to 9.1 ml/min/kg. However, the average exercise duration and maximal arterial lactate levels were unchanged. Only 1 patient had an increase in VOz max of more than 1.0 ml/min/kg and did so only at the expense of an 11.6 mg/dl increase in maximal lactate concentration. Therefore, these investigators speculated that dobutamine does not improve blood flow to working skeletal muscle. However, they did not directly measure leg flow or metabolism. The failure of dobutamine to improve leg metabolism in our patients suggests that impaired skeletal muscle nutritive flow in CHF is not due simply to an inability of the heart to increase cardiac output normally during exercise. Indeed, our observation that leg metabolism did not change despite heightened leg flow suggests the presence of a defect within muscle which prevented the increased flow from being delivered to or utilized by ischemic working muscle. This defect could be intrinsic to muscle or, far less likely, be due to dobutamine. Dobutamine causes /3z adrenoreceptor stimulation,3P36 an effect that could alter flow distribution in muscle.37 However, such stimulation usually does not occur until doses exceed 10 ~g/kg/min.lzf4 Moreover, such stimulation is thought to improve, rather than worsen, nutritive flo~.~~ Therefore, our findings are most consistent with the presence of an intrinsic defect in skeletal muscle that interferes with nutritive flow delivery or utilization, or both. Studies by Zelis et a15p6also suggest the presence of such a defect. Specifically, they observed that forearm blood flow and O2 uptake were both depressed during forearm exercise in patients with heart failure. Because the small increases in flow required by forearm exercise should be attainable even by patients with substantial cardiac dysfunction, these investigators proposed that cardiac dysfunction is probably not the cause of impaired skeletal muscle nutritive flow in heart failure.5 These investigators also documented impaired arteriolar vasodilation in skeletal muscle in patients with heart failure and suggested that this abnormality may be one reason for impaired skeletal muscle nutritive flow.11 The presence of such peripheral abnormalities could preclude the use of inotropic agents in the treatment of exertional fatigue in patients with CHF. If these abnormalities are not reversed by augmenting cardiac pump function, the administration of inotropic agents may serve no useful function as far as exercising muscle is concerned. However, our data do not indicate that cardiac pump dysfunction is unimportant. Cardiac pump dysfunction is presumably ultimately responsible for the abnormalities that impair muscle nutritive flow.
May 1. 1984
Therefore, chronic administration of inotropic agents may reverse these abnormalities and, thereby, improve skeletal muscle nutritive flow and exertional fatigue. References 1. Weber KT, Kinasewitz GT, Janicki JS, Fishman AP. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 1982;65:1218-1223. 2. Franciosa JA, Ziesche S, When M. Functional capacity of patients with chronic left ventricular failure. Relationship of bicycle exercise performance to clinical and hemodynamic characterization. Am J Med 1979;67:460466. 3. Patterson JA, Naughton J, Pletras RJ, Gunnar RY. Treadmill exercise in assessment of the functional capacity of patients with cardiac disease. Am J Cardiol 1972;30:757-762. 4. WINon JR, Ferraro N. Exercise intolerance in patients with chronic left heart failure: relation to oxygen transport and ventilatory abnormalities. Am J Cardiol 1983;51:1358-1363. Zells R, Long&et J, Capone RJ, Mason DT. A comparison of regional blood 5. flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 197450: 137-143. 6. Longhurst J, Gffford W, Zelis R. Impaired forearm oxygen consumption during static exercise in patients with congestive heart failure. Circulation 1976;54:477-480. 7. Donald KW, Wormald PN, Taylor SH, Bishop JM. Changes in the oxygen content of femoral venous blood and leg blood flow during leg exercise in relation to cardiac output response. Clin Sci 1957;16:587-591. 8. LeJemtel TH, Maekln CS, Chadwick 8, Sfnoway L. Near maximal oxygen extraction by exercising muscles in patients with severe heart failure: a limitation to benefits of physical training (abstr). J Am Coll Cardiol 1983; 1:662. 9. Huckabee WE, Judson WE. The role of anaerobic metabolism in the performance of mild muscular work. I. Relationship to oxygen consumption and cardiac output and the effect of congestive heart failure. J Clin Invest 1958:37:1577-1592. 10. Donaid KW, Gloeter J, Harris EA, Reeves J, Harris P. The production of lactic acid during exercise in normal subjects and in patients with rheumatic heart disease. Am Heart J 1961:62:494-510. Il. Zells R, Nellls SH, Lonahurst J; Lee G, Mason DT. Abnormalities in the regional circulations accompanying congestive heart failure. Prog Cardiovasc Dis 1975:18:181-199. 12. SoMenMick EH, Frtstunan WH, LeJerntei TH. Dobutamine: a new synthetic cardioactive sympathetic amine. N Engl J Med 1979;300:17-22. 13. Bruce RA, Kusuml F, Hoerher D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J 1973;85:546-562. 14. Aetrahd I. Aerobic work capacity in men and women with special reference to age. Acta Physiol Stand 1960;49:suppl 169:1-92. 15. Sidney KH, Shephard RJ. Maximum and submaximum exercise tests in men and women in the seventh. eiohth and ninth decades of life. J Aool Physiol 1977;43:280-287
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16. Moskowitz RM, Kinney EL, Zelis RF. Hemodynamic and metabolic responses to upright exercise in patients with congestive heart failure. Chest 1979;76:640-646. 17. Wilson JR, Martln JL, Ferraro N, Weber KT. Effect of hydralazine on perfusion and metabolism in the leg during upright bicycle exercise in patients with heart failure. Circulation 1983:68:425-432. 16. Jorfeldt L, Wahren J. Leg blood flow during exercise in man. Clin Sci 1971;41:459-473. 19. Garu V, Hlavova A, Fmnek A, Linhart J, Prerovsky I. Measurement of blood flow in the femoral artery in man at rest and during exercise by local thermodilution. Circulation 1964;30:86-89. 20. Jorfektt L, Jublin-Dannfeft A, Pernow B, Wassen E. Determination of human leg blood flow: a thermodilution technique based on femoral venous bolus injection. Clin Sci Mol Med 1968;54:517-523. 21. Henry JR. Clinical Chemistry, Principles and Technics. New York: Harper 8 Row, 1968:655. 22. Snedecor GW, Cochran WG. Statistical Methods. Ames, IA: Iowa State University Press, 1967. 23. Roweil LB. Human cardiovascular adiustments to exercise and thermal stress. Physiol Rev 1974;54:75-159. ’ 24. Horstman DH, Gieser M, Deiehurtt J. Effects of altering 0s delivery on VO, of isolated, working muscle. Am J Physiol 1976;230:327-334. 25. Walker PM,, idstrom J, Schersten T, Bylund-Felienius A. Metabolic response in different muscle types to reduced blood flow during exercise in oerfused rat hindlimb. Clin Sci 1982:63:293-299. 26. PentOw B, Saftln B, Wahren J, Cron&trand R, Ekestrom S. Leg blood flow and muscle metabolism in occlusive arterial disease of the legbefore and after reconstructive suroerv. Clin Sci Mol Med 1975:49:265-275. 27. Pirnay F, Lamy M,, DuJa;di; J, Deroanne R, Petit JM. Analysis of femoral venous blood durrng maximal muscular exercise. J Appl Physiol 1972; 33:289-292. 26. Doll E, Keul J, Malwald C. Oxygen tension and acid-base equilibration in venous blood of working muscle. Am J Physiol 1968;215:23-29. 29. Cobb LA, Smfth PH, Lwai S, Short FA. External iliac vein flow: its response to exercise and relation to lactate oroduction. J ADDI 1969:26: *. Phvsiol I 606-610. 30. ksekutzB Jr, Rodahi K. Respiratory quotient during exercise. J Appl Physiol 1961:16:606-610, 31. Hood’ WB Jr, Krasnow N,.Rolett EL, Yurchak PM, Gorlin R. Anaerobic metabolism of the exercrsrng leg in man. Clin Sci 1965;28:175-189. 32. Matsumura N, Nishljlma H, Kojlma S, Hashlmoto F, Minaml Y, Yasuda H. Determination of anaerobic threshold for assessment of functional state in patients with chronic heart failure. Circulation 1983;68:360-367. 33. Maekln CS. Forman R. Sonnanbiick EH. Frishman WH. LeJemtei TH. Failure of dobutamine to increase exerci& capacity despite hemodynamic improvement in severe chronic heart failure. Am J Cardiol 1983;51: 177-182. 34. Roble NW, Nutter DO, Moody C, McNay JL. In vivo analysis of adrenergic receptor activity of dobutamine. Circ Res 1974:34:663-671. 35. Sheehan RM, Rehkin EM. Influence of adrenergic drugs on blood-tissue diffusion. Pharmacologist 1965;7:178. 36. Lundvall J, Jarhutt J. Beta-adrenergic dilator component of the sympathetic vascular response in skeletal muscle. Acta Physiol Stand 1978;96: 180-192. 37. Hlrvonen L, Korobkin M, Sonnenschein RR, Wright DL. Depression of contractile force of skeletal muscle by intra-arterial vasodilator drugs. Circ Res 1964;19:525-535.