DOBUTAMINE AFTER OPEN HEART SURGERY/Sakamoto, Yamada Consultants and Associates
Jack M. Becktel James A. Hagans, M.D., Ph.D. C. Morton Hawkins, Sc.D. Sibley W. Hoobler, M.D. Arthur F. Johnson, Ph.D. H. M. Perry, M.D. Harold W. Schnaper, M.D. Lawrence W. Shaw William M. Smith, M.D.
References 1. Page IH, Hurley RE, Dustan HP: The prolonged treatment of hypertension with guanethidine. JAMA 175: 543, 1961 2. Kelly JJ Jr, Housel EL, Daly JW: Clinical experience with guanethidine in the treatment of hypertension. JAMA 176: 577, 1961 3. Maronde RF, Haywood LJ, Barbour B: Comparison of guanethidine and
525
guanethidine plus a thiazide diuretic. Am J Med Sci 242: 228, 1961 4. Editorial: Today's drugs: Bethanidine sulfate. Br Med J 2: 865, 1964 5. Gibb WE, Malpos JS, Turner P, White RJ: Comparison of bethanidine, alpha methyldopa and reserpine in essential hypertension. Lancet 2: 275, 1970 6. Prichard BNC, Johnston AW, Hill ID, Rosenheim ML: Bethanidine, guanethidine and alpha methyldopa in treatment of hypertension. A within patient comparison. Br Med J 1: 135, 1968 7. Gifford RW Jr: Bethanidine sulphate - a new antihypertensive agent. JAMA 193: 901, 1965 8. Editorial: Today's drugs: Bethanidine. Br Med J 1: 285, 1967 9. Swinyard EA, Harvey SC: Adrenergic blocking drugs. In Remington's Pharmaceutical Series, edited by Martin EW. Easton, Mack Publishing Co., 1965, pp 988-989 10. Page LB, Sidd JJ: Medical Management of Primary Hypertension. Boston, Little, Brown, 1973, pp 42-46 11. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 202: 116, 1967 12. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressures averaging 90 through 114 mm Hg. JAMA 213: 1143, 1970
Hemodynamic Effects of Dobutamine in Patients Following Open Heart Surgery TOHRU SAKAMOTO, M.D.,
AND
TAKASHI YAMADA, M.D.
SUMMARY Dobutamine, a new synthetic inotropic agent, was administered by intravenous infusion to 22 patients following open heart surgery. The dosage of dobutamine started from 2Ag/kg/min and was increased stepwise to 4, 6, and 8 ,ug/kg/min. Cardiac index increased from 2.54 ± 0.13 to 3.11 ± 0.19 and 3.50 ± 0.22 L/min/m2 with 4 and 8 ,tg/kg/min, respectively. Heart rate increased from 87.6 ± 2.9 to 96.4 ± 2.3 and 108.9 ± 3.2 beats/min with 4 and 8 ,gg/kg/min, respectively. Systolic and mean aortic pressure and systolic pulmonary arterial pressure were elevated from 126.0 ± 3.8 to 144.6 ± 6.0 mm Hg, from 91.8 ± 2.7 to 96.2 ± 3.2 mm Hg, and
from 33.4 ± 2.3 to 37.1 ± 2.5 mm Hg with 8 Ag/kg/min, while other pressures were unchanged. Mean left atrial pressure fell significantly from 15.9 ± 0.6 to 14.8 ± 0.7 mm Hg. Stroke volume index, stroke work index, and left ventricular work also increased. Premature ventricular beats were observed in only one patient during dobutamine infusion, but no other side effect was observed. We conclude that dobutamine is a potent inotropic agent which increases cardiac output without causing significant tachycardia or arrhythmias, and is useful for the treatment of patients following open heart surgery.
ISOPROTERENOL, a potent beta-adrenergic stimulator, has been widely used for the treatment of cardiac failure, cardiogenic shock, or low output syndrome following open heart surgery.1-3 Although infusion of isoproterenol improves myocardial performance, occurrence of adverse side effects such as tachycardia, ventricular arrhythmia, and reduced perfusion pressure, often necessitates the discontinuation of this drug. Furthermore, isoproterenol has been shown experimentally to intensify myocardial ischemia and to extend infarct size after coronary narrowing or occlusion resulting in acute myocardial failure.4 An agent with inotropic effect as potent as isoproterenol but without significant effects on vasomotor tone, heart rate, or rhythm would be desirable for the treatment of myocar-
dial pump failure. Recently, Tuttle and Millis synthesized a new beta-adrenergic stimulator.6 This new beta-adrenergic stimulator, dobutamine, which is synthesized by modifying the side-chain of dopamine, is reported to have a strong inotropic action with a weak chronotropic action and little effect on peripheral vessels.7-14 In this study, we examined the acute hemodynamic effects of dobutamine on patients following open heart surgery and compared the hemodynamic responses with isoproterenol infusion.
From the Division of Cardiovascular Surgery, First Department of Surgery, School of Medicine, Tokyo Medical and Dental University, Tokyo,
Japan. Address for reprints: Tohru Sakamoto, M.D., Division of Cardiovascular Surgery, First Department of Surgery, School of Medicine, Tokyo Medical and Dental University, No. 1-5-45, Yushima, Bunkyo-Ku, Tokyo, Japan. Received June 23, 1976; revision accepted September 30, 1976.
Method and Materials
The study group (table I) consisted of 22 patients hospitalized at the Tokyo Medical and Dental University Hospital for open heart surgery. Their ages ranged from 19 to 54 years with a mean of 32.5 years. The surgical procedure for aortic valve replacement with the StarrEdwards ball prosthesis was performed during either coronary perfusion or a period of anoxic arrest. For other surgical procedures which included mitral valve replacement with the Starr-Edwards disc prosthesis, an anoxic arrest was
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CIRCULATION
526 TABLE 1. Study Group Pt/Age/Sex
Diagnosis
NYHA
class
Operation
MI MS Marfan's syndrome ASD VSD + Al
III II III II
MAP OMC
K.S. /54/M Y.S. /34/F M.T. /21/M
AI MS ASD + PS
III III II
E.O. /19/F T.S. /34/M N.S. /19/F E.K. /27/F Y.O. /35/F Y.O. /33/F K.Y. /22/M H.Y. /37/F T.I. /23/M H.K. /37/M N.S. /48/F Y.H. /29/M T.O. /29/F T.M. /47/M
ASD AI + MI ASD MI AI Al ASD ASD VSD MS + PH MS MS + PH MS MI
I III I III III III I II I IV III IV II IV
N.T. S.N. A.Y. A.S. H.S.
/22/M /48/F /32/M /39/F /21/M
III
VOL 55, No 3, MARCH 1977
tricular stroke work index (LVSWI) in g-m/beat/m' and systemic vascular resistance (SVR) in units were calculated as follows: LVSWI
AVR + MVR
ASD closure VSD closure + AVP AVR OMC ASD closure + PC ASD closure AVR + MVR ASD closure MAP AVR AVR ASD closure ASD closure VSD closure OMC OMC OMC OMC MVR
Abbreviations: AI = aortic insufficiency; ASD = atrial septal defect; AVP = aortic valvuloplasty; AVR = aortic valve replacement; MAP = mitral annuloplasty; MI = mitral insufficiency; MS = mitral stenosis; MVR = mitral valve replacement; OMC = open mitral commissurotomy; PC = pulmonary commissurotomy; PH = pulmonary hypertension; PS = pulmonary valvular stenosis; VSD = ventricular septal defect.
used. The cardiopulmonary bypass technique utilized hemodilution, the Temptrol Q-100 disposable bubble oxygenator, and perfusion rates of 3.0 L/min/m2 at normothermia. At operation, 19 gauge Teflon catheters (30 cm in length) were placed in the main trunk of the pulmonary artery and the left atrium. They were connected through the operative wound to metal three-cockplates outside of the thorax. In order to keep the catheters patent postoperatively, one arm of the three-way cock was connected to a continuous microinfusion pump. The remaining arm was connected to an electric manometer. A 19 gauge polyethylene catheter (70 cm in length) was inserted into the left radial artery and passed to the aortic arch. Central aortic pressure was measured through the catheter, which was used also as the cuvette circuit for dyedilution method to determine the cardiac output. Pulmonary arterial pressure, left atrial pressure, and aortic pressure were simultaneously obtained from the Statham P-23Db pressure transducers using the midchest as the zero reference point and recorded at various paper speeds on multichannel recorder. Mean values of these pressures were also obtained using an electronic integrating circuit. Cardiac output was determined by duplicated dye-dilution technique. After sequential injections of indocyanine green (5 mg) into the main trunk of the pulmonary artery and the left atrium, arterial blood was sampled by continuous withdrawal pump at a speed of 34.5 ml/min. Dye-dilution curves were recorded and the cardiac output was computed by an -Erma Blood Flow Computer (Erma Optical Company). The arithmetic mean of cardiac output was derived from the average of the two curves which were obtained from the injections into the trunk of the pulmonary artery and the left atrium. Left ven-
=
SVI X (MAP 1000
MLAP)X
13.6
SVR = MAP CO
Where SVI = stroke volume index (ml/beat/m2), MAP = mean aortic pressure (mm Hg) and CO = cardiac output
(L/min). Studies were carried out within six hours following open heart surgery. Dobutamine was infused with a Harvard infusion pump and its dose was increased stepwise from 2 to 4, 6, and 8 Atg/kg/min at a 15 min interval. Various hemodynamic parameters mentioned above were determined before the start of infusion, during the infusion at a rate of 2, 4, 6 and 8 Mg/kg/min, and at 5 and 10 minutes after stopping the infusion. In three of the 22 patients studied, the response to dobutamine was tested in a similar manner 12 to 24 hours after the original test. Thus, the final statistical analysis of the effects of dobutamine on hemodynamics was made with a total number of 25. In nine out of the 22 patients, isoproterenol was infused with a Harvard infusion pump at 30 min after the dobutamine study and its dose was increased from 0.005 to 0.01 and 0.02 ,ug/kg/min at 15 min intervals. Hemodynamic results obtained with dobutamine and isoproterenol in the same nine patients were compared with each other. All patients received blood transfusion to maintain left atrial pressure above 12 mm Hg and 21 patients had an uneventful recovery and did not require pharmacological support therapeutically during the postoperative period. Statistical analysis utilized the Student's t-test on a paired or unpaired basis as appropriate. A P value of less than 0.05 was considered to indicate a significant difference between compared group of data. Results Table 2 shows changes in various hemodynamic parameters obtained from dobutamine infusion. With infusion of dobutamine, systolic aortic pressure showed a significant and constant increase by 17.1 mm Hg (13.6%) from an average of 126.0 ± 3.8 to 144.6 ±: 6.0 mm Hg, but on discontinuation of infusion, it immediately decreased to a level lower than the control value by 2 mm Hg (fig. 1). No significant change was observed in diastolic aortic pressure but mean aortic pressure showed a significant increase by 4.4 mm Hg (4.8%) from an average of 91.8 ± 2.7 to 96.2 ± 3.2 mm Hg. Pulmonary arterial pressure showed changes similar to aortic pressure. Systolic pulmonary arterial pressure showed a significant increase by 3.7 mm Hg (11.1%) from an average of 33.4 ± 2.3 to 37.1 ± 2.5 mm Hg with dobutamine but it showed a significantly lower value than the control after its termination. No significant change was observed either in diastolic or mean pulmonary arterial pressure with dobutamine infusion. However, mean pulmonary arterial pressure showed a significant decrease after discontinuation of dobutamine. Mean left atrial pressure showed a slight but significant decrease from an
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DOBUTAMINE AFTER OPEN HEART SURGERY/Sakamoto, Yamada
150 r 3- 140 -r
4.0 r E
.d4A\.
E 130 E LH 120 in 110
c
E %._O
-J
3.01F
40
$--
*U)rr "Inn .
527
_
L-
(. L-
0
80 70
FI
V
2.0 -
,r a
-
At
Ie
I
I,.
I
control 2 4 6 8 Dobutamine
5mirt .10min..
(mcg/Kg/min)
FIGURE 1. Changes in aortic pressure with dobutamine. Systolic and mean aortic pressures showed a significant increase. Values are mean + standard error of mean.
average of 15.9 ± 0.6 to 14.8 + 0.7 mm Hg (7.2%). After discontinuation of dobutamine, mean left atrial pressure remained at the decreased level. Cardiac index showed a significant stepwise increase with graded doses of dobutamine (fig. 2). The increase in cardiac index with each increase of dobutamine dose was 13.4, 22.4, 31.4, and 37.7%, respectively, and the overall increase was from an average of 2.54 + 0.13 to 3.50 + 0.22 L/min/m2. With cessation of dobutamine, cardiac index showed a decrease and was at the control level after 10 min. Heart rate increased significantly from an average of 87.6 ± 2.9 to 108.9 ± 3.2 beats/min (24.3%) but returned to the control value 10 min after the stop of infusion. The only arrhythmia that developed in these cases during dobutamine infusion was premature ventricular beats observed in a patient (E.K.). In a 39-year-old female patient (A.S.) with atrial septal defect, multiple premature ventricular beats were observed before infusion of dobutamine, but they disappeared during dobutamine infusion. With discontinuation of dobutamine, the arrhythmia reappeared. Left ventricular stroke work index showed a significant increase of 11.8%, from an average of 32.1 ± 2.9 to 35.9 ± 3.2 g-m/beats/m2, immediately after the onset of dobutamine infusion, and reached a plateau and returned to the control level upon the cessation of dobutamine. Calculated systemic vascular resistance showed a significant decrease, from an average of 24.7 + 1.3 to 19.3 ± 1.2 units (21.8%), but returned to the control value after dobutamine infusion. The decrease in systemic vascular resistance was due to marked increase of cardiac output by dobutamine but not to a direct vasoactive effect of the drug. During hemodynamic studies, an interesting finding was observed in a 21-year-old patient (H.S.). His urinary output was between 40 and 50 ml/hour before infusion of dobutamine but during dobutamine infusion urine volume was markedly increased to 450 ml/hour and after the infusion urine volume returned to 42 ml/hour. Hemodynamic effects of isoproterenol infusion were com-
a
I
II
I
control 2 4 6 8 5 .10 . min. min. Dobutamine (mcg/Kg/min)
.
FIGURE 2. Changes in cardiac index. With increased doses of dobutamine, cardiac index showed a significant increase and at a rate of 8 pg/kg/min, it was 37.7% higher than the control value. Values are mean + standard error of mean.
pared to dobutamine in the same nine patients out of the study group (table 3, fig. 3). With 0.02 ,ug/kg/min of isoproterenol, aortic pressure changed from an average of 124/80 (95) to 132/76 (93) mm Hg. But in dobutamine infusion, aortic pressure increased constantly from an average of 123/76 (94) to 143/82 (101) mm Hg. At a comparable heart rate, 96.3 beats/min after 4 gg/kg/min of dobutamine vs 96.6 beats/min after 0.005 pg/kg/min of isoproterenol, the increase of cardiac index from control value was larger in
4.0
dobutamine
3.5 E x
3.0
c 2.51- FTi (0
W
isoproterenol
119
2(5
80
90 100 110 120 130 140 Heart Rate (beat/min)
FIGURE 3. Changes in cardiac index and heart rate with dobutamine and isoproterenol. At comparable effects on cardiac index, the increase in heart rate is less with dobutamine than with
isoproterenol.
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VOL 55, No 3, MARCH 1977
CIRCULATION
528 TABLE 2. Hemodynamic Effects of Dobutamine A
C
B
D
E
APs (mm Hg) 144 N.T. 124 S.N. 140 S.N.* 112 Y.A. 153 A.S. 160 H.S. 121 K.S. 95 K.S.* 115 Y.S. 132 M.T. 142 E.O. 92 T.S. 98 T.S.* 126 N.S. 156 E.K. 127 Y.O. 142 Y.O. 132 K.Y. 141 H.Y. 132 T.I. H.K. 103 123 N.S. 120 Y.H. 102 T.O. T.M. 119 126.0 Mean SE 3.8 P
150 120 146 116 160 166 115 106 113 151 156 98 98 137 149 138 145 155 160 148 108 138 118 114 124 133.2 4.2 0.001
168 128 148 124 178 175 113 108 115 166 168 98 105 123 150 143 150 176 170 170 105 143 118 110 125 139.1 5.4 0.001
130 166 141 158 183 178 166 109 143 143 110 124 143.1 5.7 0.001
160 132 152 123 204 186 126 110 121 152 178 96 105 148 149 140 151 186 175 189 107 150 142 110 122 144.6 6.0 0.001
APm (mm Hg) 102 N.T. 91 S.N. S.N.* 100 79 Y.A. 113 A.S. 111 H.S. K.S. 91 73 K.S.* 85 Y.S. M.T. 91 96 E.O. T.S. 73 75 T.S.* N.S. 77 E.K. 82 89 Y.O. Y.O. 118 K.Y. 99 H.Y. 109 111 T.I. 72 H.K. N.S. 98 86 Y.H. T.O. 88 T.M. 85 Mean 91.8 SE 2.7 P
103 85 102 86 120 110 84 76 82 96 98 73 71 86 83 97 119 115 117 115 75 101 92 86 89 94.4 3.0 0.05
110 92 102 86 118 115 80 81 84 97 98 71 73 85 82 99 108 123 125 116 78 105 91 87 89 95.8 3.2 0.01
104 86 101 90 131 115 81 81 90 90 95 72 71 82 84 94 108 124 131 117 78 105 92 87 86 95.8 3.4 0.05
99 92 104 87 128 110 84 77 91 92 96 76 73 83 89 93 110 123 125 118 78 108 92 90 86 96.2 3.2 0.01
PAPd (mm Hg) N.T. 12 S.N. 19 37 S.N.* Y.A. 24 A.S. 13 H.S. 17 K.S. 18 13 K.S.* Y.S. 20 M.T. 11
12 19 40 23 14 14
17 13 21 12
12 20 44 24 13 12 15 13 20 12
160 122 144 127 192 189 118 116 119 162 178 97 102
12 20 41 24 13 11 15
13 21 11
12 21
47 24 13 10 15 12 21 12
F
150 121 136 116 142 159 101 105 113 124 155 90 98 128 147 125 141 136 145 137
102 138 109 101 107 125.0 4.0 NS
G
140 120 130 119 146 157 100 104 113 125 151 88 98 129 151 124 133 132 151 132 112 135 111 100 103 124.2 3.8 NS
103 87 96 87 104 106 77 76 88 83 92 71 71 85 84 89 106 103 117 113 78 106 91 87 78 91.1 2.6 NS
105 108 80 77 93 86 95 71 72 82 83 91 114 101 117 111 77 106 89 87 76 91.4 2.6 NS
13 20 35 25 9 10 14 14 20 10
12 19 36 26 10 12 13 14 20 11
97 88 91 88
A
B
APd (mm Hg) 84 80 80 74 75 68 80 80 79 72 75 70 95 85 88 92 93 91 66 76 69 61 67 63 66 64 75 76 81 73 69 72 74 64 66 66 66 58 55 64 64 61 60 61 59 78 76 72 109 104 90 89 77 94 102 91 89 100 93 94 60 52 55 84 87 78 65 76 68 75 74 75 73 66 71 75.0 75.2 76.8 2.5 2.5 2.7 NS NS PAPs (mm Hg) 27 30 45 47 37 40 61 61 26 28 29 25 29 28 22 24 32 32 25 28 22 26 30 30 27 28 26 28 29 29 30 28 35 34 25 30 29 25 29 27 56 52
33 66 38 26 33.4 2.3
39 68 35 28 34.0 2.3 NS
PAPm (mm Hg) 17 18 18 28 24 25 40 40 17 19 21 18 22 21
16 24 16
17 25 17
D
E
F
G
76 68 80 74 93 85 70 64 78 71 71 66 63 64 66
78 72 80 73 91 80 68 60 78 72 71 66 66 64 62 75 100 94 100 93 60 89 74
80 70 76 73
76 72 72 75 84 83 70 64 77 71 70 63 65 67 64 81 101 83 96 86 63 86 76 79
C
33
80 89 97 101 97 58
87 74 75 71 76.7 2.4 NS
35
53 53 44 41 61 63 29 29 27 27 28 26 24 26 32 34 30 32 31 32 30 30 29 27 28 28 29 29 30 31 37 42 36 37 25 27 28 27 52 54 41 47 65 64 36 36 30 29 35.5 36.2 2.2 2.3 0.05 0.01
19 28 25 41 18 17 19 17 24 18
19 28
24 40 18 16 19 17 25 18
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75 70 76.4 2.4 NS
77 86 66 61 68 72 65 61 65 67 65 79 88 82 97 98 60 82 74
77 65 74.2 2.1 NS
56 75.2
2.2 NS
35
26
26
54 47 63 30 28 26 28 34 32 35 28 27 26 28 31 42 35 26 28 58 49 70 37 30 37.1 2.5 0.01
45
40
35 59 21 22 24 25 33 25 24 28 27 22 30 27 31 24 21 23 53 38 65 35 29 31.7 2.4 0.05
36 59 20 22 23 26 33 25 22 28 27 21 29 26 30 23 22 22 49 40 60 38 29 31.0 2.2 0.01
17 28 22
26 21
40
40 13
19 32 27 40 19 16 19 17 25 19
13 14 17 18 24 15
17
15 16 18 24 15
DOBUTAMINE AFTER OPEN HEART SURGERY/Sakamoto, Yamada
529
TABLE 2.
E.O. T.S. T.S.* N.S. E.K. Y.O. Y.O. K.Y. H.Y. T.I. H.K. N.S. Y.H. T.O. T.M. Mean SE
A
B
C
12 18 15 13 15 15 23 13 13 12 26 14 36 18 17 17.8 1.4
11 18 13 13 16 15 20 14 12 12 28 15 36 18 18 17.8 1.5 NS
10 17 13 12 15 15 20 17 12 12 29 17 34 18 20 17.8 1.6 NS
12 18 15 19 16 14 17 13 24 12 11 18 13 12 16 15 15 15 13 11 19 17
12 18 15 19 15 12 15 13 23 12
p
LAPm (mm Hg) 12 N.T. S.N. 18 16 S.N.* Y.A. 18 16 A.S. H.S. 17 K.S. 18 13 E.S.* 24 Y.S. 11 M.T. 12 E.O. T.S. 18 T.S.* 15 N.S. 13 16 E.K. 16 Y.O. Y.O. 18 K.Y. 13 H.Y. 15 T.I. 11 H.K. 18 N.S. 17 Y.H. 21 16 T.O. T.M. 16 Mean 15.9 SE 0.6 p
HR (beats/mmn) N.T. 81 S.N. 96 S.N.* 70 Y.A. 96 A.S. 78 H.S. 94 K.S. 113 106 K.S.* Y.S. 106 M.T. 89 E.O. 57 T.S. 80 T.S.* 88 N.S. 76 E.K. 105 Y.O. 112 Y.O. 95 K.Y. 82 H.Y. 64 T.I. 85
19 13 16 15.3 0.6
91 86 106 113 100
92 65 95
E
10 16 13 11
17 12 15 15 20 16 12 12 30 18 32 18 19 17.8 1.5 NS 12 18 14 19 15 11 15 13 24
10
11 10
17 13 10 15 15 17 16 13 10 19 19 19
17 17 8 15 16 17 14 13 10 20 19 17
11
11
16 14.9 0.7 0.05 0.0r5
93 104 71 99 86 95 109 103 103 89 69 80
D
10 17
108 100 84 100 86 104 110 108 102 96 78 80 97 100 87 120 110 98 77 102
15 14.8 0.7 0.05
121 110 85 102 89 120 112 106 102 108 86 83 95 112 110 124 120 110 80 105
15 15 20 15 11 12 30 19 34 20 21 18.0 1.7 NS 12 17 14 19 14 10 15 12 24 12 10
16 13 12 16 16 16 13 13 10
20 20 18 12 15 14.8 0.7 0.05
130 114 102 105 97 127 115 109 102 130 96 90 100 138 87 130 122 120 86 110
F
G
A
B
10 15 14 11 16 15 16 11 12 12 28 17 31 20 20 16.7
10 18 14 11 15
15 22 18 17 22 23 26 18 20 20 36 21 46 26 20 23.0 1.5
16 22 18 18 23 23 24 21 19 19 36 23 47 25 21 23.3 1.5 NS
1.4 NS 13 18 14 20 12 10
14 14 23 10 10 15 14 11 15 16 15 13 13 10 22 19 18 16 15 14.8 0.7 0.05
105 108 86 104 85 107 108 105 96 91 72 79 89 99
96 109 103 99 64 105
15 19 12 11 14 28 17 35 21 19 17.3 1.5 NS
12 17 14 20 13 12 13 14 24 11 10
18 14 11 15 16 15 14 13 12 18 19 19 15 16 15.0 0.7 0.05
94 109 72 102 84 96 103 101 98 92 65 79 89 90 96 110 102 96 60 87
C
D
17
17
21 18 17 23 23 26 24 19 19 37 26 44 24 23 23.5 1.5
21 20 17 23 24 27 23 20 19 38 27 43 26 22 23.6 1.5
NS
NS
E
18 20 18 16 22 24 26 21 18 20 39 29 46 27 24 24.0 1.6 NS
CI (L/min/m2) 2.50 2.86 3.19 3.40 3.67 3.17 3.72 4.03 4.27 4.06 2.28 2.54 3.11 3.18 3.79 1.79 2.07 2.24 2.33 2.52 3.74 3.82 3.54 3.89 3.71 2.78 3.22 3.57 4.27 4.13 2.26 2.61 2.67 2.95 3.11 1.83 2.02 1.95 2.10 2.29 2.10 2.10 2.06 2.37 2.13 2.56 2.75 2.85 2.97 3.19 2.99 3.94 4.46 5.17 5.44 2.23 2.32 2.33 2.59 2.55 2.18 2.43 2.63 2.77 2.80 3.84 4.76 5.21 5.30 5.38 1.85 1.96 2.01 2.30 2.07 1.94 2.10 2.16 2.22 2.39 2.66 3.15 3.10 3.37 3.39 3.73 4.09 4.66 5.16 5.82 2.15 2.79 2.50 2.64 3.33 3.25 3.29 4.60 4.90 5.30 3.09 3.19 3.24 3.34 4.02 2.01 2.43 2.66 2.93 2.98 1.89 2.45 2.92 2.76 3.04 2.86 3.42 3.93 4.10 4.17 1.85 1.99 2.13 2.23 2.19 2.54 2.88 3.11 3.34 3.50 0.13 0.15 0.19 0.20 0.22 0.001 0.001 0.001 0.001 SVI (ml/beat/M2) 31 30 31 33 36 40 33 36 37 19 21 22 44 41 48 34 30 34 20 24 24 17 20 18 20 20 20 30 29 31 53 57 57 28 29 29 27 27 25 52 50 55 23 18 18 17 18 19 32 28 28 45 45 48 32 34 43 38 35 45
28 39 37 23 44 36 26 20 23 28 60 31 29 47 21 18 28 47 33 47
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28 36 37 24 38 33 27 21 21 25 57 28 28 39 24 18 28 49 39 48
F
G
15 21 18 15 21 22 21 17 18 18 36 26 42 26 23 21.9 1.5 0.05
14 21 18 14 20 22 22 17 18 17 35 26 43 28 22 21.7 1.6 0.05
3.05 3.66 2.55 2.20 3.21 3.32 2.30 1.96 2.26 2.40 3.99 2.22 2.35 3.80 2.07 2.00 2.64 3.65 2.38 4.60 3.76 2.22 2.74 2.49 2.08 2.80 0.15 0.01
2.85 3.20 2.42 2.04 3.06 2.85 1.91 1.80 1.94 2.57 3.58 2.09 2.18 3.60 2.14 1.89 2.59 2.82 1.99 3.76 2.68 2.21 2.24 2.42 1.89 2.51 0.12 NS
29 34 30 21 38 31 21 19 24 26 55 28 26 38 22 18 26 37 37 44
30 29 34 20 36 30 19 18 20 28 55 26 25 40 22
17 25 29 34 43
530
CIRCULATION
VOL 55, No 3, MARCH 1977
TABLE 2. (Continued) A
H.K. N.S. Y.H. T.O. T.M. Mean SE P
86 81
95 75 80 87.6 2.9
B
86
C
90 91 90 109 82
86 96 94 80 91.6 96.4 2.5 2.3 0.01 0.001
LVSWI (gm-nm/beat/M2) N.T. 38 38 S.N. 33 33 S.N.* 38 42 Y.A. 16 19 A.S. 63 62 H.S. 44 38 K.S. 20 22 14 K.S.* 17 Y.S. 17 16 M.T. 32 35 E.O. 61 67 T.S. 21 22 T.S.* 20 21 N.S. 43 56 E.K. 16 17 Y.O. 17 21 Y.O. 38 45 K.Y. 53 61 H.Y. 43 61 T.I. 52 50 H.K. 26 28 N.S. 28 32 Y.H. 18 26 T.O. 37 36 T.M. 22 25 Mean 32.1 35.9 SE 2.9 3.2 P 0.001
40 40 43 20 58 48 21 17 17 35 68 21 22 53 21 21 35 70 49 65 29 34 32 37 26 36.8 3.3 0.001
D
E
F
G
97 94 94 120 82 102.7 2.7 0.001
95 105 98 130 85 108.9 3.2 0.001
93 84 88 85 80 93.6 2.4 0.01
80 82 92 81 77 89.5 2.6 NS
35 36 44 22 69 51 23 19 21 30 69 23 21 47 20 19 35 70 53 68 27 37 30 35 26 37.2 3.5 0.001
33 37 45 22 59 45 25 19 19 27 67 23 23 38 24 19 36 73 59 71 33 33 31 34 25 36.8 3.3 0.001
36 32 33 19 47 41 18 16 21 26 61 21 20 38 21 18 32 45 52 62 31 31 31 28 22 32.1 2.6 NS
35 28 36 18 45 39 17 15 19 29 64 19 20 38 20 17 34 35 48 58 27 32 23 30 20 30.6 2.6 NS
A
36
25 20 38 23 33.3 2.1
B
37 28 26 36 25 32.4 2.1 0.01
SVR (unit) 24.8 21.8 19.8 15.8 30.3 27.7 26.2 24.8 22.9 23.8 25.8 22.0 30.5 24.4 30.3 28.5 28.5 27.5 20.3 20.0 23.1 17.9 17.8 17.1 18.7 15.8 13.2 11.9 32.8 31.4 28.6 28.9 27.2 23.2 15.6 16.5 34.0 28.1 17.3 17.7 15.5 15.6 36.4 31.1 29.8 24.5 21.1 17.2 27.3 26.6 24.7 22.4 1.3 1.1 0.001
D
E
F
G
34 27 32.8 2.0 0.01
42 28 31 32 26 32.3 1.9 NS
40 26 31 29 26 30.2 1.7 NS
34 27 24 30 25 28.8 1.7 NS
18.5 13.9 21.9 23.0 25.5 17.4 20.8 29.2 26.7 17.3 13.2 15.1 13.9 10.2 27.1 26.5 19.6 14.2 33.2 12.1 15.5 26.8 21.8 14.6 22.9 20.0 1.2 0.001
16.3 15.6 18.9 20.5 26.1 17.2 20.4 25.5 30.1 16.5 12.7 16.2 14.2 10.1 31.8 24.3 19.9 12.4 25.2 11.3 12.9 27.1 19.8 14.8 23.4 19.3 1.2 0.001
20.5 16.4 25.9 23.6 24.5 20.6 25.3 29.3 27.4 19.8 16.6 17.4 16.4 14.7 30.0 27.8 24.7 16.6 33.0 14.1 13.7 35.6 21.7 24.0 22.3 22.5 1.2 0.05
20.6
C
36
29 32 36 26 32.6 2.1 0.01 20.9 15.8 22.5 22.9 25.3 20.8 22.7 31.4 28.8
19.5 15.8 16.6 15.1 10.7 30.3 28.7 21.4 15.5 33.6 12.8 15.9 29.5 20.4 15.2 24.9 21.5 1.3 0.001
34 31
29
19.0 25.9 25.7 26.0 24.4 31.7 32.4
33.7 19.2 19.1 18.4 17.9 15.0 28.7 30.1 27.0 21.1 39.4 15.0 19.0 35.8 25.9 24.6 23.9 24.8 1.3 NS
Abbreviations: A = control; B = 2mcg/kg/min; C = 4mcg/kg/min; D = 6mcg/kg/min; E = 8mcg/kg/min; F = 5 min after dobutamine; G = 10 min after dobutamine; APd = diastolic aortic pressure; APm = mean aortic pressure; APs = systolic aortic pressure; CI = cardiac index; HR = heart rate; MLAP = mean left atrial pressure; PAPd = diastolic pulmonary arterial pressure; PAPm = mean pulmonary arterial pressure; PAPs = systolic pulmonary arterial pressure; SVI = stroke volume index; SVR = systemic vascular resistance; SWI = stroke work index. sIB = standard error of mean. P values derived from paired t-test comparing A vs B, C, D, E, F, G. *indicates the second test of dobutamine infusion.
the former (0.57 L/min/m2) than the latter (0.41 L/min/m2), but this difference was not significant statistically. Moreover, comparison in stroke volume index was not significantly different in these dosage of both drugs. But the increase in heart rate was considerably greater with isoproterenol than that with dobutamine. It appears that inotropically, 2 and 8 ,sg/kg/min of dobutamine were comparable to 0.005 and 0.01 Ag/kg/min of isoproterenol, respectively (fig. 3). A representative case (Y.O.) is presented below (fig. 4). Aortic valve replacement by the Starr-Edwards ball prosthesis was performed for aortic insufficiency. Immediately postop, the patient was in a stable condition and aortic pressure was 123/71 (90) mm Hg; pulmonary arterial pressure, 31/16 (23) mm Hg; mean left atrial pressure, 15.5 mm Hg, and cardiac index 1.92 L/min/m2. Fourteen hours after surgery, aortic pressure fell to 90/65 (74) mm Hg, cardiac index decreased to 1.06 L/min/m2, and pulmonary arterial pressure and mean left atrial pressure increased. A diagnosis
of severe left ventricular failure was made and the infusion of dobutamine at a rate of 6 Ag/kg/min was started. After aortic pressure had been elevated to a safe level, the infusion of phenoxybenzamine at a dose of I mg/kg was added for the purpose of reducing the afterload of the left ventricle. Subsequently cardiac index increased to over 2.0 L/min/m2 and systolic aortic pressure stabilized at 120 mm Hg. The infusion of dobutamine was stopped at 8 hours after initiation, but there was no change in hemodynamics and the patient remained in a satisfactory condition. Sufficient urinary output was also maintained. Discussion With the administration of isoproterenol, tachycardia or arrhythmia often develops and necessitates the cessation of infusion before a sufficient increase in cardiac output can be obtained. Myocardial oxygen consumption (MVO2) increases markedly as both myocardial contractile force and
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DOBUTAMINE AFTER OPEN HEART SURGERY/Sakamoto, Yamada heart rate increase with isoproterenol, thus shifting the myocardial metabolism to anaerobic."5 In an attempt to develop a new beta-adrenergic stimulator without these adverse effects on cardiac rhythm or myocardial metabolism, dobutamine has been synthesized by modifying the side-chain of dopamine.6 It has been reported that dobutamine increases myocardial contractile force selectively.8 12 In the present study, dobutamine increased systolic and mean aortic pressure and systolic pulmonary arterial pressure significantly but diastolic aortic pressure and diastolic pulmonary arterial pressure remained unaltered. These changes demonstrate that dobutamine produced relatively little change in peripheral vascular resistance at doses less than 8 ,Ag/kg/min. Dobutamine has been shown to possess both vasoconstricting and vasodilating effects on peripheral vessels."6' 17 At low doses, a mild peripheral alpha-adrenergic action predominates, while with higher doses, beta-adrenergic effect is predominant. Holloway et al. observed this biphasic response clinically with dobutamine, with 10 gg/kg/min being the cut-off point,'3 and Robie et al. reported that as the dose of dobutamine was increased to higher than 16 gg/kg/min peripheral vasodilation became predominant and aortic pressure and total peripheral resistance began to lower.", Since dobutamine does not lower aortic pressure, it is expected that the inflow pressure of the coronary arteries is not lowered, thus acting favorably on coronary perfusion. This advantage makes an interesting contrast to isoproterenol which reduces diastolic aortic pressure because of its potent vasodilating action on peripheral vessels.'8 Tuttle et al. reported that in experimental dogs P02 in coronary sinus increased by 35% after infusion of dobutamine, but decreased by 11% after isoproterenol.7 They considered that dobutamine increased myocardial oxygen supply more significantly than myocardial oxygen consumption. The fact obtained from our study that the diastolic aortic pressure was unchanged during dobutamine infusion may also have been responsible for the finding by Tuttle et al.7 Vatner et al."' reported that in the presence of experimental moderate global ischemia, dobutamine is not as deleterious as isoproterenol. In their experiment, left ventricular function was maintained during dobutamine infusion but acute depression of cardiac function occurred when isoproterenol was substituted for dobutamine. In the present study, mean left atrial pressure showed a significant, gradual decrease after the start of dobutamine infusion because of the improvement of left ventricular function. These changes in pressure were very similar to those reported by Jewitt et al." As far as clinical investigations are concerned, cardiac index was found to be increased with dobutamine by 82% (Akhtar et al.8), 82% (Beregovich et al.9" 10), and 43% (Jewitt et al."). Loeb et al."2 reported on 36 patients of whom 17 patients had impaired left ventricular performance. Dobutamine augmented cardiac index by 48% (7.5 ,g/kg/min) in patients with normal left ventricular function and 82% (10.7 Ag/kg/min) in patients with depressed left ventricular function. Discrepancies of the degree of increase in cardiac index is thought to be related to the differences in myocardial contractility reserve before the administration of dobutamine. This is supported by the fact
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Jack M. Becktel James A. Hagans, M.D., Ph.D. C. Morton Hawkins, Sc.D. Sibley W. Hoobler, M.D. Arthur F. Johnson, Ph.D. H. M. Perry, M.D. Harold W. Schnaper, M.D. Lawrence W. Shaw William M. Smith, M.D.
References 1. Page IH, Hurley RE, Dustan HP: The prolonged treatment of hypertension with guanethidine. JAMA 175: 543, 1961 2. Kelly JJ Jr, Housel EL, Daly JW: Clinical experience with guanethidine in the treatment of hypertension. JAMA 176: 577, 1961 3. Maronde RF, Haywood LJ, Barbour B: Comparison of guanethidine and
525
guanethidine plus a thiazide diuretic. Am J Med Sci 242: 228, 1961 4. Editorial: Today's drugs: Bethanidine sulfate. Br Med J 2: 865, 1964 5. Gibb WE, Malpos JS, Turner P, White RJ: Comparison of bethanidine, alpha methyldopa and reserpine in essential hypertension. Lancet 2: 275, 1970 6. Prichard BNC, Johnston AW, Hill ID, Rosenheim ML: Bethanidine, guanethidine and alpha methyldopa in treatment of hypertension. A within patient comparison. Br Med J 1: 135, 1968 7. Gifford RW Jr: Bethanidine sulphate - a new antihypertensive agent. JAMA 193: 901, 1965 8. Editorial: Today's drugs: Bethanidine. Br Med J 1: 285, 1967 9. Swinyard EA, Harvey SC: Adrenergic blocking drugs. In Remington's Pharmaceutical Series, edited by Martin EW. Easton, Mack Publishing Co., 1965, pp 988-989 10. Page LB, Sidd JJ: Medical Management of Primary Hypertension. Boston, Little, Brown, 1973, pp 42-46 11. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 202: 116, 1967 12. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressures averaging 90 through 114 mm Hg. JAMA 213: 1143, 1970
Hemodynamic Effects of Dobutamine in Patients Following Open Heart Surgery TOHRU SAKAMOTO, M.D.,
AND
TAKASHI YAMADA, M.D.
SUMMARY Dobutamine, a new synthetic inotropic agent, was administered by intravenous infusion to 22 patients following open heart surgery. The dosage of dobutamine started from 2Ag/kg/min and was increased stepwise to 4, 6, and 8 ,ug/kg/min. Cardiac index increased from 2.54 ± 0.13 to 3.11 ± 0.19 and 3.50 ± 0.22 L/min/m2 with 4 and 8 ,tg/kg/min, respectively. Heart rate increased from 87.6 ± 2.9 to 96.4 ± 2.3 and 108.9 ± 3.2 beats/min with 4 and 8 ,gg/kg/min, respectively. Systolic and mean aortic pressure and systolic pulmonary arterial pressure were elevated from 126.0 ± 3.8 to 144.6 ± 6.0 mm Hg, from 91.8 ± 2.7 to 96.2 ± 3.2 mm Hg, and
from 33.4 ± 2.3 to 37.1 ± 2.5 mm Hg with 8 Ag/kg/min, while other pressures were unchanged. Mean left atrial pressure fell significantly from 15.9 ± 0.6 to 14.8 ± 0.7 mm Hg. Stroke volume index, stroke work index, and left ventricular work also increased. Premature ventricular beats were observed in only one patient during dobutamine infusion, but no other side effect was observed. We conclude that dobutamine is a potent inotropic agent which increases cardiac output without causing significant tachycardia or arrhythmias, and is useful for the treatment of patients following open heart surgery.
ISOPROTERENOL, a potent beta-adrenergic stimulator, has been widely used for the treatment of cardiac failure, cardiogenic shock, or low output syndrome following open heart surgery.1-3 Although infusion of isoproterenol improves myocardial performance, occurrence of adverse side effects such as tachycardia, ventricular arrhythmia, and reduced perfusion pressure, often necessitates the discontinuation of this drug. Furthermore, isoproterenol has been shown experimentally to intensify myocardial ischemia and to extend infarct size after coronary narrowing or occlusion resulting in acute myocardial failure.4 An agent with inotropic effect as potent as isoproterenol but without significant effects on vasomotor tone, heart rate, or rhythm would be desirable for the treatment of myocar-
dial pump failure. Recently, Tuttle and Millis synthesized a new beta-adrenergic stimulator.6 This new beta-adrenergic stimulator, dobutamine, which is synthesized by modifying the side-chain of dopamine, is reported to have a strong inotropic action with a weak chronotropic action and little effect on peripheral vessels.7-14 In this study, we examined the acute hemodynamic effects of dobutamine on patients following open heart surgery and compared the hemodynamic responses with isoproterenol infusion.
From the Division of Cardiovascular Surgery, First Department of Surgery, School of Medicine, Tokyo Medical and Dental University, Tokyo,
Japan. Address for reprints: Tohru Sakamoto, M.D., Division of Cardiovascular Surgery, First Department of Surgery, School of Medicine, Tokyo Medical and Dental University, No. 1-5-45, Yushima, Bunkyo-Ku, Tokyo, Japan. Received June 23, 1976; revision accepted September 30, 1976.
Method and Materials
The study group (table I) consisted of 22 patients hospitalized at the Tokyo Medical and Dental University Hospital for open heart surgery. Their ages ranged from 19 to 54 years with a mean of 32.5 years. The surgical procedure for aortic valve replacement with the StarrEdwards ball prosthesis was performed during either coronary perfusion or a period of anoxic arrest. For other surgical procedures which included mitral valve replacement with the Starr-Edwards disc prosthesis, an anoxic arrest was
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CIRCULATION
526 TABLE 1. Study Group Pt/Age/Sex
Diagnosis
NYHA
class
Operation
MI MS Marfan's syndrome ASD VSD + Al
III II III II
MAP OMC
K.S. /54/M Y.S. /34/F M.T. /21/M
AI MS ASD + PS
III III II
E.O. /19/F T.S. /34/M N.S. /19/F E.K. /27/F Y.O. /35/F Y.O. /33/F K.Y. /22/M H.Y. /37/F T.I. /23/M H.K. /37/M N.S. /48/F Y.H. /29/M T.O. /29/F T.M. /47/M
ASD AI + MI ASD MI AI Al ASD ASD VSD MS + PH MS MS + PH MS MI
I III I III III III I II I IV III IV II IV
N.T. S.N. A.Y. A.S. H.S.
/22/M /48/F /32/M /39/F /21/M
III
VOL 55, No 3, MARCH 1977
tricular stroke work index (LVSWI) in g-m/beat/m' and systemic vascular resistance (SVR) in units were calculated as follows: LVSWI
AVR + MVR
ASD closure VSD closure + AVP AVR OMC ASD closure + PC ASD closure AVR + MVR ASD closure MAP AVR AVR ASD closure ASD closure VSD closure OMC OMC OMC OMC MVR
Abbreviations: AI = aortic insufficiency; ASD = atrial septal defect; AVP = aortic valvuloplasty; AVR = aortic valve replacement; MAP = mitral annuloplasty; MI = mitral insufficiency; MS = mitral stenosis; MVR = mitral valve replacement; OMC = open mitral commissurotomy; PC = pulmonary commissurotomy; PH = pulmonary hypertension; PS = pulmonary valvular stenosis; VSD = ventricular septal defect.
used. The cardiopulmonary bypass technique utilized hemodilution, the Temptrol Q-100 disposable bubble oxygenator, and perfusion rates of 3.0 L/min/m2 at normothermia. At operation, 19 gauge Teflon catheters (30 cm in length) were placed in the main trunk of the pulmonary artery and the left atrium. They were connected through the operative wound to metal three-cockplates outside of the thorax. In order to keep the catheters patent postoperatively, one arm of the three-way cock was connected to a continuous microinfusion pump. The remaining arm was connected to an electric manometer. A 19 gauge polyethylene catheter (70 cm in length) was inserted into the left radial artery and passed to the aortic arch. Central aortic pressure was measured through the catheter, which was used also as the cuvette circuit for dyedilution method to determine the cardiac output. Pulmonary arterial pressure, left atrial pressure, and aortic pressure were simultaneously obtained from the Statham P-23Db pressure transducers using the midchest as the zero reference point and recorded at various paper speeds on multichannel recorder. Mean values of these pressures were also obtained using an electronic integrating circuit. Cardiac output was determined by duplicated dye-dilution technique. After sequential injections of indocyanine green (5 mg) into the main trunk of the pulmonary artery and the left atrium, arterial blood was sampled by continuous withdrawal pump at a speed of 34.5 ml/min. Dye-dilution curves were recorded and the cardiac output was computed by an -Erma Blood Flow Computer (Erma Optical Company). The arithmetic mean of cardiac output was derived from the average of the two curves which were obtained from the injections into the trunk of the pulmonary artery and the left atrium. Left ven-
=
SVI X (MAP 1000
MLAP)X
13.6
SVR = MAP CO
Where SVI = stroke volume index (ml/beat/m2), MAP = mean aortic pressure (mm Hg) and CO = cardiac output
(L/min). Studies were carried out within six hours following open heart surgery. Dobutamine was infused with a Harvard infusion pump and its dose was increased stepwise from 2 to 4, 6, and 8 Atg/kg/min at a 15 min interval. Various hemodynamic parameters mentioned above were determined before the start of infusion, during the infusion at a rate of 2, 4, 6 and 8 Mg/kg/min, and at 5 and 10 minutes after stopping the infusion. In three of the 22 patients studied, the response to dobutamine was tested in a similar manner 12 to 24 hours after the original test. Thus, the final statistical analysis of the effects of dobutamine on hemodynamics was made with a total number of 25. In nine out of the 22 patients, isoproterenol was infused with a Harvard infusion pump at 30 min after the dobutamine study and its dose was increased from 0.005 to 0.01 and 0.02 ,ug/kg/min at 15 min intervals. Hemodynamic results obtained with dobutamine and isoproterenol in the same nine patients were compared with each other. All patients received blood transfusion to maintain left atrial pressure above 12 mm Hg and 21 patients had an uneventful recovery and did not require pharmacological support therapeutically during the postoperative period. Statistical analysis utilized the Student's t-test on a paired or unpaired basis as appropriate. A P value of less than 0.05 was considered to indicate a significant difference between compared group of data. Results Table 2 shows changes in various hemodynamic parameters obtained from dobutamine infusion. With infusion of dobutamine, systolic aortic pressure showed a significant and constant increase by 17.1 mm Hg (13.6%) from an average of 126.0 ± 3.8 to 144.6 ±: 6.0 mm Hg, but on discontinuation of infusion, it immediately decreased to a level lower than the control value by 2 mm Hg (fig. 1). No significant change was observed in diastolic aortic pressure but mean aortic pressure showed a significant increase by 4.4 mm Hg (4.8%) from an average of 91.8 ± 2.7 to 96.2 ± 3.2 mm Hg. Pulmonary arterial pressure showed changes similar to aortic pressure. Systolic pulmonary arterial pressure showed a significant increase by 3.7 mm Hg (11.1%) from an average of 33.4 ± 2.3 to 37.1 ± 2.5 mm Hg with dobutamine but it showed a significantly lower value than the control after its termination. No significant change was observed either in diastolic or mean pulmonary arterial pressure with dobutamine infusion. However, mean pulmonary arterial pressure showed a significant decrease after discontinuation of dobutamine. Mean left atrial pressure showed a slight but significant decrease from an
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DOBUTAMINE AFTER OPEN HEART SURGERY/Sakamoto, Yamada
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FIGURE 1. Changes in aortic pressure with dobutamine. Systolic and mean aortic pressures showed a significant increase. Values are mean + standard error of mean.
average of 15.9 ± 0.6 to 14.8 + 0.7 mm Hg (7.2%). After discontinuation of dobutamine, mean left atrial pressure remained at the decreased level. Cardiac index showed a significant stepwise increase with graded doses of dobutamine (fig. 2). The increase in cardiac index with each increase of dobutamine dose was 13.4, 22.4, 31.4, and 37.7%, respectively, and the overall increase was from an average of 2.54 + 0.13 to 3.50 + 0.22 L/min/m2. With cessation of dobutamine, cardiac index showed a decrease and was at the control level after 10 min. Heart rate increased significantly from an average of 87.6 ± 2.9 to 108.9 ± 3.2 beats/min (24.3%) but returned to the control value 10 min after the stop of infusion. The only arrhythmia that developed in these cases during dobutamine infusion was premature ventricular beats observed in a patient (E.K.). In a 39-year-old female patient (A.S.) with atrial septal defect, multiple premature ventricular beats were observed before infusion of dobutamine, but they disappeared during dobutamine infusion. With discontinuation of dobutamine, the arrhythmia reappeared. Left ventricular stroke work index showed a significant increase of 11.8%, from an average of 32.1 ± 2.9 to 35.9 ± 3.2 g-m/beats/m2, immediately after the onset of dobutamine infusion, and reached a plateau and returned to the control level upon the cessation of dobutamine. Calculated systemic vascular resistance showed a significant decrease, from an average of 24.7 + 1.3 to 19.3 ± 1.2 units (21.8%), but returned to the control value after dobutamine infusion. The decrease in systemic vascular resistance was due to marked increase of cardiac output by dobutamine but not to a direct vasoactive effect of the drug. During hemodynamic studies, an interesting finding was observed in a 21-year-old patient (H.S.). His urinary output was between 40 and 50 ml/hour before infusion of dobutamine but during dobutamine infusion urine volume was markedly increased to 450 ml/hour and after the infusion urine volume returned to 42 ml/hour. Hemodynamic effects of isoproterenol infusion were com-
a
I
II
I
control 2 4 6 8 5 .10 . min. min. Dobutamine (mcg/Kg/min)
.
FIGURE 2. Changes in cardiac index. With increased doses of dobutamine, cardiac index showed a significant increase and at a rate of 8 pg/kg/min, it was 37.7% higher than the control value. Values are mean + standard error of mean.
pared to dobutamine in the same nine patients out of the study group (table 3, fig. 3). With 0.02 ,ug/kg/min of isoproterenol, aortic pressure changed from an average of 124/80 (95) to 132/76 (93) mm Hg. But in dobutamine infusion, aortic pressure increased constantly from an average of 123/76 (94) to 143/82 (101) mm Hg. At a comparable heart rate, 96.3 beats/min after 4 gg/kg/min of dobutamine vs 96.6 beats/min after 0.005 pg/kg/min of isoproterenol, the increase of cardiac index from control value was larger in
4.0
dobutamine
3.5 E x
3.0
c 2.51- FTi (0
W
isoproterenol
119
2(5
80
90 100 110 120 130 140 Heart Rate (beat/min)
FIGURE 3. Changes in cardiac index and heart rate with dobutamine and isoproterenol. At comparable effects on cardiac index, the increase in heart rate is less with dobutamine than with
isoproterenol.
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VOL 55, No 3, MARCH 1977
CIRCULATION
528 TABLE 2. Hemodynamic Effects of Dobutamine A
C
B
D
E
APs (mm Hg) 144 N.T. 124 S.N. 140 S.N.* 112 Y.A. 153 A.S. 160 H.S. 121 K.S. 95 K.S.* 115 Y.S. 132 M.T. 142 E.O. 92 T.S. 98 T.S.* 126 N.S. 156 E.K. 127 Y.O. 142 Y.O. 132 K.Y. 141 H.Y. 132 T.I. H.K. 103 123 N.S. 120 Y.H. 102 T.O. T.M. 119 126.0 Mean SE 3.8 P
150 120 146 116 160 166 115 106 113 151 156 98 98 137 149 138 145 155 160 148 108 138 118 114 124 133.2 4.2 0.001
168 128 148 124 178 175 113 108 115 166 168 98 105 123 150 143 150 176 170 170 105 143 118 110 125 139.1 5.4 0.001
130 166 141 158 183 178 166 109 143 143 110 124 143.1 5.7 0.001
160 132 152 123 204 186 126 110 121 152 178 96 105 148 149 140 151 186 175 189 107 150 142 110 122 144.6 6.0 0.001
APm (mm Hg) 102 N.T. 91 S.N. S.N.* 100 79 Y.A. 113 A.S. 111 H.S. K.S. 91 73 K.S.* 85 Y.S. M.T. 91 96 E.O. T.S. 73 75 T.S.* N.S. 77 E.K. 82 89 Y.O. Y.O. 118 K.Y. 99 H.Y. 109 111 T.I. 72 H.K. N.S. 98 86 Y.H. T.O. 88 T.M. 85 Mean 91.8 SE 2.7 P
103 85 102 86 120 110 84 76 82 96 98 73 71 86 83 97 119 115 117 115 75 101 92 86 89 94.4 3.0 0.05
110 92 102 86 118 115 80 81 84 97 98 71 73 85 82 99 108 123 125 116 78 105 91 87 89 95.8 3.2 0.01
104 86 101 90 131 115 81 81 90 90 95 72 71 82 84 94 108 124 131 117 78 105 92 87 86 95.8 3.4 0.05
99 92 104 87 128 110 84 77 91 92 96 76 73 83 89 93 110 123 125 118 78 108 92 90 86 96.2 3.2 0.01
PAPd (mm Hg) N.T. 12 S.N. 19 37 S.N.* Y.A. 24 A.S. 13 H.S. 17 K.S. 18 13 K.S.* Y.S. 20 M.T. 11
12 19 40 23 14 14
17 13 21 12
12 20 44 24 13 12 15 13 20 12
160 122 144 127 192 189 118 116 119 162 178 97 102
12 20 41 24 13 11 15
13 21 11
12 21
47 24 13 10 15 12 21 12
F
150 121 136 116 142 159 101 105 113 124 155 90 98 128 147 125 141 136 145 137
102 138 109 101 107 125.0 4.0 NS
G
140 120 130 119 146 157 100 104 113 125 151 88 98 129 151 124 133 132 151 132 112 135 111 100 103 124.2 3.8 NS
103 87 96 87 104 106 77 76 88 83 92 71 71 85 84 89 106 103 117 113 78 106 91 87 78 91.1 2.6 NS
105 108 80 77 93 86 95 71 72 82 83 91 114 101 117 111 77 106 89 87 76 91.4 2.6 NS
13 20 35 25 9 10 14 14 20 10
12 19 36 26 10 12 13 14 20 11
97 88 91 88
A
B
APd (mm Hg) 84 80 80 74 75 68 80 80 79 72 75 70 95 85 88 92 93 91 66 76 69 61 67 63 66 64 75 76 81 73 69 72 74 64 66 66 66 58 55 64 64 61 60 61 59 78 76 72 109 104 90 89 77 94 102 91 89 100 93 94 60 52 55 84 87 78 65 76 68 75 74 75 73 66 71 75.0 75.2 76.8 2.5 2.5 2.7 NS NS PAPs (mm Hg) 27 30 45 47 37 40 61 61 26 28 29 25 29 28 22 24 32 32 25 28 22 26 30 30 27 28 26 28 29 29 30 28 35 34 25 30 29 25 29 27 56 52
33 66 38 26 33.4 2.3
39 68 35 28 34.0 2.3 NS
PAPm (mm Hg) 17 18 18 28 24 25 40 40 17 19 21 18 22 21
16 24 16
17 25 17
D
E
F
G
76 68 80 74 93 85 70 64 78 71 71 66 63 64 66
78 72 80 73 91 80 68 60 78 72 71 66 66 64 62 75 100 94 100 93 60 89 74
80 70 76 73
76 72 72 75 84 83 70 64 77 71 70 63 65 67 64 81 101 83 96 86 63 86 76 79
C
33
80 89 97 101 97 58
87 74 75 71 76.7 2.4 NS
35
53 53 44 41 61 63 29 29 27 27 28 26 24 26 32 34 30 32 31 32 30 30 29 27 28 28 29 29 30 31 37 42 36 37 25 27 28 27 52 54 41 47 65 64 36 36 30 29 35.5 36.2 2.2 2.3 0.05 0.01
19 28 25 41 18 17 19 17 24 18
19 28
24 40 18 16 19 17 25 18
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75 70 76.4 2.4 NS
77 86 66 61 68 72 65 61 65 67 65 79 88 82 97 98 60 82 74
77 65 74.2 2.1 NS
56 75.2
2.2 NS
35
26
26
54 47 63 30 28 26 28 34 32 35 28 27 26 28 31 42 35 26 28 58 49 70 37 30 37.1 2.5 0.01
45
40
35 59 21 22 24 25 33 25 24 28 27 22 30 27 31 24 21 23 53 38 65 35 29 31.7 2.4 0.05
36 59 20 22 23 26 33 25 22 28 27 21 29 26 30 23 22 22 49 40 60 38 29 31.0 2.2 0.01
17 28 22
26 21
40
40 13
19 32 27 40 19 16 19 17 25 19
13 14 17 18 24 15
17
15 16 18 24 15
DOBUTAMINE AFTER OPEN HEART SURGERY/Sakamoto, Yamada
529
TABLE 2.
E.O. T.S. T.S.* N.S. E.K. Y.O. Y.O. K.Y. H.Y. T.I. H.K. N.S. Y.H. T.O. T.M. Mean SE
A
B
C
12 18 15 13 15 15 23 13 13 12 26 14 36 18 17 17.8 1.4
11 18 13 13 16 15 20 14 12 12 28 15 36 18 18 17.8 1.5 NS
10 17 13 12 15 15 20 17 12 12 29 17 34 18 20 17.8 1.6 NS
12 18 15 19 16 14 17 13 24 12 11 18 13 12 16 15 15 15 13 11 19 17
12 18 15 19 15 12 15 13 23 12
p
LAPm (mm Hg) 12 N.T. S.N. 18 16 S.N.* Y.A. 18 16 A.S. H.S. 17 K.S. 18 13 E.S.* 24 Y.S. 11 M.T. 12 E.O. T.S. 18 T.S.* 15 N.S. 13 16 E.K. 16 Y.O. Y.O. 18 K.Y. 13 H.Y. 15 T.I. 11 H.K. 18 N.S. 17 Y.H. 21 16 T.O. T.M. 16 Mean 15.9 SE 0.6 p
HR (beats/mmn) N.T. 81 S.N. 96 S.N.* 70 Y.A. 96 A.S. 78 H.S. 94 K.S. 113 106 K.S.* Y.S. 106 M.T. 89 E.O. 57 T.S. 80 T.S.* 88 N.S. 76 E.K. 105 Y.O. 112 Y.O. 95 K.Y. 82 H.Y. 64 T.I. 85
19 13 16 15.3 0.6
91 86 106 113 100
92 65 95
E
10 16 13 11
17 12 15 15 20 16 12 12 30 18 32 18 19 17.8 1.5 NS 12 18 14 19 15 11 15 13 24
10
11 10
17 13 10 15 15 17 16 13 10 19 19 19
17 17 8 15 16 17 14 13 10 20 19 17
11
11
16 14.9 0.7 0.05 0.0r5
93 104 71 99 86 95 109 103 103 89 69 80
D
10 17
108 100 84 100 86 104 110 108 102 96 78 80 97 100 87 120 110 98 77 102
15 14.8 0.7 0.05
121 110 85 102 89 120 112 106 102 108 86 83 95 112 110 124 120 110 80 105
15 15 20 15 11 12 30 19 34 20 21 18.0 1.7 NS 12 17 14 19 14 10 15 12 24 12 10
16 13 12 16 16 16 13 13 10
20 20 18 12 15 14.8 0.7 0.05
130 114 102 105 97 127 115 109 102 130 96 90 100 138 87 130 122 120 86 110
F
G
A
B
10 15 14 11 16 15 16 11 12 12 28 17 31 20 20 16.7
10 18 14 11 15
15 22 18 17 22 23 26 18 20 20 36 21 46 26 20 23.0 1.5
16 22 18 18 23 23 24 21 19 19 36 23 47 25 21 23.3 1.5 NS
1.4 NS 13 18 14 20 12 10
14 14 23 10 10 15 14 11 15 16 15 13 13 10 22 19 18 16 15 14.8 0.7 0.05
105 108 86 104 85 107 108 105 96 91 72 79 89 99
96 109 103 99 64 105
15 19 12 11 14 28 17 35 21 19 17.3 1.5 NS
12 17 14 20 13 12 13 14 24 11 10
18 14 11 15 16 15 14 13 12 18 19 19 15 16 15.0 0.7 0.05
94 109 72 102 84 96 103 101 98 92 65 79 89 90 96 110 102 96 60 87
C
D
17
17
21 18 17 23 23 26 24 19 19 37 26 44 24 23 23.5 1.5
21 20 17 23 24 27 23 20 19 38 27 43 26 22 23.6 1.5
NS
NS
E
18 20 18 16 22 24 26 21 18 20 39 29 46 27 24 24.0 1.6 NS
CI (L/min/m2) 2.50 2.86 3.19 3.40 3.67 3.17 3.72 4.03 4.27 4.06 2.28 2.54 3.11 3.18 3.79 1.79 2.07 2.24 2.33 2.52 3.74 3.82 3.54 3.89 3.71 2.78 3.22 3.57 4.27 4.13 2.26 2.61 2.67 2.95 3.11 1.83 2.02 1.95 2.10 2.29 2.10 2.10 2.06 2.37 2.13 2.56 2.75 2.85 2.97 3.19 2.99 3.94 4.46 5.17 5.44 2.23 2.32 2.33 2.59 2.55 2.18 2.43 2.63 2.77 2.80 3.84 4.76 5.21 5.30 5.38 1.85 1.96 2.01 2.30 2.07 1.94 2.10 2.16 2.22 2.39 2.66 3.15 3.10 3.37 3.39 3.73 4.09 4.66 5.16 5.82 2.15 2.79 2.50 2.64 3.33 3.25 3.29 4.60 4.90 5.30 3.09 3.19 3.24 3.34 4.02 2.01 2.43 2.66 2.93 2.98 1.89 2.45 2.92 2.76 3.04 2.86 3.42 3.93 4.10 4.17 1.85 1.99 2.13 2.23 2.19 2.54 2.88 3.11 3.34 3.50 0.13 0.15 0.19 0.20 0.22 0.001 0.001 0.001 0.001 SVI (ml/beat/M2) 31 30 31 33 36 40 33 36 37 19 21 22 44 41 48 34 30 34 20 24 24 17 20 18 20 20 20 30 29 31 53 57 57 28 29 29 27 27 25 52 50 55 23 18 18 17 18 19 32 28 28 45 45 48 32 34 43 38 35 45
28 39 37 23 44 36 26 20 23 28 60 31 29 47 21 18 28 47 33 47
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28 36 37 24 38 33 27 21 21 25 57 28 28 39 24 18 28 49 39 48
F
G
15 21 18 15 21 22 21 17 18 18 36 26 42 26 23 21.9 1.5 0.05
14 21 18 14 20 22 22 17 18 17 35 26 43 28 22 21.7 1.6 0.05
3.05 3.66 2.55 2.20 3.21 3.32 2.30 1.96 2.26 2.40 3.99 2.22 2.35 3.80 2.07 2.00 2.64 3.65 2.38 4.60 3.76 2.22 2.74 2.49 2.08 2.80 0.15 0.01
2.85 3.20 2.42 2.04 3.06 2.85 1.91 1.80 1.94 2.57 3.58 2.09 2.18 3.60 2.14 1.89 2.59 2.82 1.99 3.76 2.68 2.21 2.24 2.42 1.89 2.51 0.12 NS
29 34 30 21 38 31 21 19 24 26 55 28 26 38 22 18 26 37 37 44
30 29 34 20 36 30 19 18 20 28 55 26 25 40 22
17 25 29 34 43
530
CIRCULATION
VOL 55, No 3, MARCH 1977
TABLE 2. (Continued) A
H.K. N.S. Y.H. T.O. T.M. Mean SE P
86 81
95 75 80 87.6 2.9
B
86
C
90 91 90 109 82
86 96 94 80 91.6 96.4 2.5 2.3 0.01 0.001
LVSWI (gm-nm/beat/M2) N.T. 38 38 S.N. 33 33 S.N.* 38 42 Y.A. 16 19 A.S. 63 62 H.S. 44 38 K.S. 20 22 14 K.S.* 17 Y.S. 17 16 M.T. 32 35 E.O. 61 67 T.S. 21 22 T.S.* 20 21 N.S. 43 56 E.K. 16 17 Y.O. 17 21 Y.O. 38 45 K.Y. 53 61 H.Y. 43 61 T.I. 52 50 H.K. 26 28 N.S. 28 32 Y.H. 18 26 T.O. 37 36 T.M. 22 25 Mean 32.1 35.9 SE 2.9 3.2 P 0.001
40 40 43 20 58 48 21 17 17 35 68 21 22 53 21 21 35 70 49 65 29 34 32 37 26 36.8 3.3 0.001
D
E
F
G
97 94 94 120 82 102.7 2.7 0.001
95 105 98 130 85 108.9 3.2 0.001
93 84 88 85 80 93.6 2.4 0.01
80 82 92 81 77 89.5 2.6 NS
35 36 44 22 69 51 23 19 21 30 69 23 21 47 20 19 35 70 53 68 27 37 30 35 26 37.2 3.5 0.001
33 37 45 22 59 45 25 19 19 27 67 23 23 38 24 19 36 73 59 71 33 33 31 34 25 36.8 3.3 0.001
36 32 33 19 47 41 18 16 21 26 61 21 20 38 21 18 32 45 52 62 31 31 31 28 22 32.1 2.6 NS
35 28 36 18 45 39 17 15 19 29 64 19 20 38 20 17 34 35 48 58 27 32 23 30 20 30.6 2.6 NS
A
36
25 20 38 23 33.3 2.1
B
37 28 26 36 25 32.4 2.1 0.01
SVR (unit) 24.8 21.8 19.8 15.8 30.3 27.7 26.2 24.8 22.9 23.8 25.8 22.0 30.5 24.4 30.3 28.5 28.5 27.5 20.3 20.0 23.1 17.9 17.8 17.1 18.7 15.8 13.2 11.9 32.8 31.4 28.6 28.9 27.2 23.2 15.6 16.5 34.0 28.1 17.3 17.7 15.5 15.6 36.4 31.1 29.8 24.5 21.1 17.2 27.3 26.6 24.7 22.4 1.3 1.1 0.001
D
E
F
G
34 27 32.8 2.0 0.01
42 28 31 32 26 32.3 1.9 NS
40 26 31 29 26 30.2 1.7 NS
34 27 24 30 25 28.8 1.7 NS
18.5 13.9 21.9 23.0 25.5 17.4 20.8 29.2 26.7 17.3 13.2 15.1 13.9 10.2 27.1 26.5 19.6 14.2 33.2 12.1 15.5 26.8 21.8 14.6 22.9 20.0 1.2 0.001
16.3 15.6 18.9 20.5 26.1 17.2 20.4 25.5 30.1 16.5 12.7 16.2 14.2 10.1 31.8 24.3 19.9 12.4 25.2 11.3 12.9 27.1 19.8 14.8 23.4 19.3 1.2 0.001
20.5 16.4 25.9 23.6 24.5 20.6 25.3 29.3 27.4 19.8 16.6 17.4 16.4 14.7 30.0 27.8 24.7 16.6 33.0 14.1 13.7 35.6 21.7 24.0 22.3 22.5 1.2 0.05
20.6
C
36
29 32 36 26 32.6 2.1 0.01 20.9 15.8 22.5 22.9 25.3 20.8 22.7 31.4 28.8
19.5 15.8 16.6 15.1 10.7 30.3 28.7 21.4 15.5 33.6 12.8 15.9 29.5 20.4 15.2 24.9 21.5 1.3 0.001
34 31
29
19.0 25.9 25.7 26.0 24.4 31.7 32.4
33.7 19.2 19.1 18.4 17.9 15.0 28.7 30.1 27.0 21.1 39.4 15.0 19.0 35.8 25.9 24.6 23.9 24.8 1.3 NS
Abbreviations: A = control; B = 2mcg/kg/min; C = 4mcg/kg/min; D = 6mcg/kg/min; E = 8mcg/kg/min; F = 5 min after dobutamine; G = 10 min after dobutamine; APd = diastolic aortic pressure; APm = mean aortic pressure; APs = systolic aortic pressure; CI = cardiac index; HR = heart rate; MLAP = mean left atrial pressure; PAPd = diastolic pulmonary arterial pressure; PAPm = mean pulmonary arterial pressure; PAPs = systolic pulmonary arterial pressure; SVI = stroke volume index; SVR = systemic vascular resistance; SWI = stroke work index. sIB = standard error of mean. P values derived from paired t-test comparing A vs B, C, D, E, F, G. *indicates the second test of dobutamine infusion.
the former (0.57 L/min/m2) than the latter (0.41 L/min/m2), but this difference was not significant statistically. Moreover, comparison in stroke volume index was not significantly different in these dosage of both drugs. But the increase in heart rate was considerably greater with isoproterenol than that with dobutamine. It appears that inotropically, 2 and 8 ,sg/kg/min of dobutamine were comparable to 0.005 and 0.01 Ag/kg/min of isoproterenol, respectively (fig. 3). A representative case (Y.O.) is presented below (fig. 4). Aortic valve replacement by the Starr-Edwards ball prosthesis was performed for aortic insufficiency. Immediately postop, the patient was in a stable condition and aortic pressure was 123/71 (90) mm Hg; pulmonary arterial pressure, 31/16 (23) mm Hg; mean left atrial pressure, 15.5 mm Hg, and cardiac index 1.92 L/min/m2. Fourteen hours after surgery, aortic pressure fell to 90/65 (74) mm Hg, cardiac index decreased to 1.06 L/min/m2, and pulmonary arterial pressure and mean left atrial pressure increased. A diagnosis
of severe left ventricular failure was made and the infusion of dobutamine at a rate of 6 Ag/kg/min was started. After aortic pressure had been elevated to a safe level, the infusion of phenoxybenzamine at a dose of I mg/kg was added for the purpose of reducing the afterload of the left ventricle. Subsequently cardiac index increased to over 2.0 L/min/m2 and systolic aortic pressure stabilized at 120 mm Hg. The infusion of dobutamine was stopped at 8 hours after initiation, but there was no change in hemodynamics and the patient remained in a satisfactory condition. Sufficient urinary output was also maintained. Discussion With the administration of isoproterenol, tachycardia or arrhythmia often develops and necessitates the cessation of infusion before a sufficient increase in cardiac output can be obtained. Myocardial oxygen consumption (MVO2) increases markedly as both myocardial contractile force and
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DOBUTAMINE AFTER OPEN HEART SURGERY/Sakamoto, Yamada heart rate increase with isoproterenol, thus shifting the myocardial metabolism to anaerobic."5 In an attempt to develop a new beta-adrenergic stimulator without these adverse effects on cardiac rhythm or myocardial metabolism, dobutamine has been synthesized by modifying the side-chain of dopamine.6 It has been reported that dobutamine increases myocardial contractile force selectively.8 12 In the present study, dobutamine increased systolic and mean aortic pressure and systolic pulmonary arterial pressure significantly but diastolic aortic pressure and diastolic pulmonary arterial pressure remained unaltered. These changes demonstrate that dobutamine produced relatively little change in peripheral vascular resistance at doses less than 8 ,Ag/kg/min. Dobutamine has been shown to possess both vasoconstricting and vasodilating effects on peripheral vessels."6' 17 At low doses, a mild peripheral alpha-adrenergic action predominates, while with higher doses, beta-adrenergic effect is predominant. Holloway et al. observed this biphasic response clinically with dobutamine, with 10 gg/kg/min being the cut-off point,'3 and Robie et al. reported that as the dose of dobutamine was increased to higher than 16 gg/kg/min peripheral vasodilation became predominant and aortic pressure and total peripheral resistance began to lower.", Since dobutamine does not lower aortic pressure, it is expected that the inflow pressure of the coronary arteries is not lowered, thus acting favorably on coronary perfusion. This advantage makes an interesting contrast to isoproterenol which reduces diastolic aortic pressure because of its potent vasodilating action on peripheral vessels.'8 Tuttle et al. reported that in experimental dogs P02 in coronary sinus increased by 35% after infusion of dobutamine, but decreased by 11% after isoproterenol.7 They considered that dobutamine increased myocardial oxygen supply more significantly than myocardial oxygen consumption. The fact obtained from our study that the diastolic aortic pressure was unchanged during dobutamine infusion may also have been responsible for the finding by Tuttle et al.7 Vatner et al."' reported that in the presence of experimental moderate global ischemia, dobutamine is not as deleterious as isoproterenol. In their experiment, left ventricular function was maintained during dobutamine infusion but acute depression of cardiac function occurred when isoproterenol was substituted for dobutamine. In the present study, mean left atrial pressure showed a significant, gradual decrease after the start of dobutamine infusion because of the improvement of left ventricular function. These changes in pressure were very similar to those reported by Jewitt et al." As far as clinical investigations are concerned, cardiac index was found to be increased with dobutamine by 82% (Akhtar et al.8), 82% (Beregovich et al.9" 10), and 43% (Jewitt et al."). Loeb et al."2 reported on 36 patients of whom 17 patients had impaired left ventricular performance. Dobutamine augmented cardiac index by 48% (7.5 ,g/kg/min) in patients with normal left ventricular function and 82% (10.7 Ag/kg/min) in patients with depressed left ventricular function. Discrepancies of the degree of increase in cardiac index is thought to be related to the differences in myocardial contractility reserve before the administration of dobutamine. This is supported by the fact
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