- Email: [email protected]
Normal stroke volume and cardiac output response during dobutamine stress echocardiography in subjects without left ventricular wall motion abnormalities
Normal Stroke Volume and Cardiac Output Response During Dobutamine StressEchocardiograph In Subjects Without left Ventricular Wa TI Motion Abnormalities Patricia A. Pellikka, MD, Veronique L. Roger, MD, Robert B. McCully, MB, ChB, Douglas W. Mahoney, MS, Kent R. Bailey, PhD, James B. Seward, MD, and A. Jamil Tajik, MD Dobutamine stress echocardiogmphy has become wide ly utilized for evaluation of coronary artery disease, but the expected responses of stroke volume and cardiac output to the high doses of dobutamine administered in these studies are not known. To determine these responses, stroke volume and cardiac output were measured with 2-dimensional Doppler echocardiography at each sta e of dobutamine stress echocardiography and after a d ministration of atropine in 47 patients without resting or inducible wall motion abnormalities. Heart rate increased si nificantly at each stage of dobutamine infusion and aYter atropine. Mean blood pressure decreased at the 5 Pg/kg/min dose, then showed little change. Stroke volume increased 27 + 18% from baseline, with significant increases occurring at both the 5 and 10 Pg/kg/min doses (p ~0.00001). With
higher doses of dobutamine, stroke volume tended to plateau or decrease. Mean changes in stroke volume were not si n&ant between the doses of 10,20, and 30 P /kg Pmin. The mean change in stroke volume from fe 30 to the 40 pg/kg/min dose was a si nificant decrease of 6.3% (p = 0.004); the decrease 3 mm the 40 Pg/kg/min dose to atropine approached statistical significance (p = 0.06). Cardiac output increased throughout dobutamine infusion. Stroke volume during dobutamine stress echocard’ mphy is commonly maximum at a dose of 20 Pg/k 7 min and tends to decline at higher infusion rates. At 3, igher doses, increases in cardiac output are mediated primarily by increases in heart rate. (Am J Cardiol 1595;76:881-886)
obutamineis a synthetic catecholaminethat is known to increase cardiac output.’ In patients treated for D heart failure, the hemodynamic effects of doses in the
echocardiography.The findings in 47 patients with normal wall motion during dobutamine stressechocardiography are reported.
range of 5 to 15 pg/kg/min are well-documented.2A At these doses, cardiac output is augmented predominantly by an increase in myocardial contractility. Recently, dobutamine stressechocardiography has become widely utilized for the evaluation of coronary artery disease.5-7This technique involves the use of substantially higher doses of dobutamine (30 to 50 pg/kg/min) than those usedtherapeutically. With thesedoses,there is significant increase in heart rate. In addition, atropine is often administered to augment heart rate. Dobutamine Doppler echocardiography has also been proposed as a means of assessingthe severity of aortic stenosis in a patient with low cardiac output.8,9The expectedresponses of stroke volume and cardiac output during dobutamine stressechocardiography have not been well characterized. Two-dimensional Doppler echocardiography is an accuratenoninvasive method for measuring stroke volume and its changes,lOJand can be performed without interference with the usual dobutamine stressechocardiography protocol. In this study, stroke volume and cardiac output were measuredwith 2-dimensional Doppler echocardiographyat eachstageof dobutamine stress From the Drvision of Cardiovascular Diseases and Internal Medicine and Section of Brostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Manuscript received April 26, 1995; revised manuscript received and accepted Jul 27, 1995. Address for reprints: Patricra A. PeYlikka, MD, Mayo Clinic, 200 First Street, S.W , Rochester, Minnesota 5590.5.
CORONARY
METHODS Patients: The group was derived from 71 patients with normal wall motion at rest undergoing clinically indicated dobutamine stressechocardiography.All patients underwent pulsed-wave Doppler examination of the left ventricular outflow tract at baseline and at each stageof dobutamine infusion. Twenty-four patients developed regional wall motion abnormalities with dobutamine. Because resting or stress-induced wall motion abnormalities could affect the stroke volume response, only the 47 patients (16 men and 31 women, mean age 69 years, range 48 to 92) with normal wall motion were included in this report. All but 5 patients had a physical limitation that precluded standard exercise testing. Dobutamine stress echocardiography was performed for preoperative evaluation for noncardiac surgery in 21 patients (45%) and for evaluation of chest pain or dyspnea in 26 patients (55%). Twenty-one patients (45%) had a history of hypertension and 4 (9%) had mild left ventricular hypertrophy by echocardiography. Eight patients (17%) were taking B blockers at the time of the study, 20 patients (43%) were taking diuretics, and 7 patients (15%) were taking vasodilators. All patients were in sinus rhythm. All had normal ejection fraction (mean 63%, range 50% to 80%) by 2-dimensional echocardiography. None had significant valvular disease; 1 patient had mild aortic stenosis (mean gradient 15 mm
ARTERY DISEASE/STROKE
VOLUME
DURING
DOBUTAMINE
STRESS ECHO
881
TABLE I Doppler-Derived
Stroke Volume
ond Cardiac
Output
Responses
Dobutamine
Number of patients Heart rate (beats/min) Mean blood pressure (mm Hg) Time velocity integral (cm) Stroke volume (ml) Cardiac output (t/min)
During
10
47 692 12
47 74i 13 93 * 14 24 * 4 79i 16 5.8 LIZ1.4
84t220 92i 17 26 zt 5 86* 18 7.2 i 2.1
73* 14 5.0 f 1.2
30
40
20 107 zt 23 88* 18 25 ct 6 85i 19 8.4 i 1.8
18 116i20 88i 16 25 f 6 82 * 20 9.3 i 2.3
20
5
; 10
Stress Echocardiography
Dose (pg/kg/min)
0
1::
Dobutamine
100 91 27 89 8.6
37 * 26 f 17 * 5 sz 21 * 2.6
40 kg/kg/min plus Atropine
10 134 i 18 87* 17 21 +5 75 * 22 10 * 3.5
Valuer ore expressed (II meon * SD.
Hg). No patient developed chest pain, electrocardiographic evidence of ischemia, or stress-inducedregional wall motion abnormalities. One patient underwent coronary angiography within 6 months of the dobutamine stress echocardiography; coronary arteries were normal. Dobulumine stress echocardiography: Dobutamine was infused in incremental doses of 5, 10, 20, 30, and 40 pg/kg/rnin, each stage 3.5 minutes in duration, according to a previously described protocol.12The mean peak dose was 38 + 10 pg/kg/min. During peak dobutamine infusion in 20 patients, an-opinewas administered intravenously in incrementsof 0.25 to 0.5 mg (meantotal dose 0.6, range 0.25 to 1.5) to augment heart rate response.End points for terminating the study were target heart rate (85% of the age-predicted maximum) in 38 patients (81%), administration of maximal dose in 3 patients (6%), hypertension in 2 patients (4%), hypotension in 2 patients (4%), arrhythmia in 1 patient (2%), and headachein 1 patient (2%). Left ventricular outflow tract diameter was measured at the annulus using the parastemal long-axis view at the site of attachment of the aortic valve leatlets. This measurementwas repeated at the peak dose of dobutamine. The cross-sectional area was calculated, assuming a circular and constant orifice. l3 Left ventricular outflow tract blood flow velocities were recorded with pulsed-wave Doppler from the
apical long-axis position. The ultrasound beam was aligned parallel to the direction of blood flow with the sample volume at the aortic annular level. Left ventricular outflow tract time-velocity integral was measured on-line, by tracing the black/white interface of the pulsed-wave Doppler signal planimetrically using a commercially available measurementpackage(HewlettPackard Sonos 1000 or 1500 [Andover, Massachusetts] or Acuson XP 128 [Mountain View, California]). Measurements of 23 beats at each stage of infusion were averaged. Ectopic and postectopic beats were not utilized for measurements.Doppler measurementswere begun after 2.5 minutes of each stageof dobutamine infusion (typical requirement 1 minute), and were completed before each dose increment. Continuous-wave Doppler examination of the left ventricular cavity and outflow tract was also performed at baseline and at peak dose. Mean blood pressure and Doppler-derived stroke volume and cardiac output were calculated at baseline and at each stage of dobutamine infusion. Calculations were as follows: Stroke volume = (left ventricular outflow tract diameter)2 X 0.785 X left ventricular outflow tract timevelocity integral Cardiac output = stroke volume X heart rate Mean blood pressure = (systolic blood pressure diastolic blood pressure+ 3) + diastolic blood pressure
FIGURE 1. Mean relative (‘70)change in stroke volume, heart rate, cardiac output, and mean blood pressure from baseline to each infusion rate is plotted. Vertica/ bars represent 1 SD.
-5o-5o-
I 5
10
1
20
30
40
Atropine
Dobutamine dose (pglkglmin)
882
THE AMERICAN JOURNAL OF CARDIOLOGY@
VOL. 76
NOVEMBER 1, 1995
TABLE II Mean Dobutamine Dose Increment
Incremental
Changes
h/kg/mini
Mean Blood Pressure
Rest to 5 51010 1oto20 20 to 30 30 to 40 40 to atropine
-7 * -1 *9 -1 f -4* -1 f Ok
11 12 11 13 16
(%)
p Value -=0.0001 0.42 0.25 <0.005 0.5 0.32
Stroke Volume 9.2 10.2 2.2 -1.7 -6.3 -13.8
f ct zt f f *
p Value 10.9 11.8 9.8 7.9 6.6 8.0
Heort Rate 7.3 13.4 20.0 14.6 13.1 28.5
i 11.6 sz 13.8 LIC15.8 ct 15.1 f 10.7 i 20.6
p Value <0.00001 <0.00001
Cardiac output 18.0 24.3 22.4 11.7 7.9 20.3
i i * f i i
20.4 18.3 19.2 11.4 13.6 16.1
p Value
Values ore expressed es mean * SD.
Wall motion was assessedin each of 16 segments.14 The development of hyperdynamic wall motion during dobutamine infusion was considered normal. Statistical analysis: Changesin stroke volume, cardiac output, and heart rate were calculated at each dose of dobutamine relative to baseline and also between successivedosesof dobutamine.Changesareexpressedboth asabsolutechangesand asrelative (percent) changesand are summarized by mean f SD, and tested for significance by the Wilcoxon signed rank test. To test the significance of various patient characteristicson stroke volume, cardiac output, and heart rate, a multivariate repeatedmeasuresdesign was used.To determine whether left ventricular hypertrophy or diuretics influenced the development of dynamic intracavitary obstruction, Fisher’s exact test was used.
RESULTS Mean heart rate, blood pressure,left ventricular outflow tract time-velocity integral, and Doppler-derived stroke volume and cardiac output data at baseline and at each stage of dobutamine infusion are listed in Table I. The mean increase in heart rate from rest to peak stress was 64 + 19 beats/mm. The mean change in systolic blood pressure was -13 + 28 mm Hg, and the mean changein diastolic blood pressurewas -15 f 15 mm Hg. At baseline, the left ventricular outllow tract diameter averaged 2.1 + 0.2 cm and did not change at the peak infusion rate of dobutamine in any patient. The mean maximal increase in stroke volume from baseline was 27 & 18%. Mean stroke volume was greatest at a dose of 20 lq&$nin, and in 32 patients (68%), declined at a higher infusion rate of dobutamine or after administration of atropine. The pulsed-wave Doppler signal in the left ventricular outflow tract tended to alias at high infusion rates. This precluded determination of the time-velocity integral at peak infusion rate in 14 patients, 9 of whom also developed dynamic intracavitary obstruction.l2 The dose-response curves with the mean relative change in heart rate, mean blood pressure, stroke volume, and cardiac output from baseline to each infusion rate are shown in Figure 1. The mean incremental (percent) changesand p values are listed in Table II. Heart rate increased significantly at each stage of dobutamine infusion. Cardiac output increasedsignificantly throughout dobutamine infusion, with early increasesmediated by both stroke volume and heart rate increases,and later increasesmediated by heart rate increasesalone.
Although the mean stroke volume was greatest at a dose of 20 @kg/mm, there was variation in individual responses.Stroke volume was maximal at dosesof 520 pg/kg/min in 41 patients (87%), but stroke volume reached a peak in 5 patients at a dose of 30 pg/kg/min and in 1 patient at 40 lq&$nin. No patient had an increase in stroke volume after an-opineadministration. Maximal stroke volumes tended to occur at heart rates of 70 to 90 beats/mm,but in 7 patients they occurred at heart rates of 2110beats/mm. To investigate the separateeffects of heart rate and dose on stroke volume, data for each patient were stratified according to maximal dose of dobutamine. There were 6 patients in whom the maximal dose was 120 lq&$nin. In these patients, the infusion was stopped becausethe target heart rate was achieved. Heart rate and stroke volume increases were more rapid in these patients; in all 6 “rapid responders,” stroke volume peaked earlier at a dose of 10 &kg/mm versus 20 @kg/min in the remaining 41 patients (Figure 2). None of the rapid responderswas receiving P-blocker therapy. None had anemia or abnormalities of thyroid function. Compared with the 33 patients who were not taking l3 blockers and received a maximal dose of >20 pg/kg/min, there was no difference in body surfacearea, gender,heart rate at baseline or peak, systolic or diastolic blood pressure,or therapy with diuretics or vasodilators. However, the rapid responderswere significantly older (78 vs 65 years, p ~0.01) and had a significantly greater change in heart rate from baseline to peak stress (75 vs 60 beats/mm,p = 0.03). The drop out of the rapid responders is shown in Figure 1 by a flattening of the slope of the cardiac output curve at its midportion. Mean stroke volumes at each dose of dobutamine were not significantly different between the 8 patients receiving and the 39 not receiving P-blocker therapy. Mean changes in heart rate and systolic and diastolic blood pressure from rest to peak stress did not differ between these patients. As expected,heart rate and cardiac output were significantly lower in patients receiving l3 blockers at baseline and with dobutamine infusion to a rate of 20 pg/kg/min. However, at higher infusion rates of dobutamine and after atropine, there was no significant difference between the 2 groups, although heart rates tended to be lower in patients taking l3 blockers (Figure 3). The heart rate at which stroke volume was the highest was similar for both groups (81 vs 88 beat&in, p = 0.31). The mean maximal dose of dobutamine was similar in both groups (40 vs 37 pg/kg/rnin,
CORONARY ARTERY DISEASE/STROKE VOLUME DURING DOBUTAMINE
STRESS ECHO
883
AISO-
-
Maximum dotm s 20 p@kg/min (n - 6) Maximum doaa >2oO(lglkglmin(n=41)
-----
m-
40’ 1 1 8weline 5
1
10
20
30
1
40
Atmpine
Dobulamine dose (pglkglmin) P value
0.74
025
0.17
0.73
190-v-- -0
p = NS). However, atropine was administered to 6 of 8 patients (75%) taking p blockers comparedwith 14 of 39 patients (36%) who were not (p = 0.06). The 20 patients who were receiving diuretics had a lower mean blood pressure during dobutamine infusion than those not receiving diuretics (p = 0.05). However, the diuretic group did not differ in heart rate or stroke volume at baseline or during dobutamine infusion. The 7 patients receiving vasodilators had a lower diastolic blood pressureat baseline and during dobutamine infusion (p = 0.02) but did not differ in other hemodynamic variables. The development of dynamic intracavitary obstruction in 9 patients did not appear to be potentiated by the presence of left ventricular hypertrophy or diuretic therapy. Twenty percent of patients with versus26% of thosewithout left ventricular hypertrophy developed obstruction (p = 0.99). Fifteen percent of those taking versus 33% of those not taking diuretics developed obstruction (p = 0.19). However, those with obstruction had a higher time-velocity integral at baseline and during dobutamine infusion (p = 0.011).
DISCUSSION 50-
40’ I 8wuline
I 5
1
I
r
I
10
20
30
40
I Abopim
Dobutamine do88 (@kg/min) Pvalue
’
0.95
0.28
0.01
181718-
o.wo4
-
Mexlmum do8e CZOCllllkglmin(n=8)
-----
Maximum dose >ZO pg/k@min (n=41)
I=
“BLsAte i
lb
2lJ
io
io
Al&ine
Dobutamine do88 (@/kg/min) Pvelue
0.68
0.11
0.02
0.05
FIGURE2. Mean values for stroke volume (4, heart rate {Bj, and cardiac output /Cl at each stage of dobutamine infusion are plotted for the 6 tients who heart rate at 520 pg/kg/min compared with r e 41 patients infusion rates. The overall p value was significant t not for stroke volume or co&c output. 884
THE AMERICAN JOURNAL OF CARDIOLOGY”
VOL. 76
far heart
Dobutamine administration is recognized to increase cardiac output by increasing both heart rate and myocardial contractility. Thus, myocardial oxygen consumption is increased. When dobutamine is given to patients with coronary artery diseaseat dosesthat increaseheart rate, ischemia occurs in regions subtended by a stenosedcoronary artery and abnormalities of regional wall motion occur. Although the normal heart responds to dobutamine infusion with an increase in contractility and heart rate, the extent of the changein stroke volume and its relation to the changein heart rate with progressively increasing doses of dobutamine have not been previously characterized. The results of this study indicate that in patients with normal ventricular function, the increase in stroke volume with dobutamine is usually greatest at doses ranging from 10 to 20 pg/kg/min. Stroke volume can be expectedto increase 27% from baseline. In the patients studied, a decreasein stroke volume often occurred at higher doses. A decreasein stroke volume has been noted in normal hearts during rapid atrial pacingI and during maximal exer-
NOVEMBER 1, 1995
cise.16At high heart rates, the time for ventricular filling is reduced. Like muscular exercise,dobutamineis knotin to reduce systemic vascular resistance.However,unlike exercise,with dobutamine infusion, venous return is not increased.17 A decreasein ventricular volume is often observed during dobutamine stressechocardiography.18,19 The decreasesin venous return and systemic vascular resistance and the shortenedtime for ventricular filling at high heart rates may contribute to the decreasesin ventricular volume and stroke volume observed with high doses of dobutamine. Considerable individual variation in stroke volume and heart rate responseto dobutamine was present. The dose of dobutamine at which maximal stroke volume was achieved ranged from 5 to 40 p,g/kg/min. Six patients had a rapid increase in heart rate and stroke volume, achieving a target heart rate at a dobutamine dose of 120 pg/kg/min. These 6 patients did not differ with regard to body surface area or gender but were significantly older (78 vs 6.5 years, p ~0.01). This suggeststhat at least someolder patients may be more sensitive to the hemodynamic effects of dobutamine. As expected, patients receiving pblocker therapy tended to have lower heart ratesand cardiac output at eachdose of dobutamine than those not receiving pblocker therapy. However, changes in stroke volume during dobutamine infusion were not affectedby P-blocker therapy. Diuretics and vasodilators did not appear to affect heart rate or stroke volume responseto dobutamine. Study limitations: The group described was not completely “normal,” although dobutamine studies were normal. Most of the patients studied were elderly; the stroke volume responsemay be different in a younger population. Comorbidities, including lung disease,peripheral vascular disease,and orthopedic limitations preventedthesepatients from performing exercise tests. Hypertension was present in 45% of patients and many of the patients were taking medications.The study design and number of subjects did not permit evaluation of the putative effectsof hypertension on left ventricular response to dobutamine. The stages of dobutamine infusion were short (3.5 minutes); therefore, the changes in hemodynamics do not reflect a steady state at each dosage of dobutamine. The responseat different times during a longer stageof infusion (i.e., 10min-
r A NO140130-
l-0
?i
io
40
At&h
Dobutamine dose (pg/kg/min) Pvalue
0.13
0.28
-
40-
I 8aeline
0.62
0.67
0.29
0.49
I 20
1 30
I 40
0.70
No beta blockers
5
10
I Atropine
Dobutamine dose (pgkglmin) P value
0.01
c ‘a2
l71615-
5 s
ii12-
$ 28 E
:;ges
3
7654-
0.01
0.01
0.01
0.27
0.29
0.69
-----6etabkckers -
No beta blockers
3' : eaaetlne
5
0.002
0.003
1
I
I
I
10
20
30
40
Atropim,
Dohtamina dose (pg/kg/min) PvakJe
0.01
0.04
0.07
0.95
0.25
FIGURE 3. Mean values for stroke volume (a), heart rate (61, and cardiac output (Cl at each stage of dobutamine infusion are plotted for the 8 patients receiving and the 39 patients not receiving p-blocker therap . The overall p vales were significantly different for heart rate (p -zO.OOS) a J cardiac output (p = 0.01) but not for stroke volume. However, stroke volume was highest at a higher mean dose of dobutamine in the p-blocker group (23 vs 13 pg/kg/min, p = 0.02).
CORONARY ARTERY DISEASE/STROKE VOLUME DURING DOBUTAMINE
STRESS ECHO
885
utes) may differ and should be studied. Another limitation was the inability to measuretime-velocity integrals with pulsed-wave Doppler examination at high heart rates in 14 patients, becauseof velocity aliasing. We do not believe that the ability to measureall time-velocity integrals would have changedour conclusions. Although peak velocity increasedwith higher heart rates, the systolic ejection period decreased,resulting in a reduction in the time-velocity integral. The useof continuous-wave Doppler would have overcome the problem of aliasing, but would have provided spurious information regarding stroke volume in patients who developed intracavitary obstruction. This study used Doppler for determination of stroke volume. Although Doppler cannot be considered the “gold standard’ for these hemodynamic measurements, it has been validated as an accuratenoninvasive method of measuring stroke volume and its changes.lO,l 1. L&r CV, Unvetferth DV. Dobutamine. Ann Intern Med 1983;99:49&496. 2. Akhtar N, Mikulic E, Kahn JN, Cbaudry MH. Hemodynamic effects of dobutamine in patients with severe heart failure. Am J Cardiol 1975;36:202-205. 3. Leier CV, Webel J, Bush CA. The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure. Circularion 1977;56: 468-472. 4. Pozen RG, Dibianco R, Katz RJ, Bottz R, Myerburg RG, Fletcher RD. Myocardial metabolic and hemodynamic effects of dobutamine in heart failure complicating coronary atety disease. Circulation 1981;63:1279-1285. 5. Sawada SC, Segar DS, Ryan T, Brown SE, Dohao AM, Williams R, Fineberg NS, Armstrong WF, Feigenbaum H. Echocardiographic detection of coronary artery disease during dobutamine infusion. Circulation 199 1;83: 1605-1614. 6. Marwick T, Willemart B, D’Hondt AM, Baudhuin T, Wigns W, Detry JM, Melin J. Selection of the optimal non-exercise stress for the evaluation of ischemic regional myocardial dysfunction and malperfusion: comparison of dobutamine and adeno-
sine using echocardiography and 99m-Tc-MIBI single photon emission computed tomography. Circulation 1993;87:345-354. 7. Mazeika PK, Nadazdin A, Oakley CM. Dobutamine stress echocardiography for detection and assessment of coronary artery disease. .I Am Coil Cardiol 1992;19: 1203.1211. 8. Pascoe RD. Roger VL, Pellikka PA, Seward JB, Tajik AJ. Use of dobutamine stress echocardiography in patients with aortic stenosis, reduced left ventricular ejection fraction and low mean tmnsvalvular gradient: preliminary experience (abstr). J Am Sot Echocardiogr 1994;7:S8. 9. DeFilippi CR, Will&t DL, Brickner ME, Appleton CP, Yancy CW, Eichom EJ, Graybum PA. Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aottic stenosis in patients with depressed left ventricular function and low transvalvular gradients. Am .I Cardiol 1995;75:191-194. 10. Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical validation of two new methods using the apical window. Circulation 1984,70:42543 1. 1 I. IMen H, Myhre E, Pamlie I, Forfang K, Lawn S. Changes in left ventricular stroke volume measured by Doppler whocardiography. Br Heart .I 1985;54:378-383. 12. Pellikka PA, Oh JK, Bailey KR, Nichols BA, Monahan KH, Tajik AJ. Dynamic intraventicular obstruction during dobutamine stress echocardiography: a new observation. Circu[ation 1992;86:1429-1432. 13. Christie J, Sheldahl LM, Tristani FE, Sagar KB, F’tacin MJ, Warm S. Determination of stroke volume and cardiac output doting exercise: comparison of twodimensional and Doppler echocardiography, Fick oximetry and thermodilution. Circulation 1987;76:539-547. 14. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Sot Echocardiogr 1989;2:358-367. 15. Ross J, Linhart JW, Braunwald E. Effects of changing heart rate in man by electrical stimulation of the right atrium. Circulation 1965;32:549-558. 16. Opie LH. Myocardial oxygen uptake: heart work and exercise. In: The Heart: Physiology and Metabolism. 2nd ed. New York: Raven Press, 1991:339-368. 17. Pierard LA, Betthe C, Albert A, Carlier J, Kulbertus HE. Hemodynamic alterations during ischemia induced by dobutamine stress testing. Eur Heart J 1989; 10:783-790. 18. Olson CE. Porter TR, Deligonul U, Xie F, Anderson JR. Left ventricular volume changes during dobutamine stress echocardiography identify patients with more extensive coronary artery disease. .I Am Coil Cardiol 1994.24: 1268-1273. 19. Attenhofer CH, Pellikka PA, Oh JK, Roger VL, Sohn DW, Seward JB. Comparison of ischemic response during exercise and dobutamine echocardiography in patients with left main coronary artery disease. J Am CON Cardiol (in press).
886
NOVEMBER 1, 1995
THE AMERICAN JOURNAL OF CARDIOLOGYa
VOL. 76
higher doses of dobutamine, stroke volume tended to plateau or decrease. Mean changes in stroke volume were not si n&ant between the doses of 10,20, and 30 P /kg Pmin. The mean change in stroke volume from fe 30 to the 40 pg/kg/min dose was a si nificant decrease of 6.3% (p = 0.004); the decrease 3 mm the 40 Pg/kg/min dose to atropine approached statistical significance (p = 0.06). Cardiac output increased throughout dobutamine infusion. Stroke volume during dobutamine stress echocard’ mphy is commonly maximum at a dose of 20 Pg/k 7 min and tends to decline at higher infusion rates. At 3, igher doses, increases in cardiac output are mediated primarily by increases in heart rate. (Am J Cardiol 1595;76:881-886)
obutamineis a synthetic catecholaminethat is known to increase cardiac output.’ In patients treated for D heart failure, the hemodynamic effects of doses in the
echocardiography.The findings in 47 patients with normal wall motion during dobutamine stressechocardiography are reported.
range of 5 to 15 pg/kg/min are well-documented.2A At these doses, cardiac output is augmented predominantly by an increase in myocardial contractility. Recently, dobutamine stressechocardiography has become widely utilized for the evaluation of coronary artery disease.5-7This technique involves the use of substantially higher doses of dobutamine (30 to 50 pg/kg/min) than those usedtherapeutically. With thesedoses,there is significant increase in heart rate. In addition, atropine is often administered to augment heart rate. Dobutamine Doppler echocardiography has also been proposed as a means of assessingthe severity of aortic stenosis in a patient with low cardiac output.8,9The expectedresponses of stroke volume and cardiac output during dobutamine stressechocardiography have not been well characterized. Two-dimensional Doppler echocardiography is an accuratenoninvasive method for measuring stroke volume and its changes,lOJand can be performed without interference with the usual dobutamine stressechocardiography protocol. In this study, stroke volume and cardiac output were measuredwith 2-dimensional Doppler echocardiographyat eachstageof dobutamine stress From the Drvision of Cardiovascular Diseases and Internal Medicine and Section of Brostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Manuscript received April 26, 1995; revised manuscript received and accepted Jul 27, 1995. Address for reprints: Patricra A. PeYlikka, MD, Mayo Clinic, 200 First Street, S.W , Rochester, Minnesota 5590.5.
CORONARY
METHODS Patients: The group was derived from 71 patients with normal wall motion at rest undergoing clinically indicated dobutamine stressechocardiography.All patients underwent pulsed-wave Doppler examination of the left ventricular outflow tract at baseline and at each stageof dobutamine infusion. Twenty-four patients developed regional wall motion abnormalities with dobutamine. Because resting or stress-induced wall motion abnormalities could affect the stroke volume response, only the 47 patients (16 men and 31 women, mean age 69 years, range 48 to 92) with normal wall motion were included in this report. All but 5 patients had a physical limitation that precluded standard exercise testing. Dobutamine stress echocardiography was performed for preoperative evaluation for noncardiac surgery in 21 patients (45%) and for evaluation of chest pain or dyspnea in 26 patients (55%). Twenty-one patients (45%) had a history of hypertension and 4 (9%) had mild left ventricular hypertrophy by echocardiography. Eight patients (17%) were taking B blockers at the time of the study, 20 patients (43%) were taking diuretics, and 7 patients (15%) were taking vasodilators. All patients were in sinus rhythm. All had normal ejection fraction (mean 63%, range 50% to 80%) by 2-dimensional echocardiography. None had significant valvular disease; 1 patient had mild aortic stenosis (mean gradient 15 mm
ARTERY DISEASE/STROKE
VOLUME
DURING
DOBUTAMINE
STRESS ECHO
881
TABLE I Doppler-Derived
Stroke Volume
ond Cardiac
Output
Responses
Dobutamine
Number of patients Heart rate (beats/min) Mean blood pressure (mm Hg) Time velocity integral (cm) Stroke volume (ml) Cardiac output (t/min)
During
10
47 692 12
47 74i 13 93 * 14 24 * 4 79i 16 5.8 LIZ1.4
84t220 92i 17 26 zt 5 86* 18 7.2 i 2.1
73* 14 5.0 f 1.2
30
40
20 107 zt 23 88* 18 25 ct 6 85i 19 8.4 i 1.8
18 116i20 88i 16 25 f 6 82 * 20 9.3 i 2.3
20
5
; 10
Stress Echocardiography
Dose (pg/kg/min)
0
1::
Dobutamine
100 91 27 89 8.6
37 * 26 f 17 * 5 sz 21 * 2.6
40 kg/kg/min plus Atropine
10 134 i 18 87* 17 21 +5 75 * 22 10 * 3.5
Valuer ore expressed (II meon * SD.
Hg). No patient developed chest pain, electrocardiographic evidence of ischemia, or stress-inducedregional wall motion abnormalities. One patient underwent coronary angiography within 6 months of the dobutamine stress echocardiography; coronary arteries were normal. Dobulumine stress echocardiography: Dobutamine was infused in incremental doses of 5, 10, 20, 30, and 40 pg/kg/rnin, each stage 3.5 minutes in duration, according to a previously described protocol.12The mean peak dose was 38 + 10 pg/kg/min. During peak dobutamine infusion in 20 patients, an-opinewas administered intravenously in incrementsof 0.25 to 0.5 mg (meantotal dose 0.6, range 0.25 to 1.5) to augment heart rate response.End points for terminating the study were target heart rate (85% of the age-predicted maximum) in 38 patients (81%), administration of maximal dose in 3 patients (6%), hypertension in 2 patients (4%), hypotension in 2 patients (4%), arrhythmia in 1 patient (2%), and headachein 1 patient (2%). Left ventricular outflow tract diameter was measured at the annulus using the parastemal long-axis view at the site of attachment of the aortic valve leatlets. This measurementwas repeated at the peak dose of dobutamine. The cross-sectional area was calculated, assuming a circular and constant orifice. l3 Left ventricular outflow tract blood flow velocities were recorded with pulsed-wave Doppler from the
apical long-axis position. The ultrasound beam was aligned parallel to the direction of blood flow with the sample volume at the aortic annular level. Left ventricular outflow tract time-velocity integral was measured on-line, by tracing the black/white interface of the pulsed-wave Doppler signal planimetrically using a commercially available measurementpackage(HewlettPackard Sonos 1000 or 1500 [Andover, Massachusetts] or Acuson XP 128 [Mountain View, California]). Measurements of 23 beats at each stage of infusion were averaged. Ectopic and postectopic beats were not utilized for measurements.Doppler measurementswere begun after 2.5 minutes of each stageof dobutamine infusion (typical requirement 1 minute), and were completed before each dose increment. Continuous-wave Doppler examination of the left ventricular cavity and outflow tract was also performed at baseline and at peak dose. Mean blood pressure and Doppler-derived stroke volume and cardiac output were calculated at baseline and at each stage of dobutamine infusion. Calculations were as follows: Stroke volume = (left ventricular outflow tract diameter)2 X 0.785 X left ventricular outflow tract timevelocity integral Cardiac output = stroke volume X heart rate Mean blood pressure = (systolic blood pressure diastolic blood pressure+ 3) + diastolic blood pressure
FIGURE 1. Mean relative (‘70)change in stroke volume, heart rate, cardiac output, and mean blood pressure from baseline to each infusion rate is plotted. Vertica/ bars represent 1 SD.
-5o-5o-
I 5
10
1
20
30
40
Atropine
Dobutamine dose (pglkglmin)
882
THE AMERICAN JOURNAL OF CARDIOLOGY@
VOL. 76
NOVEMBER 1, 1995
TABLE II Mean Dobutamine Dose Increment
Incremental
Changes
h/kg/mini
Mean Blood Pressure
Rest to 5 51010 1oto20 20 to 30 30 to 40 40 to atropine
-7 * -1 *9 -1 f -4* -1 f Ok
11 12 11 13 16
(%)
p Value -=0.0001 0.42 0.25 <0.005 0.5 0.32
Stroke Volume 9.2 10.2 2.2 -1.7 -6.3 -13.8
f ct zt f f *
p Value 10.9 11.8 9.8 7.9 6.6 8.0
Heort Rate 7.3 13.4 20.0 14.6 13.1 28.5
i 11.6 sz 13.8 LIC15.8 ct 15.1 f 10.7 i 20.6
p Value <0.00001 <0.00001
Cardiac output 18.0 24.3 22.4 11.7 7.9 20.3
i i * f i i
20.4 18.3 19.2 11.4 13.6 16.1
p Value
Values ore expressed es mean * SD.
Wall motion was assessedin each of 16 segments.14 The development of hyperdynamic wall motion during dobutamine infusion was considered normal. Statistical analysis: Changesin stroke volume, cardiac output, and heart rate were calculated at each dose of dobutamine relative to baseline and also between successivedosesof dobutamine.Changesareexpressedboth asabsolutechangesand asrelative (percent) changesand are summarized by mean f SD, and tested for significance by the Wilcoxon signed rank test. To test the significance of various patient characteristicson stroke volume, cardiac output, and heart rate, a multivariate repeatedmeasuresdesign was used.To determine whether left ventricular hypertrophy or diuretics influenced the development of dynamic intracavitary obstruction, Fisher’s exact test was used.
RESULTS Mean heart rate, blood pressure,left ventricular outflow tract time-velocity integral, and Doppler-derived stroke volume and cardiac output data at baseline and at each stage of dobutamine infusion are listed in Table I. The mean increase in heart rate from rest to peak stress was 64 + 19 beats/mm. The mean change in systolic blood pressure was -13 + 28 mm Hg, and the mean changein diastolic blood pressurewas -15 f 15 mm Hg. At baseline, the left ventricular outllow tract diameter averaged 2.1 + 0.2 cm and did not change at the peak infusion rate of dobutamine in any patient. The mean maximal increase in stroke volume from baseline was 27 & 18%. Mean stroke volume was greatest at a dose of 20 lq&$nin, and in 32 patients (68%), declined at a higher infusion rate of dobutamine or after administration of atropine. The pulsed-wave Doppler signal in the left ventricular outflow tract tended to alias at high infusion rates. This precluded determination of the time-velocity integral at peak infusion rate in 14 patients, 9 of whom also developed dynamic intracavitary obstruction.l2 The dose-response curves with the mean relative change in heart rate, mean blood pressure, stroke volume, and cardiac output from baseline to each infusion rate are shown in Figure 1. The mean incremental (percent) changesand p values are listed in Table II. Heart rate increased significantly at each stage of dobutamine infusion. Cardiac output increasedsignificantly throughout dobutamine infusion, with early increasesmediated by both stroke volume and heart rate increases,and later increasesmediated by heart rate increasesalone.
Although the mean stroke volume was greatest at a dose of 20 @kg/mm, there was variation in individual responses.Stroke volume was maximal at dosesof 520 pg/kg/min in 41 patients (87%), but stroke volume reached a peak in 5 patients at a dose of 30 pg/kg/min and in 1 patient at 40 lq&$nin. No patient had an increase in stroke volume after an-opineadministration. Maximal stroke volumes tended to occur at heart rates of 70 to 90 beats/mm,but in 7 patients they occurred at heart rates of 2110beats/mm. To investigate the separateeffects of heart rate and dose on stroke volume, data for each patient were stratified according to maximal dose of dobutamine. There were 6 patients in whom the maximal dose was 120 lq&$nin. In these patients, the infusion was stopped becausethe target heart rate was achieved. Heart rate and stroke volume increases were more rapid in these patients; in all 6 “rapid responders,” stroke volume peaked earlier at a dose of 10 &kg/mm versus 20 @kg/min in the remaining 41 patients (Figure 2). None of the rapid responderswas receiving P-blocker therapy. None had anemia or abnormalities of thyroid function. Compared with the 33 patients who were not taking l3 blockers and received a maximal dose of >20 pg/kg/min, there was no difference in body surfacearea, gender,heart rate at baseline or peak, systolic or diastolic blood pressure,or therapy with diuretics or vasodilators. However, the rapid responderswere significantly older (78 vs 65 years, p ~0.01) and had a significantly greater change in heart rate from baseline to peak stress (75 vs 60 beats/mm,p = 0.03). The drop out of the rapid responders is shown in Figure 1 by a flattening of the slope of the cardiac output curve at its midportion. Mean stroke volumes at each dose of dobutamine were not significantly different between the 8 patients receiving and the 39 not receiving P-blocker therapy. Mean changes in heart rate and systolic and diastolic blood pressure from rest to peak stress did not differ between these patients. As expected,heart rate and cardiac output were significantly lower in patients receiving l3 blockers at baseline and with dobutamine infusion to a rate of 20 pg/kg/min. However, at higher infusion rates of dobutamine and after atropine, there was no significant difference between the 2 groups, although heart rates tended to be lower in patients taking l3 blockers (Figure 3). The heart rate at which stroke volume was the highest was similar for both groups (81 vs 88 beat&in, p = 0.31). The mean maximal dose of dobutamine was similar in both groups (40 vs 37 pg/kg/rnin,
CORONARY ARTERY DISEASE/STROKE VOLUME DURING DOBUTAMINE
STRESS ECHO
883
AISO-
-
Maximum dotm s 20 p@kg/min (n - 6) Maximum doaa >2oO(lglkglmin(n=41)
-----
m-
40’ 1 1 8weline 5
1
10
20
30
1
40
Atmpine
Dobulamine dose (pglkglmin) P value
0.74
025
0.17
0.73
190-v-- -0
p = NS). However, atropine was administered to 6 of 8 patients (75%) taking p blockers comparedwith 14 of 39 patients (36%) who were not (p = 0.06). The 20 patients who were receiving diuretics had a lower mean blood pressure during dobutamine infusion than those not receiving diuretics (p = 0.05). However, the diuretic group did not differ in heart rate or stroke volume at baseline or during dobutamine infusion. The 7 patients receiving vasodilators had a lower diastolic blood pressureat baseline and during dobutamine infusion (p = 0.02) but did not differ in other hemodynamic variables. The development of dynamic intracavitary obstruction in 9 patients did not appear to be potentiated by the presence of left ventricular hypertrophy or diuretic therapy. Twenty percent of patients with versus26% of thosewithout left ventricular hypertrophy developed obstruction (p = 0.99). Fifteen percent of those taking versus 33% of those not taking diuretics developed obstruction (p = 0.19). However, those with obstruction had a higher time-velocity integral at baseline and during dobutamine infusion (p = 0.011).
DISCUSSION 50-
40’ I 8wuline
I 5
1
I
r
I
10
20
30
40
I Abopim
Dobutamine do88 (@kg/min) Pvalue
’
0.95
0.28
0.01
181718-
o.wo4
-
Mexlmum do8e CZOCllllkglmin(n=8)
-----
Maximum dose >ZO pg/k@min (n=41)
I=
“BLsAte i
lb
2lJ
io
io
Al&ine
Dobutamine do88 (@/kg/min) Pvelue
0.68
0.11
0.02
0.05
FIGURE2. Mean values for stroke volume (4, heart rate {Bj, and cardiac output /Cl at each stage of dobutamine infusion are plotted for the 6 tients who heart rate at 520 pg/kg/min compared with r e 41 patients infusion rates. The overall p value was significant t not for stroke volume or co&c output. 884
THE AMERICAN JOURNAL OF CARDIOLOGY”
VOL. 76
far heart
Dobutamine administration is recognized to increase cardiac output by increasing both heart rate and myocardial contractility. Thus, myocardial oxygen consumption is increased. When dobutamine is given to patients with coronary artery diseaseat dosesthat increaseheart rate, ischemia occurs in regions subtended by a stenosedcoronary artery and abnormalities of regional wall motion occur. Although the normal heart responds to dobutamine infusion with an increase in contractility and heart rate, the extent of the changein stroke volume and its relation to the changein heart rate with progressively increasing doses of dobutamine have not been previously characterized. The results of this study indicate that in patients with normal ventricular function, the increase in stroke volume with dobutamine is usually greatest at doses ranging from 10 to 20 pg/kg/min. Stroke volume can be expectedto increase 27% from baseline. In the patients studied, a decreasein stroke volume often occurred at higher doses. A decreasein stroke volume has been noted in normal hearts during rapid atrial pacingI and during maximal exer-
NOVEMBER 1, 1995
cise.16At high heart rates, the time for ventricular filling is reduced. Like muscular exercise,dobutamineis knotin to reduce systemic vascular resistance.However,unlike exercise,with dobutamine infusion, venous return is not increased.17 A decreasein ventricular volume is often observed during dobutamine stressechocardiography.18,19 The decreasesin venous return and systemic vascular resistance and the shortenedtime for ventricular filling at high heart rates may contribute to the decreasesin ventricular volume and stroke volume observed with high doses of dobutamine. Considerable individual variation in stroke volume and heart rate responseto dobutamine was present. The dose of dobutamine at which maximal stroke volume was achieved ranged from 5 to 40 p,g/kg/min. Six patients had a rapid increase in heart rate and stroke volume, achieving a target heart rate at a dobutamine dose of 120 pg/kg/min. These 6 patients did not differ with regard to body surface area or gender but were significantly older (78 vs 6.5 years, p ~0.01). This suggeststhat at least someolder patients may be more sensitive to the hemodynamic effects of dobutamine. As expected, patients receiving pblocker therapy tended to have lower heart ratesand cardiac output at eachdose of dobutamine than those not receiving pblocker therapy. However, changes in stroke volume during dobutamine infusion were not affectedby P-blocker therapy. Diuretics and vasodilators did not appear to affect heart rate or stroke volume responseto dobutamine. Study limitations: The group described was not completely “normal,” although dobutamine studies were normal. Most of the patients studied were elderly; the stroke volume responsemay be different in a younger population. Comorbidities, including lung disease,peripheral vascular disease,and orthopedic limitations preventedthesepatients from performing exercise tests. Hypertension was present in 45% of patients and many of the patients were taking medications.The study design and number of subjects did not permit evaluation of the putative effectsof hypertension on left ventricular response to dobutamine. The stages of dobutamine infusion were short (3.5 minutes); therefore, the changes in hemodynamics do not reflect a steady state at each dosage of dobutamine. The responseat different times during a longer stageof infusion (i.e., 10min-
r A NO140130-
l-0
?i
io
40
At&h
Dobutamine dose (pg/kg/min) Pvalue
0.13
0.28
-
40-
I 8aeline
0.62
0.67
0.29
0.49
I 20
1 30
I 40
0.70
No beta blockers
5
10
I Atropine
Dobutamine dose (pgkglmin) P value
0.01
c ‘a2
l71615-
5 s
ii12-
$ 28 E
:;ges
3
7654-
0.01
0.01
0.01
0.27
0.29
0.69
-----6etabkckers -
No beta blockers
3' : eaaetlne
5
0.002
0.003
1
I
I
I
10
20
30
40
Atropim,
Dohtamina dose (pg/kg/min) PvakJe
0.01
0.04
0.07
0.95
0.25
FIGURE 3. Mean values for stroke volume (a), heart rate (61, and cardiac output (Cl at each stage of dobutamine infusion are plotted for the 8 patients receiving and the 39 patients not receiving p-blocker therap . The overall p vales were significantly different for heart rate (p -zO.OOS) a J cardiac output (p = 0.01) but not for stroke volume. However, stroke volume was highest at a higher mean dose of dobutamine in the p-blocker group (23 vs 13 pg/kg/min, p = 0.02).
CORONARY ARTERY DISEASE/STROKE VOLUME DURING DOBUTAMINE
STRESS ECHO
885
utes) may differ and should be studied. Another limitation was the inability to measuretime-velocity integrals with pulsed-wave Doppler examination at high heart rates in 14 patients, becauseof velocity aliasing. We do not believe that the ability to measureall time-velocity integrals would have changedour conclusions. Although peak velocity increasedwith higher heart rates, the systolic ejection period decreased,resulting in a reduction in the time-velocity integral. The useof continuous-wave Doppler would have overcome the problem of aliasing, but would have provided spurious information regarding stroke volume in patients who developed intracavitary obstruction. This study used Doppler for determination of stroke volume. Although Doppler cannot be considered the “gold standard’ for these hemodynamic measurements, it has been validated as an accuratenoninvasive method of measuring stroke volume and its changes.lO,l 1. L&r CV, Unvetferth DV. Dobutamine. Ann Intern Med 1983;99:49&496. 2. Akhtar N, Mikulic E, Kahn JN, Cbaudry MH. Hemodynamic effects of dobutamine in patients with severe heart failure. Am J Cardiol 1975;36:202-205. 3. Leier CV, Webel J, Bush CA. The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure. Circularion 1977;56: 468-472. 4. Pozen RG, Dibianco R, Katz RJ, Bottz R, Myerburg RG, Fletcher RD. Myocardial metabolic and hemodynamic effects of dobutamine in heart failure complicating coronary atety disease. Circulation 1981;63:1279-1285. 5. Sawada SC, Segar DS, Ryan T, Brown SE, Dohao AM, Williams R, Fineberg NS, Armstrong WF, Feigenbaum H. Echocardiographic detection of coronary artery disease during dobutamine infusion. Circulation 199 1;83: 1605-1614. 6. Marwick T, Willemart B, D’Hondt AM, Baudhuin T, Wigns W, Detry JM, Melin J. Selection of the optimal non-exercise stress for the evaluation of ischemic regional myocardial dysfunction and malperfusion: comparison of dobutamine and adeno-
sine using echocardiography and 99m-Tc-MIBI single photon emission computed tomography. Circulation 1993;87:345-354. 7. Mazeika PK, Nadazdin A, Oakley CM. Dobutamine stress echocardiography for detection and assessment of coronary artery disease. .I Am Coil Cardiol 1992;19: 1203.1211. 8. Pascoe RD. Roger VL, Pellikka PA, Seward JB, Tajik AJ. Use of dobutamine stress echocardiography in patients with aortic stenosis, reduced left ventricular ejection fraction and low mean tmnsvalvular gradient: preliminary experience (abstr). J Am Sot Echocardiogr 1994;7:S8. 9. DeFilippi CR, Will&t DL, Brickner ME, Appleton CP, Yancy CW, Eichom EJ, Graybum PA. Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aottic stenosis in patients with depressed left ventricular function and low transvalvular gradients. Am .I Cardiol 1995;75:191-194. 10. Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical validation of two new methods using the apical window. Circulation 1984,70:42543 1. 1 I. IMen H, Myhre E, Pamlie I, Forfang K, Lawn S. Changes in left ventricular stroke volume measured by Doppler whocardiography. Br Heart .I 1985;54:378-383. 12. Pellikka PA, Oh JK, Bailey KR, Nichols BA, Monahan KH, Tajik AJ. Dynamic intraventicular obstruction during dobutamine stress echocardiography: a new observation. Circu[ation 1992;86:1429-1432. 13. Christie J, Sheldahl LM, Tristani FE, Sagar KB, F’tacin MJ, Warm S. Determination of stroke volume and cardiac output doting exercise: comparison of twodimensional and Doppler echocardiography, Fick oximetry and thermodilution. Circulation 1987;76:539-547. 14. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Sot Echocardiogr 1989;2:358-367. 15. Ross J, Linhart JW, Braunwald E. Effects of changing heart rate in man by electrical stimulation of the right atrium. Circulation 1965;32:549-558. 16. Opie LH. Myocardial oxygen uptake: heart work and exercise. In: The Heart: Physiology and Metabolism. 2nd ed. New York: Raven Press, 1991:339-368. 17. Pierard LA, Betthe C, Albert A, Carlier J, Kulbertus HE. Hemodynamic alterations during ischemia induced by dobutamine stress testing. Eur Heart J 1989; 10:783-790. 18. Olson CE. Porter TR, Deligonul U, Xie F, Anderson JR. Left ventricular volume changes during dobutamine stress echocardiography identify patients with more extensive coronary artery disease. .I Am Coil Cardiol 1994.24: 1268-1273. 19. Attenhofer CH, Pellikka PA, Oh JK, Roger VL, Sohn DW, Seward JB. Comparison of ischemic response during exercise and dobutamine echocardiography in patients with left main coronary artery disease. J Am CON Cardiol (in press).
886
NOVEMBER 1, 1995
THE AMERICAN JOURNAL OF CARDIOLOGYa
VOL. 76