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Hemodynamic effects of metaraminol
Hemodynamic II.
Effects of Metaraminol
Patients with Acute Myocardial
RAOUL MALMCRONA, M.D., GUSTAV SCHRBDER, Gothenburg,
M.D.
Infarction*
and LARS WERK~,
Sweden
1 had atria1 fibrillation with slow ventricular rate and 1 developed total atrioventricular block before the study. All were treated with bedrest, dicoumarol and analgesics. Oxygen inhalation through a nasal catheter was given according to the ordinary routine of the hospital. One patient suddenly died on the tenth day. The others left the hospital after about one month. Methods: The methods used were the same as in a report on the effects of metaraminol in normal subjects that appears in this issue.6 Procedure: Blood pressures were recorded at intervals of 2 to 5 min. About 30 minutes after the insertion of the catheters the first cardiac output determination was made. The blood loss of about 40 ml. was substituted by an equal amount of stored blood. A second determination was made about 30 minutes, in one case 110 minutes, after the first. The blood was again substituted and an intravenous metaraminol infusion was started, 50 mg. metaraminol in 500 ml. saline being given at a rate of 5 to 15 drops/min. The drip rate was adjusted to give a slight elevation of blood pressure. Determination of cardiac output was made 9 to 27 minutes after the infusion had been started. The drip rate was then raised to 10 to 20 drops/min. to increase the blood pressure further. Another determination of cardiac output was made 17 to 30 minutes later. The blood loss of the last two determinations of cardiac output was then substituted. In 7 patients 1 or 2 more such
T
HE high mortality, 70 to 90 per cent, of patients with myocardial infarction and circulatory failure diminished to 50 to 70 per cent when norepinephrine came into use in 1952.1W3 This improvement was ascribed to the peripheral vasoconstrictive action of norepinephrine. Gazes et a1.,4 however, ascribed the effect of sympathomimetic amines in shock accompanying myocardial infarction to their Sarnoff et ale6 effect of increasing heart force. found that a new norepinephrine-like substance, metaraminol, had a marked positive inotropic effect as well as a vasoconstrictor effect. They also demonstrated that the inotropic action of the drug relieved the signs of left ventricular failure in dogs with experimental coronary insufficiency. No hemodynamic studies of the effect of this drug in patients with myocardial infarction have been published. The present report describes such studies in 11 patients with acute myocardial infarction. Cardiac output and brachial arterial blood pressure were determined repeatedly before, during and after an intravenous infusion of metaraminol. MATERIAL AND METHODS Material: Nine male and 2 female patients aged 39 to 74 years, mean 58, were studied (Table I). All had clinical signs of severe myocardial infarction and electrocardiographic signs of transmural infarction. All showed a temperature reaction. The highest serum glutamic oxalacetic transaminase value in each patient was between 73 and 567 units, mean 261. Five patients had periods with systolic blood pressure below 100 mm. Hg. Three had episodes of pain in the chest also after the initial attack; 2 of them had cold sweat and slight chest pain also during the circulatory study. Two patients developed signs of left ventricular failure during their hospital stay. Nine patients had sinus rhythm,
determinations were made 26 to 86 minutes after the onset of the metaraminol infusion. Figure 1 shows the procedure and the results in a representative patient.
RESULTS The effect of metaraminol infusion on the circulation in the 9 patients with sinus rhythm is first described followed by the results in the 2 patients with arrhythmia prior to metaraminol infusion. During the infusion there were short periods of sinus arrest and supraventricular
* From Medical Department I, Sahlgrenska Sjukhuset, University of Gothenburg, Sweden. ported by a grant from the Swedish National Association Against Heart and Chest Diseases.
JANUARY1964
M.D.
15
This study was sup-
Malmcrona,
16
SchrGder
and
WerEi
TABLE I Clinical Data on 11 Patients with Myocardial
Patient
Age (yr.)
Height (cm.)
Previous Related Disease
Weight (kg.)
Duration of Fever Over 38” c.
2
60
ECG Localization
Blood Pressure Levels (mm. Hg)
(days)
1
GOT* (units)
Infarction
78.2
None
76.0
Hypertension
known 2
2
440
160/90 on adm. Later 1 lo/70 to 120/85
Anterior
2
176
160/115 on adm. Later 105/80 to 120/90
Anterior
yr. 3
58
79.9
None
1
440
150/90 on adm. 120/80
Later
Diaphragmatic
4
39
69.7
None
2
142
100/75 on adm. Later 90/60 to 130/80
Diaphragmatic
5
51
None
1
220
120/90 on adm. lOO-110/80
Later
Anterior
6f
74
163
66.5
Exertional
0
73
200/110 on adm. 60/- to 150/90
Later
Diaphragmatic
7
59
184
64
None
4
180
105/65 on adm. Later 100/70 to 115/70
Diaphragmatic and lateral
8
54
None
2
237
180/l 15 on adm. Later 90/70 to 110/70
Diaphragmatic and lateral
9
70
None
1
567
150/l 10 on adm. Later 90/70 to 120/70
Anterior
10
50
186
77.9
Blood donor; venesection same morning
4
220
70/40 on adm. Later 100/70 to 120/70
Diaphragmatic
ll$
74
154
68.6
Exertional dyspnea. Hypertension known 1
2
174
160/70 on adm. Later 110/70 to 150/80
Diaphragmatic
dyspnea
yr. * GOT = glutamic oxalacetic transaminase. t All temperatures morning temperatures. $ Female patients.
rhythm in 1 patient, and in another there was a 10 minute period of supraventricular rhythm before the determination of cardiac output. Individual values of the hemodynamic investigation are given in Tables II and III, mean values in Table IV and per cent of changes in Table v. Heart Rate: At the time of determination of cardiac output the mean heart rate was 91 beats/min. before the infusion and 83 at both levels of metaraminol infusion. The heart rate was unaltered in 1 patient and lower in all the other patients. The fall in heart rate was found within 2 or 3 minutes after commencement of the infusion. In the 6 patients in sinus rhythm in whom
determinations of cardiac output were made after cessation of infusion, the heart rate was 83 beats/min. during the infusion and afterward rose to 90. The decrease in heart rate during the infusion was 8 per cent and the rise afterward 8 per cent. The individual heart rates at determinations of cardiac output are given in Tables II and III and shown
in Figure
2.
Cardiac Output: The cardiac output was between 7.0 and 3.1 L./min., mean 5.0, before the infusion and between 8.6 and 3.5 L./min. during the infusion (Fig. 3). The means on the two levels of metaraminol infusion were 5.3 L./min. The 5 patients with systolic THE AMERICANJOURNAL OF CARDIOLOGY
Hemodynamics ‘rABLE
Day of Study & Temperaturet ( C) --___
I (continued)
Remarks
Observation Time, Follow-up, Necropsy Diagnosis
___
3rd
38.0 38.2
3 mo. Dyspnea on exertion and pulmonary stasis
4th
37.8 37.4
2 mo. Uneventful recovery
3rd
37.7 38.2
2 mo. Uneventful recovery
2nd
37.2 37.7
4 mo. Uneventful recovery
2nd
38.7 38.2
2nd
37.3
1 mo. Uneventful recovery
3rd
39.0
1 mo. Uneventful recovery
8th
37.3
Tired
1 mo. Uneventful recovery
3rd
37.4
Pains and cold sweat
1 mo. Uneventful recovery
Tired. Sinus rhythm, then total A-V block and again sinus rhythm
2 mo. Uneventful recovery
1st
2nd
Pains and cold sweat
38. G Atria1 fibrillation 37.7
Suddenly died on 10th day. Total occlusion of descending branch of left coronary artery
2 mo. Uneventful recovery
blood pressure 100 mm. Hg or over at the start of the investigation had a mean cardiac output of 5.6 L./min. The 4 patients with a blood pressure below 100 mm. Hg had a mean cardiac output of 4.2 L./min. In both groups were patients with different output to metaraminol responses of cardiac infusion. The patient with the highest cardiac output had a blood pressure of 120/90 mm. Hg on admission with only a slight fall in pressure. He had, however, cold sweat and slight chest pain during the study. His cardiac output rose from 6.7 to 8.2 L./min. (22%) during the metaraminol infusion. The patient with the lowest cardiac output had a systolic pressure JANUARY
1964
of Metaraminol.
II
17
below 100 mm. Hg many times during the first days of hospitalization and was kept on metaraminol treatment. At the beginning of the study his systolic blood pressure was 86 mm. Hg. He had cold sweat and chest pain. The cardiac output was 3.1 and 3.3 L.jmin. before the infusion and 3.5 L./min. at slow as well as at a faster infusion rate when systolic pressure had risen to 99 and 111 mm. Hg, respectively. In 6 patients cardiac output determinations were made after cessation of infusion. The mean values were similar during and after infusion, but the variation was large. Stroke Volume: The stroke volume was between 30 and 89 ml., mean 58, before the infusion and between 34 and 113, mean 68, during the infusion. The stroke volume was unchanged in 1 patient and higher in all the others (Fig. 4). In 6 patients whose cardiac outputs were determined after cessation of infusion, the stroke volume was 68 ml. during the infusion and 61 afterward. Stroke volume decreased The rise in stroke volume in 5 of the 6 patients. was 16 per cent and the fall when metaraminol infusion was stopped, 9 per cent. Brachial Arterial Pressure: The brachial arterial systolic pressure averaged 105 mm. Hg (85 to 140) before the infusion, 120 mm. Hg (99 to 158) at the first level of metaraminol infusion and 135 mm. Hg (111 to 170) at the second level of infusion. The average diastolic pressure rose from 54 to 64 and the average mean blood pressure from 74 to 89 mm. Hg. The increase in pressure was noticeable within 1 or 2 minutes after the start of the metaraminol infusion. The rise in pressures continued for about 20 minutes with unchanged drip rate. At increasing drip rate, the pressures continued to rise, the diastolic pressure less than the systolic, giving an increased pulse pressure. All patients showed exactly the same reaction. In 6 cases determinations were made after cessation of metaraminol infusion; the systolic pressure was 127 during the infusion and 106 mm. Hg afterward. The diastolic pressure decreased from 63 to 58 and the mean pressure There was a fall of the from 87 to 76 mm. Hg. pressures in all patients. The rise in brachial arterial systolic, diastolic and mean pressures during metaraminol infusion was 22, 18 and 19 per cent, respectively, and the fall was 17, 11 and 12 per cent, respectively (Fig. 5). Peripheral Vascular Resistance: The mean total
18
Malmcrona, Schrijder and We&ii
Heart
rate
Brachlal
beats/min
arterial
pressure
mm Hg
150 1 Cardiac
output
l/min
2
1
0 Symbols
:
s I
blood
H D x heart
pressure
I
rate
cardiac
3
hours
output
EZI
blood
m
metaraminol
replacement infusion
FIG. 1. Patient 4. Hemodynamic data before, during and after infusion of metaraminol. Heart rates, brachial arterial systolic, diastolic and mean pressures and cardiac output are given. Duration of investigation and times of metaraminol infusions and blood replacements are indicated at baseline.
Heart
rate,
beats/minute Cardiac
IO ::l::
output
L/min.
r
6 ::zy
cl 40 _
2 Onset
I
Onset of metaraminol.
00 60
01 I 0
30
60
90
120
I’
o
before
and
0
during
metaramlnol
I
sinus
after
metaraminol
metaraminol
InfusIon
0
rhythm
arrhythmia
FIG. 2. Heart rates of 11 patients with acute myocardial infarction before, during and after metaraminol infusion. Time till and after onset of metaraminol infusion is indicated at baseline.
0
before
and
during
infusion
infusIon
I
30
I
30
I
60
I
90
120
I
150
minutes
150
minutes
/
I
60
30
of
infusion
;
5fnus ,’
after
metaramlno!
metaramlnol
lnfuslon
InfusIon
rhythm
arrhythmia
FIG. 3. Cardiac output of 11 patients with acute myocardial infarction before, during and after metaraminol infusion (symbols as in Fig. 2).
THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Hemodynamics Stroke
volume,
of Metaraminol.
19
II
ml_. Resistance,
units
2f3
r
21;
t 2f1
t If5
60
t 1:
20 Onset of metaramlnol
t
01 /
I
,
60
InfusIon
I
30
I
0
30
after
metaramlnol
I
60
90
I
120
1 150 Onset
minutes 0
before
l
during
and
metaramlnol
*(“us
/ 8’
,
60
30
0
30
60
90
arterial
mean
pressure,
0
before
.
during
/
mm.Hg
150
I’
41”~s ’
and
after
metaraminol
metaramlnol
Infusion
infuslo”
rhythm
arTbyth”l,a
6. Resistance of 11 patients with acute myocardial infarction before, during and after metaraminol infusion (symbols as in Fig. 2). FIG.
60
Onset
I 60
120
minutes
120r
I 30
0
of
metaramlnot
I 30
I 60
InfusIon
I 90
I 120
I 150
minutes before
and
dur, “g 7 ,’
InfusIon
arrhytbmla
.Brachial
0
metaramlnol
~“tusfo”
rhythm
FIG. 4. Stroke volume of 11 patients with acute myocardial infarction before, during and after metaraminol infusion (symbols as in Fig. 2).
0
of
Infuslo”
Sl”lJ5
after
metaramlnOL
metaram,nol
,nfus,on
infuslo”
rhythm
arrhythmia
FIG. 5. Brachial arterial mean pressure of 11 patients with acute myocardial infarction before, during and after metaraminol infusion (symbols as in Fig. 2). JANUARY 1964
peripheral vascular resistance increased from 15.9 units (12.2 to 19.4) to 16.5 units (11.2 t.0 22.1) on the first level of metaraminol infusion and to 18.1 units (14.3 to 22.4) on the second level. The resistance was essentially unchanged in 3 patients with marked increase in cardiac output and rose in the others (Fig. 6). In 6 patients whose cardiac output was determined after cessation of metaraminol infusion, the resistance was 17.7 units during the infusion and 14.8 afterward. There was a fall in all but 1 patient. The resistance increased 13 per cent during the metaraminol infusion and fell 15 per cent afterward. Left Ventricular Work and Left Ventricular Stroke Work: Both left ventricular work and left ventricular stroke work increased, the former from 5.1 to 6.6 kg.-M./min. (290/,), the latter from 59 to 82 gm.-M. (38yc). Patient with Complete A-V Heart Block: In 1 patient with sinus rhythm on admission, complete A-V block developed with a ventricular rate of 47 before the hemodynamic investiga-
Malmcrona,
20
Schrijder
and We&ii
TABLE II Hemodynamic
Data Before and During Metaraminol Before Metaraminol
Patient
Time Before Starting Infusion (min.)
Heart Rate (beats/ min.)
Cardiac
Output (L./min.)
Stroke Volume (ml.)
Infusion
Infusion Brachial Arterial Pressure (mm. H,q) Ii* tii s.*
Resistante (units)
LVW* (kg.-M./ min.)
LVSW (gm.-M.)
41 14
97 94
5.1 5.2
52 56
100 103
55 60
73 74
14.4 14.2
5.0 5.1
52 54
2
55 18
94 93
5.8 5.8
62 62
123 120
74 69
96 90
21.1 20.9
9.8 9.4
104 101
3
48 17
84 82
5.0 5.4
60 66
100 108
53 56
72 80
20.0 20.1
6.2 7.9
74 97
4
34 13
48 47
4.3 4.0
89 86
95 104
44 50
63 70
14.8 17.3
3.7 3.9
76 82
5
43 21
110 112
7.0 6.3
64 57
111 107
67 65
88 85
12.5 13.4
8.4 7.3
77 66
6
46 20
84 79
5.0 5.3
59 67
132 140
60 56
80 90
16.0 17.1
5.4 6.5
64 82
7
134 25
131 119
4.4 4.4
34 37
97 93
51 51
64 63
14.4 14.2
3.9 3.8
30 32
8
64 27
73 75
5.3 4.7
73 62
88 95
45 45
65 66
12.2 14.2
4.70 4.18
64.5 55.7
9
44 20
104 103
3.1 3.4
30 33
87 85
37 40
60 58
19.4 17.1
2.53 2.67
24.5 26.0
10t
36 13
47 46
4.0 4.3
85 92
112 105
50 45
65 62
16.2 14.6
3.5 3.6
75 78
ll$
45 17
55 53
2.5 2.6
48 48
112 132
37 41
60 60
23.7 23.4
2.1 2.1
39 39
LVSW
= left ven-
* Abbreviations: S. = systolic; D. = diastolic; M. = mean; LVW = left ventricular work; tricular stroke work. t Case 10. Atrioventricular heart block before the metaraminol infusion, then sinus rhythm. 1 Case 11. Atria1 fibrillation.
tion. Cardiac output was 4.1 and 4.3 L./min. Blood pressure was 107/45 mm. Hg, mean 60, just before metaraminol infusion was started. Two minutes later the pressures was 115/53, mean 68 and after 3 minutes when pressure was 130/65, mean 82, there was regular sinus rhythm. At the ninth and thirty-ninth minute of metaraminol infusion, the heart rate was 60, cardiac output 5.4 and blood pressure 140/68, mean 90, and 168/82, mean 115, respectively. The patient maintained sinus rhythm and normal blood pressure after infusion was stopped. Patient with Atria1 Fibrillation: One patient had mitral insufficiency and atria1 fibrillation prior to infarction. Her heart rate was 54 at the hemodynamic investigation. She had low cardiac output (2.5 and 2.6 L./min.) and high Her systolic pressure was well resistance. maintained, 112 and 132 mm. Hg; the mean 60.
During metaraminol infusion the heart rate was essentially unchanged. On the higher dose of metaraminol infusion cardiac output and resistance rose and the pressures rose to 166/ 49, mean 77. When metaraminol infusion was stopped, the pressure fell as did the cardiac output and resistance. Atria1 fibrillation was maintained. DISCUSSION The
present
study
has
shown
an
increase
of
the stroke volume in patients with myocardial infarction when they were given metaraminol. The increase in mean brachial arterial pressure was shown to depend on rises in cardiac output or resistance or in both. A total A-V block in 1 patient was changed to sinus rhythm by the metaraminol infusion. One patient with atria1 fibrillation responded like those in sinus rhythm when given metaraminol. THE AMERICANJOURNAL OF CARDIOLOGY
Hemodynamics
of Metaraminol.
TABLE
II(continued)
During Metaraminol Time After Metaraminol Infusion (min.)
Heart Rate (beats/ min. )
Cardiac output (L./min.)
Stroke Volume (ml.)
21
II
Infusion
Brachial Arterial Pressure (mm. Hg) S.* D.* M.*
Resistante (units)
Lvw* (kg.-M./ min.)
LVSW (gm.-M.)
17 38
96 97
6.5 6.4
67 66
121 129
64 65
90 92
13.9 14.3
7.9 8.0
82 83
10 27
91 88
6.2 6.7
68 77
130 142
76 80
97 106
21.1 21 .I
10.9 13.0
120 147
12 33
75 73
5.5 4.7
77 65
114 120
65 69
88 93
20.9 25.3
8.6 7.7
122 106
27 51
41 42
4.1 4.8
100 113
120 138
52 58
70 83
17.0 17.5
3.9 5.4
95 127
23 47
102 110
8.6 7.8
84 70
121 140
71 94
96 113
11.2 14.6
11.2 11.9
110 108
25 44
70 66
4.3 4.9
61 75
158 170
58 70
95 100
22.1 20.3
5.6 6.7
79 102
17 38
107 112
5.0 5.3
47 47
108 123
56 65
78 87
15.6 16.4
5.3 6.3
50 56
23 50
65 63
4.3 4.2
67 67
110 144
54 65
74 94
17.1 22.4
4.36 5.35
62.4 85.6
16 36
99 99
3.5 3.5
35 35
99 111
46 50
68 72
19.5 20.8
3.23 3.39
32.4 34.3
9 39
60 60
5.4 5.4
89 90
140 168
68 82
90 115
16.5 21.3
6.7 8.5
109 141
18 40
52 52
2.5 2.9
49 55
132 166
38 49
62 77
24.5 27.0
2.1 3.0
41 58
TABLE
Hemodynamic
Patient
Time After Onset of Aramine Infusion
Heart Rate
III
Data After Metaraminol
Cardiac output (L./min.)
Stroke Volume (ml.)
Infusion
Brachial Arterial Pressure (mm. Hg) S. D. M.
Resistance (units)
LVW (kg.-M./min.)
LVSW (gm.-M.)
3
27 52
81 81
4.3 4.4
59 55
108 102
60 60
83 79
17.7 18.0
5.3 4.7
65 58
4
26 61
48 50
4.6 4.7
96 94
108 105
42 45
68 65
14.7 13.9
4.3 4.2
89 83
5
47 71
107 105
6.7 6.8
63 64
121 105
92 77
106 94
15.8 13.9
9.7 8.7
91 82
6
39 65
89 93
6.9 5.1
77 55
142 147
62 62
92 95
13.4 18.6
8.6 6.6
96 71 46
7
86
110
5.6
51
88
50
66
11.7
5.1
9
36
104
3.5
34
76
36
49
14.0
2.13
22
11
33
51
2.6
50
100
35
59
22.7
2.1
40
M. = mean;
LVW
S. = systolic; JANUARY
1964
D. = diastolic;
= left ventricular
work;
LVSW
= left ventricular
stroke work.
Malmcrona,
22
,Schrijder and Werkij TABLE IV
Mean Hemodynamic
Heart Rate (beats/min.)
A. Bcfort
Cardiac Output (L./min.)
and During
Mctaraminol
Before metaraminol infusion
M & SE SD
90.5
f 7.5 22.6
4.97 * 0.97
During metaraminol infusion
M f SD
SE
83.1
f 22.6
5.32zto.49 1.46
Difference
M f SD
SE
Probability
level
7.6
-7.4zt1.7 5.0
+0.35
P
and A&r
Infusion
M z!z SE SD
83.0
zk 10.8 26.5
5.13zt0.66 1.63
After metaraminol infusion
M f SD
90.2
* 22.8
5.18 f 1.17
Difference
M zt SE
Probability
Ieve
P
58.6
z& 3.4 8.4 -
i-0.05
Heart Rate
Cardiac Output
During metaraminol infusion compared with values before
-8.2
+7.6
26-86 min. after infusion compared with values during
+8.4
0.
with sinus rltythm)
5.2
54.3 f 10.4
3.5
74.3 f 11.7
3.9
68.Ozt 6.6 19.9
127.8 f 16.5
5.5
64.3 i 10.7
3.6
88.7 ;t 11.5
3.8
f 2.1 6.4
+22.7f
Stroke Volume
2.4
+lO.O+
7.1
1.2
+14.4f
3.7
001
1.3 4.0
(0.001
(6 pnlicnts with sinus rhythm),
f 25.1
10.2
61.2f8.2 20.2
0.13
Changes due to Metaraminol
M.
105.1 f 15.5
+9.4
0.48
f 1.05 -
Arterial Pressure Hg)--------D.
i 5.6 16.7
67.5
TABLE
Mean Percentage
(Qpolicnts
During metaraminol infusion
+7.2
Infusion
0.11
Mctaraminol
9.3
Brachial ,-----(mm. s.
Volume
(ml.1
<0.02
B. During
SE
Stroke
0.32
f 0.33
Data
-6.3
f 3.1 7.6 -
127.0 f 2.05
8.4
62.8zlz11.7 26.2
86.9 zk 13.0 29.1
105.7 f 23.6
9.7
56.0f 37.9
76.2 zt 19.4 43.4
-21.3
;t 6.4
2.6
-6.8
f 12.8
16.7 5.7
-10.8
-
f 15.6 -
7.0
v
infusion in 9 and 6 Patients, Respectively Brachial Arterial ~Pressure~S. D. M.
Resistante
LVW
LVSW
+16.4
+21.6
-i-18.3
i-19.5
$13.6
+28.7
j-38.3
-
-16.8
-10.8
-12.8
-16.1
-11.4
-19.5
Only 1 patient who had a systolic blood pressure below 90 mm. Hg and was cold and sweating at the investigation would have been treated with metaraminol on therapeutic grounds. Thus, conclusions regarding hemodynamic effects of metaraminol in patients in cardiogenic shock after a myocardial infarction cannot be drawn directly from the present investigation. induces a In normal subjects6*’ metaraminol fall in heart rate, a rise in stroke volume, no change in cardiac output and a rise in brachial arterial blood pressure. The rise in mean brachial arterial pressure is then essentially due to a rise in total peripheral resistance. The contractile force of the myocardium has been shown to increase in open-chest dogs,5 in isolated rat hearts” and in patients investigated during
8.9
heart operations.s In subjects made hypotensive by administration of hexamethonium and then normotensive by metaraminol, there was a rise to normal values in central blood flow.‘O When patients in cardiogenic shock have been given metaraminoln-14 there has nearly always been a rise in blood pressure, and many have survived. The decrease of heart rate in our patients was of the same order as reported earlier in normal subjects.6*7 It is presumably due to a vagal depression of the activity of the sinoauricular node, since increased blood pressure affects pressure receptors in the aortic arch and carotid sinus. The decrease in heart rate may per se be regarded as beneficial, since myocardial oxygen consumption at any given work load has been shown to increase with heart rate, THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Hemodynamics ‘rARLE
I”
of Metaraminol.
(Conti?ZZUd)
-Resistance (units) -w=
LVW (kg.-M./min.)
LVSW (gm.-M.)
=zz==z=--
16 3 f 2.9
1.o
5.58 f 2.25
0.75
64.5 f 25.1
8.4
18.4f 3.5
1.2
7.16 f 3.04
1.01
89.0+ 10.1
3.4
+2.1
f 2.0
10.7
+1.58
<0.02
f 0.41 1.22
+24.4
f 31. 9.4
18.4 f 6.4
3.8
6.61 f 6.55
2.93
85.2 f 34.1
13.9
15.7 f 8.8
3 9
5.84 f 5.48
2.45
67.8 f 27.0
11 .O
-2.6
f 6.8 -
3.1
-0.77
f 2.91 -
1.30
--17.4
* 10.5
4.3
and in the presence of coronary stenosis in dogs left ventricular failure could simply be induced by increasing the heart rate.15 The signs of failure were relieved by allowing the heart rate to decrease. The cardiac output rose in some and fell in other patients as it does in normal subjects6v7 The response could not be related to an initially more or less decreased blood pressure or to high or low cardiac output. The significance of the change in cardiac output is very difficult to evaluate because it is the ultimate effect of many alterations in the circulation. Increased cardiac output may be due to increased myocardial contractility6 s8,16 and/or to increased venous return on account of venoconstriction. The stroke volume rose in most patients as it does in normal subjects. The rise may be ascribed to a positive inotropic effect of the drug. It is, however, not a definite proof of such an effect because the heart rate was lower and many reflexes may have influenced the heart. The rise in mean arterial pressure depended in one third of the patients on increased cardiac resistance output, in one third on increased and in the remaining third on increased blood flow and resistance. The cause of the rise of blood pressure is similarly variable in normal persons.6*7 The patient whose rhythm changed from
JANUARY
1964
II
23
total A-V block to sinus rhythm had an increase in both cardiac output and resistance when pressure rose. Increase in arteriolar tone may improve the myocardial oxygen supply through increased coronary blood flow secondary to the higher blood pressure. The decrease in heart rate may, however, in this respect be more important because it decreases the need for oxygen.15 In shock, in the acute stage of myocardial infarction, central and peripheral changes of the circulation are involved. Measurements of the contractility of undamaged myocardium when other parts are infarcted have not been reported. As the net effect of contractility and other factors, the cardiac output is lowered. The low cardiac output can, however, depend on a purely mechanical factor such as bulging of the infarcted area during systole. The total peripheral systemic resistance may be increased, unchanged or decreased, a high temperature usually being associated with a decreased resistance.” The essential feature of shock is, however, the decreased cardiac output. This induces a fall in pressure and a reflex vasoconstriction. This vasoconstriction may be insufficient if there has been a rise in temperature, and in some patients it may fail. In most instances of cardiogenic shock the beneficial effect of sympathomimetic amines is attributable to their positive inotropic effect. Only drugs with that effect may thus be used. In patients with insufficient or failing vasoconstriction, there is additional advantage of the peripheral action. In most patients with shock, vasoconstriction is adequate, and further increase of the vasoconstriction is then unnecessary. A positive inotropic effect should also be achieved by digitalis glucosides, but no direct or indirect signs of such an effect were observed when patients in acute myocardial infarction were given lanatoside-C.18 A peripheral vasoconstrictive action of the digitalis glucoside was, however, observed in those acute experiments in conformity with studies using extracorporeal circulation in man.lg The reduction in heart rate produced by the sympathomimetic drug used in this study may be of special value since the need for myocardial oxygen thereby is reduced. In the experiments with digitalis there was an increase of the heart rate when digitalis was given. Metaraminol caused fewer arrhythmias in these patients than in normal subjects whose blood pressure was more increased.6 The re-
24
Malmcrona,
Schrdder
suits reported here on hemodynamic effects of metaraminol thus indicate that the drug may be useful for falling blood pressure and cardiogenic shock after myocardial infarction. SUMMARY Eleven patients with acute myocardial infarction have been studied by recordings of intraarterial pressure and determinations of cardiac output before, during and, in 7 cases, also after cessation of metaraminol infusion. The heart rate was lower and the stroke volume higher in the patients during infusion. The arterial pressure rose in all patients. In some the rise depended on a rise in cardiac output, in some on a rise in resistance, but in most patients on small rises in both output and The type of reaction was not resistance. directly correlated to the factor apparently responsible for a low blood pressure. Metaraminol seems thus a useful drug when the blood pressure decreases after myocardial infarction and may also be of value in the treatment of cardiogenic shock. REFERENCES
7.
8.
9.
10.
11. 12.
13. 14.
15.
1. HELLERSTEIN,H. K., BROFMAN,B. L. and CASKEY, W. H. Shock accompanying myocardiai infarc2.
3.
4.
5.
6.
tion: Treatment with pressor amines. Am. Heart J., 44: 407, 1952. KURLAND, G. S. and MALACH, M. The clinical use of norepinephrine in the treatment of shock accompanying myocardial infarction and other New England J. Med., 247: 383, 1952. conditions. MILLER, A. J. and BAKER,L. A. L-arterenol (Levophed) in the treatment of shock due to acute myocardial infarction. Arch. Znt. Med., 89: 591, 1952. GAZES, P. C., GOLDBERG, L. I. and DARBY, T. D. Heart force effects of sympathomimetic amines as a basis for their use in shock accompanying myocardial infarction. Circulation, 8: 883, 1953. SARNOPF, S. J., CASE, R. B., BERGLUND, E. and SARNOFF, L. G. Ventricular function. The Mechanism of circulatory effects of Aramine. action of “vasopressor” drugs in cardiogenic shock. Circulation, 10: 84, 1954. MALMCRONA, R., SCHRGDER, G. and WERK~ L.
16.
17.
18.
19.
and
Werkii
Hemodynamic effects of metaraminol in normal subjects. Am. J. Cardial., 13: 10, 1964. LIVESAY, W. R., MOYER, J. H. and CHAPMAN,D. W. The cardiovascular and renal hemodynamic effects of Aramine. Am. Heart J., 47: 745, 1954. MEIJLER, F. L., MEERSCHWAM,I. S. and KOSTER, M. De invloed van metaraminol-bitartraat op de contractiliteit van het hart. Ned&. tijdschr. Geneesk., 106: 1800, 1962. GOLDBERG,L. I., BLOODMIELL,R. D., BRAUNWALD, E. and MORROW, A. G. The direct effects of norepinephrine, epinephrine, and methoxamine on myocardial contractile force in man. Circulation, 22: 1125, 1960. MILLS, L. C., VOUDOUKIS,I. J., MOYER, J. H. and HEIDER, C. Treatment of shock with sympathomimetic drugs. Use of metaraminol and comparison with other vasopressor agents. A.M.A. Arch. Znt. Med., 106: 816, 1960. BESTERMAN,E. M. M. Treatment of cardiac shock by metaraminol. &it. M. J.,: 1081, 1959. MOYER, J. H. and BEAZLEY, L. Effectiveness of Aramine in the treatment of shock. Am. Heart J., 48: 136, 1955. STEEHEL,G. H. et al. The use of Aramine in clinical shock. Circulation, 13: 834, 1956. Clinical studies on a vasopressor WEJL, M. H. agent: metaraminol (aramine). II. Observations on its use in the management of shock. Am. J. M. SC., 230: 357, 1955. BERGLUND, E., BORST, H. G., DUFF, F. and SCHREINER,G. L. Effect of heart rate on cardiac work, myocardial oxygen consumption and coronary blood flow in the dog. Acta physiol. scandinav., 42: 185, 1958. BRAUNWALD,E., BINION,J. T., MORGAN, W. L. and SARNOFF, S. J. Alterations in central blood volume and cardiac output induced by positive pressure breathing and counteracted by metaraminol (Aramine). Circulation Res., 5: 670, 1957. MALMCRONA, R., and VARNAUSKAS,E. Hemodynamic data of patients in acute myocardial infarction. Acta med. scandinav., (in press). MALMCRONA, R., SCHRBDER, G. and WERKB, L. Hemodynamic effects of digitalization of patients with acute myocardial infarction. In preparation. BRAUNWALD, E., BLOOD~ELL, R. D., GOLDBERG, L. I. and MORROW, A. G. Studies on digitalis. IV. Observations in man on the effects of digitalis preparations on the contractility of the nonfailing heart and on total vascular resistance. J. C/in. Invest., 40: 52, 1961.
THE AMERICANJOURNAL OF CARDIOLOGY
Effects of Metaraminol
Patients with Acute Myocardial
RAOUL MALMCRONA, M.D., GUSTAV SCHRBDER, Gothenburg,
M.D.
Infarction*
and LARS WERK~,
Sweden
1 had atria1 fibrillation with slow ventricular rate and 1 developed total atrioventricular block before the study. All were treated with bedrest, dicoumarol and analgesics. Oxygen inhalation through a nasal catheter was given according to the ordinary routine of the hospital. One patient suddenly died on the tenth day. The others left the hospital after about one month. Methods: The methods used were the same as in a report on the effects of metaraminol in normal subjects that appears in this issue.6 Procedure: Blood pressures were recorded at intervals of 2 to 5 min. About 30 minutes after the insertion of the catheters the first cardiac output determination was made. The blood loss of about 40 ml. was substituted by an equal amount of stored blood. A second determination was made about 30 minutes, in one case 110 minutes, after the first. The blood was again substituted and an intravenous metaraminol infusion was started, 50 mg. metaraminol in 500 ml. saline being given at a rate of 5 to 15 drops/min. The drip rate was adjusted to give a slight elevation of blood pressure. Determination of cardiac output was made 9 to 27 minutes after the infusion had been started. The drip rate was then raised to 10 to 20 drops/min. to increase the blood pressure further. Another determination of cardiac output was made 17 to 30 minutes later. The blood loss of the last two determinations of cardiac output was then substituted. In 7 patients 1 or 2 more such
T
HE high mortality, 70 to 90 per cent, of patients with myocardial infarction and circulatory failure diminished to 50 to 70 per cent when norepinephrine came into use in 1952.1W3 This improvement was ascribed to the peripheral vasoconstrictive action of norepinephrine. Gazes et a1.,4 however, ascribed the effect of sympathomimetic amines in shock accompanying myocardial infarction to their Sarnoff et ale6 effect of increasing heart force. found that a new norepinephrine-like substance, metaraminol, had a marked positive inotropic effect as well as a vasoconstrictor effect. They also demonstrated that the inotropic action of the drug relieved the signs of left ventricular failure in dogs with experimental coronary insufficiency. No hemodynamic studies of the effect of this drug in patients with myocardial infarction have been published. The present report describes such studies in 11 patients with acute myocardial infarction. Cardiac output and brachial arterial blood pressure were determined repeatedly before, during and after an intravenous infusion of metaraminol. MATERIAL AND METHODS Material: Nine male and 2 female patients aged 39 to 74 years, mean 58, were studied (Table I). All had clinical signs of severe myocardial infarction and electrocardiographic signs of transmural infarction. All showed a temperature reaction. The highest serum glutamic oxalacetic transaminase value in each patient was between 73 and 567 units, mean 261. Five patients had periods with systolic blood pressure below 100 mm. Hg. Three had episodes of pain in the chest also after the initial attack; 2 of them had cold sweat and slight chest pain also during the circulatory study. Two patients developed signs of left ventricular failure during their hospital stay. Nine patients had sinus rhythm,
determinations were made 26 to 86 minutes after the onset of the metaraminol infusion. Figure 1 shows the procedure and the results in a representative patient.
RESULTS The effect of metaraminol infusion on the circulation in the 9 patients with sinus rhythm is first described followed by the results in the 2 patients with arrhythmia prior to metaraminol infusion. During the infusion there were short periods of sinus arrest and supraventricular
* From Medical Department I, Sahlgrenska Sjukhuset, University of Gothenburg, Sweden. ported by a grant from the Swedish National Association Against Heart and Chest Diseases.
JANUARY1964
M.D.
15
This study was sup-
Malmcrona,
16
SchrGder
and
WerEi
TABLE I Clinical Data on 11 Patients with Myocardial
Patient
Age (yr.)
Height (cm.)
Previous Related Disease
Weight (kg.)
Duration of Fever Over 38” c.
2
60
ECG Localization
Blood Pressure Levels (mm. Hg)
(days)
1
GOT* (units)
Infarction
78.2
None
76.0
Hypertension
known 2
2
440
160/90 on adm. Later 1 lo/70 to 120/85
Anterior
2
176
160/115 on adm. Later 105/80 to 120/90
Anterior
yr. 3
58
79.9
None
1
440
150/90 on adm. 120/80
Later
Diaphragmatic
4
39
69.7
None
2
142
100/75 on adm. Later 90/60 to 130/80
Diaphragmatic
5
51
None
1
220
120/90 on adm. lOO-110/80
Later
Anterior
6f
74
163
66.5
Exertional
0
73
200/110 on adm. 60/- to 150/90
Later
Diaphragmatic
7
59
184
64
None
4
180
105/65 on adm. Later 100/70 to 115/70
Diaphragmatic and lateral
8
54
None
2
237
180/l 15 on adm. Later 90/70 to 110/70
Diaphragmatic and lateral
9
70
None
1
567
150/l 10 on adm. Later 90/70 to 120/70
Anterior
10
50
186
77.9
Blood donor; venesection same morning
4
220
70/40 on adm. Later 100/70 to 120/70
Diaphragmatic
ll$
74
154
68.6
Exertional dyspnea. Hypertension known 1
2
174
160/70 on adm. Later 110/70 to 150/80
Diaphragmatic
dyspnea
yr. * GOT = glutamic oxalacetic transaminase. t All temperatures morning temperatures. $ Female patients.
rhythm in 1 patient, and in another there was a 10 minute period of supraventricular rhythm before the determination of cardiac output. Individual values of the hemodynamic investigation are given in Tables II and III, mean values in Table IV and per cent of changes in Table v. Heart Rate: At the time of determination of cardiac output the mean heart rate was 91 beats/min. before the infusion and 83 at both levels of metaraminol infusion. The heart rate was unaltered in 1 patient and lower in all the other patients. The fall in heart rate was found within 2 or 3 minutes after commencement of the infusion. In the 6 patients in sinus rhythm in whom
determinations of cardiac output were made after cessation of infusion, the heart rate was 83 beats/min. during the infusion and afterward rose to 90. The decrease in heart rate during the infusion was 8 per cent and the rise afterward 8 per cent. The individual heart rates at determinations of cardiac output are given in Tables II and III and shown
in Figure
2.
Cardiac Output: The cardiac output was between 7.0 and 3.1 L./min., mean 5.0, before the infusion and between 8.6 and 3.5 L./min. during the infusion (Fig. 3). The means on the two levels of metaraminol infusion were 5.3 L./min. The 5 patients with systolic THE AMERICANJOURNAL OF CARDIOLOGY
Hemodynamics ‘rABLE
Day of Study & Temperaturet ( C) --___
I (continued)
Remarks
Observation Time, Follow-up, Necropsy Diagnosis
___
3rd
38.0 38.2
3 mo. Dyspnea on exertion and pulmonary stasis
4th
37.8 37.4
2 mo. Uneventful recovery
3rd
37.7 38.2
2 mo. Uneventful recovery
2nd
37.2 37.7
4 mo. Uneventful recovery
2nd
38.7 38.2
2nd
37.3
1 mo. Uneventful recovery
3rd
39.0
1 mo. Uneventful recovery
8th
37.3
Tired
1 mo. Uneventful recovery
3rd
37.4
Pains and cold sweat
1 mo. Uneventful recovery
Tired. Sinus rhythm, then total A-V block and again sinus rhythm
2 mo. Uneventful recovery
1st
2nd
Pains and cold sweat
38. G Atria1 fibrillation 37.7
Suddenly died on 10th day. Total occlusion of descending branch of left coronary artery
2 mo. Uneventful recovery
blood pressure 100 mm. Hg or over at the start of the investigation had a mean cardiac output of 5.6 L./min. The 4 patients with a blood pressure below 100 mm. Hg had a mean cardiac output of 4.2 L./min. In both groups were patients with different output to metaraminol responses of cardiac infusion. The patient with the highest cardiac output had a blood pressure of 120/90 mm. Hg on admission with only a slight fall in pressure. He had, however, cold sweat and slight chest pain during the study. His cardiac output rose from 6.7 to 8.2 L./min. (22%) during the metaraminol infusion. The patient with the lowest cardiac output had a systolic pressure JANUARY
1964
of Metaraminol.
II
17
below 100 mm. Hg many times during the first days of hospitalization and was kept on metaraminol treatment. At the beginning of the study his systolic blood pressure was 86 mm. Hg. He had cold sweat and chest pain. The cardiac output was 3.1 and 3.3 L.jmin. before the infusion and 3.5 L./min. at slow as well as at a faster infusion rate when systolic pressure had risen to 99 and 111 mm. Hg, respectively. In 6 patients cardiac output determinations were made after cessation of infusion. The mean values were similar during and after infusion, but the variation was large. Stroke Volume: The stroke volume was between 30 and 89 ml., mean 58, before the infusion and between 34 and 113, mean 68, during the infusion. The stroke volume was unchanged in 1 patient and higher in all the others (Fig. 4). In 6 patients whose cardiac outputs were determined after cessation of infusion, the stroke volume was 68 ml. during the infusion and 61 afterward. Stroke volume decreased The rise in stroke volume in 5 of the 6 patients. was 16 per cent and the fall when metaraminol infusion was stopped, 9 per cent. Brachial Arterial Pressure: The brachial arterial systolic pressure averaged 105 mm. Hg (85 to 140) before the infusion, 120 mm. Hg (99 to 158) at the first level of metaraminol infusion and 135 mm. Hg (111 to 170) at the second level of infusion. The average diastolic pressure rose from 54 to 64 and the average mean blood pressure from 74 to 89 mm. Hg. The increase in pressure was noticeable within 1 or 2 minutes after the start of the metaraminol infusion. The rise in pressures continued for about 20 minutes with unchanged drip rate. At increasing drip rate, the pressures continued to rise, the diastolic pressure less than the systolic, giving an increased pulse pressure. All patients showed exactly the same reaction. In 6 cases determinations were made after cessation of metaraminol infusion; the systolic pressure was 127 during the infusion and 106 mm. Hg afterward. The diastolic pressure decreased from 63 to 58 and the mean pressure There was a fall of the from 87 to 76 mm. Hg. pressures in all patients. The rise in brachial arterial systolic, diastolic and mean pressures during metaraminol infusion was 22, 18 and 19 per cent, respectively, and the fall was 17, 11 and 12 per cent, respectively (Fig. 5). Peripheral Vascular Resistance: The mean total
18
Malmcrona, Schrijder and We&ii
Heart
rate
Brachlal
beats/min
arterial
pressure
mm Hg
150 1 Cardiac
output
l/min
2
1
0 Symbols
:
s I
blood
H D x heart
pressure
I
rate
cardiac
3
hours
output
EZI
blood
m
metaraminol
replacement infusion
FIG. 1. Patient 4. Hemodynamic data before, during and after infusion of metaraminol. Heart rates, brachial arterial systolic, diastolic and mean pressures and cardiac output are given. Duration of investigation and times of metaraminol infusions and blood replacements are indicated at baseline.
Heart
rate,
beats/minute Cardiac
IO ::l::
output
L/min.
r
6 ::zy
cl 40 _
2 Onset
I
Onset of metaraminol.
00 60
01 I 0
30
60
90
120
I’
o
before
and
0
during
metaramlnol
I
sinus
after
metaraminol
metaraminol
InfusIon
0
rhythm
arrhythmia
FIG. 2. Heart rates of 11 patients with acute myocardial infarction before, during and after metaraminol infusion. Time till and after onset of metaraminol infusion is indicated at baseline.
0
before
and
during
infusion
infusIon
I
30
I
30
I
60
I
90
120
I
150
minutes
150
minutes
/
I
60
30
of
infusion
;
5fnus ,’
after
metaramlno!
metaramlnol
lnfuslon
InfusIon
rhythm
arrhythmia
FIG. 3. Cardiac output of 11 patients with acute myocardial infarction before, during and after metaraminol infusion (symbols as in Fig. 2).
THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Hemodynamics Stroke
volume,
of Metaraminol.
19
II
ml_. Resistance,
units
2f3
r
21;
t 2f1
t If5
60
t 1:
20 Onset of metaramlnol
t
01 /
I
,
60
InfusIon
I
30
I
0
30
after
metaramlnol
I
60
90
I
120
1 150 Onset
minutes 0
before
l
during
and
metaramlnol
*(“us
/ 8’
,
60
30
0
30
60
90
arterial
mean
pressure,
0
before
.
during
/
mm.Hg
150
I’
41”~s ’
and
after
metaraminol
metaramlnol
Infusion
infuslo”
rhythm
arTbyth”l,a
6. Resistance of 11 patients with acute myocardial infarction before, during and after metaraminol infusion (symbols as in Fig. 2). FIG.
60
Onset
I 60
120
minutes
120r
I 30
0
of
metaramlnot
I 30
I 60
InfusIon
I 90
I 120
I 150
minutes before
and
dur, “g 7 ,’
InfusIon
arrhytbmla
.Brachial
0
metaramlnol
~“tusfo”
rhythm
FIG. 4. Stroke volume of 11 patients with acute myocardial infarction before, during and after metaraminol infusion (symbols as in Fig. 2).
0
of
Infuslo”
Sl”lJ5
after
metaramlnOL
metaram,nol
,nfus,on
infuslo”
rhythm
arrhythmia
FIG. 5. Brachial arterial mean pressure of 11 patients with acute myocardial infarction before, during and after metaraminol infusion (symbols as in Fig. 2). JANUARY 1964
peripheral vascular resistance increased from 15.9 units (12.2 to 19.4) to 16.5 units (11.2 t.0 22.1) on the first level of metaraminol infusion and to 18.1 units (14.3 to 22.4) on the second level. The resistance was essentially unchanged in 3 patients with marked increase in cardiac output and rose in the others (Fig. 6). In 6 patients whose cardiac output was determined after cessation of metaraminol infusion, the resistance was 17.7 units during the infusion and 14.8 afterward. There was a fall in all but 1 patient. The resistance increased 13 per cent during the metaraminol infusion and fell 15 per cent afterward. Left Ventricular Work and Left Ventricular Stroke Work: Both left ventricular work and left ventricular stroke work increased, the former from 5.1 to 6.6 kg.-M./min. (290/,), the latter from 59 to 82 gm.-M. (38yc). Patient with Complete A-V Heart Block: In 1 patient with sinus rhythm on admission, complete A-V block developed with a ventricular rate of 47 before the hemodynamic investiga-
Malmcrona,
20
Schrijder
and We&ii
TABLE II Hemodynamic
Data Before and During Metaraminol Before Metaraminol
Patient
Time Before Starting Infusion (min.)
Heart Rate (beats/ min.)
Cardiac
Output (L./min.)
Stroke Volume (ml.)
Infusion
Infusion Brachial Arterial Pressure (mm. H,q) Ii* tii s.*
Resistante (units)
LVW* (kg.-M./ min.)
LVSW (gm.-M.)
41 14
97 94
5.1 5.2
52 56
100 103
55 60
73 74
14.4 14.2
5.0 5.1
52 54
2
55 18
94 93
5.8 5.8
62 62
123 120
74 69
96 90
21.1 20.9
9.8 9.4
104 101
3
48 17
84 82
5.0 5.4
60 66
100 108
53 56
72 80
20.0 20.1
6.2 7.9
74 97
4
34 13
48 47
4.3 4.0
89 86
95 104
44 50
63 70
14.8 17.3
3.7 3.9
76 82
5
43 21
110 112
7.0 6.3
64 57
111 107
67 65
88 85
12.5 13.4
8.4 7.3
77 66
6
46 20
84 79
5.0 5.3
59 67
132 140
60 56
80 90
16.0 17.1
5.4 6.5
64 82
7
134 25
131 119
4.4 4.4
34 37
97 93
51 51
64 63
14.4 14.2
3.9 3.8
30 32
8
64 27
73 75
5.3 4.7
73 62
88 95
45 45
65 66
12.2 14.2
4.70 4.18
64.5 55.7
9
44 20
104 103
3.1 3.4
30 33
87 85
37 40
60 58
19.4 17.1
2.53 2.67
24.5 26.0
10t
36 13
47 46
4.0 4.3
85 92
112 105
50 45
65 62
16.2 14.6
3.5 3.6
75 78
ll$
45 17
55 53
2.5 2.6
48 48
112 132
37 41
60 60
23.7 23.4
2.1 2.1
39 39
LVSW
= left ven-
* Abbreviations: S. = systolic; D. = diastolic; M. = mean; LVW = left ventricular work; tricular stroke work. t Case 10. Atrioventricular heart block before the metaraminol infusion, then sinus rhythm. 1 Case 11. Atria1 fibrillation.
tion. Cardiac output was 4.1 and 4.3 L./min. Blood pressure was 107/45 mm. Hg, mean 60, just before metaraminol infusion was started. Two minutes later the pressures was 115/53, mean 68 and after 3 minutes when pressure was 130/65, mean 82, there was regular sinus rhythm. At the ninth and thirty-ninth minute of metaraminol infusion, the heart rate was 60, cardiac output 5.4 and blood pressure 140/68, mean 90, and 168/82, mean 115, respectively. The patient maintained sinus rhythm and normal blood pressure after infusion was stopped. Patient with Atria1 Fibrillation: One patient had mitral insufficiency and atria1 fibrillation prior to infarction. Her heart rate was 54 at the hemodynamic investigation. She had low cardiac output (2.5 and 2.6 L./min.) and high Her systolic pressure was well resistance. maintained, 112 and 132 mm. Hg; the mean 60.
During metaraminol infusion the heart rate was essentially unchanged. On the higher dose of metaraminol infusion cardiac output and resistance rose and the pressures rose to 166/ 49, mean 77. When metaraminol infusion was stopped, the pressure fell as did the cardiac output and resistance. Atria1 fibrillation was maintained. DISCUSSION The
present
study
has
shown
an
increase
of
the stroke volume in patients with myocardial infarction when they were given metaraminol. The increase in mean brachial arterial pressure was shown to depend on rises in cardiac output or resistance or in both. A total A-V block in 1 patient was changed to sinus rhythm by the metaraminol infusion. One patient with atria1 fibrillation responded like those in sinus rhythm when given metaraminol. THE AMERICANJOURNAL OF CARDIOLOGY
Hemodynamics
of Metaraminol.
TABLE
II(continued)
During Metaraminol Time After Metaraminol Infusion (min.)
Heart Rate (beats/ min. )
Cardiac output (L./min.)
Stroke Volume (ml.)
21
II
Infusion
Brachial Arterial Pressure (mm. Hg) S.* D.* M.*
Resistante (units)
Lvw* (kg.-M./ min.)
LVSW (gm.-M.)
17 38
96 97
6.5 6.4
67 66
121 129
64 65
90 92
13.9 14.3
7.9 8.0
82 83
10 27
91 88
6.2 6.7
68 77
130 142
76 80
97 106
21.1 21 .I
10.9 13.0
120 147
12 33
75 73
5.5 4.7
77 65
114 120
65 69
88 93
20.9 25.3
8.6 7.7
122 106
27 51
41 42
4.1 4.8
100 113
120 138
52 58
70 83
17.0 17.5
3.9 5.4
95 127
23 47
102 110
8.6 7.8
84 70
121 140
71 94
96 113
11.2 14.6
11.2 11.9
110 108
25 44
70 66
4.3 4.9
61 75
158 170
58 70
95 100
22.1 20.3
5.6 6.7
79 102
17 38
107 112
5.0 5.3
47 47
108 123
56 65
78 87
15.6 16.4
5.3 6.3
50 56
23 50
65 63
4.3 4.2
67 67
110 144
54 65
74 94
17.1 22.4
4.36 5.35
62.4 85.6
16 36
99 99
3.5 3.5
35 35
99 111
46 50
68 72
19.5 20.8
3.23 3.39
32.4 34.3
9 39
60 60
5.4 5.4
89 90
140 168
68 82
90 115
16.5 21.3
6.7 8.5
109 141
18 40
52 52
2.5 2.9
49 55
132 166
38 49
62 77
24.5 27.0
2.1 3.0
41 58
TABLE
Hemodynamic
Patient
Time After Onset of Aramine Infusion
Heart Rate
III
Data After Metaraminol
Cardiac output (L./min.)
Stroke Volume (ml.)
Infusion
Brachial Arterial Pressure (mm. Hg) S. D. M.
Resistance (units)
LVW (kg.-M./min.)
LVSW (gm.-M.)
3
27 52
81 81
4.3 4.4
59 55
108 102
60 60
83 79
17.7 18.0
5.3 4.7
65 58
4
26 61
48 50
4.6 4.7
96 94
108 105
42 45
68 65
14.7 13.9
4.3 4.2
89 83
5
47 71
107 105
6.7 6.8
63 64
121 105
92 77
106 94
15.8 13.9
9.7 8.7
91 82
6
39 65
89 93
6.9 5.1
77 55
142 147
62 62
92 95
13.4 18.6
8.6 6.6
96 71 46
7
86
110
5.6
51
88
50
66
11.7
5.1
9
36
104
3.5
34
76
36
49
14.0
2.13
22
11
33
51
2.6
50
100
35
59
22.7
2.1
40
M. = mean;
LVW
S. = systolic; JANUARY
1964
D. = diastolic;
= left ventricular
work;
LVSW
= left ventricular
stroke work.
Malmcrona,
22
,Schrijder and Werkij TABLE IV
Mean Hemodynamic
Heart Rate (beats/min.)
A. Bcfort
Cardiac Output (L./min.)
and During
Mctaraminol
Before metaraminol infusion
M & SE SD
90.5
f 7.5 22.6
4.97 * 0.97
During metaraminol infusion
M f SD
SE
83.1
f 22.6
5.32zto.49 1.46
Difference
M f SD
SE
Probability
level
7.6
-7.4zt1.7 5.0
+0.35
P
and A&r
Infusion
M z!z SE SD
83.0
zk 10.8 26.5
5.13zt0.66 1.63
After metaraminol infusion
M f SD
90.2
* 22.8
5.18 f 1.17
Difference
M zt SE
Probability
Ieve
P
58.6
z& 3.4 8.4 -
i-0.05
Heart Rate
Cardiac Output
During metaraminol infusion compared with values before
-8.2
+7.6
26-86 min. after infusion compared with values during
+8.4
0.
with sinus rltythm)
5.2
54.3 f 10.4
3.5
74.3 f 11.7
3.9
68.Ozt 6.6 19.9
127.8 f 16.5
5.5
64.3 i 10.7
3.6
88.7 ;t 11.5
3.8
f 2.1 6.4
+22.7f
Stroke Volume
2.4
+lO.O+
7.1
1.2
+14.4f
3.7
001
1.3 4.0
(0.001
(6 pnlicnts with sinus rhythm),
f 25.1
10.2
61.2f8.2 20.2
0.13
Changes due to Metaraminol
M.
105.1 f 15.5
+9.4
0.48
f 1.05 -
Arterial Pressure Hg)--------D.
i 5.6 16.7
67.5
TABLE
Mean Percentage
(Qpolicnts
During metaraminol infusion
+7.2
Infusion
0.11
Mctaraminol
9.3
Brachial ,-----(mm. s.
Volume
(ml.1
<0.02
B. During
SE
Stroke
0.32
f 0.33
Data
-6.3
f 3.1 7.6 -
127.0 f 2.05
8.4
62.8zlz11.7 26.2
86.9 zk 13.0 29.1
105.7 f 23.6
9.7
56.0f 37.9
76.2 zt 19.4 43.4
-21.3
;t 6.4
2.6
-6.8
f 12.8
16.7 5.7
-10.8
-
f 15.6 -
7.0
v
infusion in 9 and 6 Patients, Respectively Brachial Arterial ~Pressure~S. D. M.
Resistante
LVW
LVSW
+16.4
+21.6
-i-18.3
i-19.5
$13.6
+28.7
j-38.3
-
-16.8
-10.8
-12.8
-16.1
-11.4
-19.5
Only 1 patient who had a systolic blood pressure below 90 mm. Hg and was cold and sweating at the investigation would have been treated with metaraminol on therapeutic grounds. Thus, conclusions regarding hemodynamic effects of metaraminol in patients in cardiogenic shock after a myocardial infarction cannot be drawn directly from the present investigation. induces a In normal subjects6*’ metaraminol fall in heart rate, a rise in stroke volume, no change in cardiac output and a rise in brachial arterial blood pressure. The rise in mean brachial arterial pressure is then essentially due to a rise in total peripheral resistance. The contractile force of the myocardium has been shown to increase in open-chest dogs,5 in isolated rat hearts” and in patients investigated during
8.9
heart operations.s In subjects made hypotensive by administration of hexamethonium and then normotensive by metaraminol, there was a rise to normal values in central blood flow.‘O When patients in cardiogenic shock have been given metaraminoln-14 there has nearly always been a rise in blood pressure, and many have survived. The decrease of heart rate in our patients was of the same order as reported earlier in normal subjects.6*7 It is presumably due to a vagal depression of the activity of the sinoauricular node, since increased blood pressure affects pressure receptors in the aortic arch and carotid sinus. The decrease in heart rate may per se be regarded as beneficial, since myocardial oxygen consumption at any given work load has been shown to increase with heart rate, THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Hemodynamics ‘rARLE
I”
of Metaraminol.
(Conti?ZZUd)
-Resistance (units) -w=
LVW (kg.-M./min.)
LVSW (gm.-M.)
=zz==z=--
16 3 f 2.9
1.o
5.58 f 2.25
0.75
64.5 f 25.1
8.4
18.4f 3.5
1.2
7.16 f 3.04
1.01
89.0+ 10.1
3.4
+2.1
f 2.0
10.7
+1.58
<0.02
f 0.41 1.22
+24.4
f 31. 9.4
18.4 f 6.4
3.8
6.61 f 6.55
2.93
85.2 f 34.1
13.9
15.7 f 8.8
3 9
5.84 f 5.48
2.45
67.8 f 27.0
11 .O
-2.6
f 6.8 -
3.1
-0.77
f 2.91 -
1.30
--17.4
* 10.5
4.3
and in the presence of coronary stenosis in dogs left ventricular failure could simply be induced by increasing the heart rate.15 The signs of failure were relieved by allowing the heart rate to decrease. The cardiac output rose in some and fell in other patients as it does in normal subjects6v7 The response could not be related to an initially more or less decreased blood pressure or to high or low cardiac output. The significance of the change in cardiac output is very difficult to evaluate because it is the ultimate effect of many alterations in the circulation. Increased cardiac output may be due to increased myocardial contractility6 s8,16 and/or to increased venous return on account of venoconstriction. The stroke volume rose in most patients as it does in normal subjects. The rise may be ascribed to a positive inotropic effect of the drug. It is, however, not a definite proof of such an effect because the heart rate was lower and many reflexes may have influenced the heart. The rise in mean arterial pressure depended in one third of the patients on increased cardiac resistance output, in one third on increased and in the remaining third on increased blood flow and resistance. The cause of the rise of blood pressure is similarly variable in normal persons.6*7 The patient whose rhythm changed from
JANUARY
1964
II
23
total A-V block to sinus rhythm had an increase in both cardiac output and resistance when pressure rose. Increase in arteriolar tone may improve the myocardial oxygen supply through increased coronary blood flow secondary to the higher blood pressure. The decrease in heart rate may, however, in this respect be more important because it decreases the need for oxygen.15 In shock, in the acute stage of myocardial infarction, central and peripheral changes of the circulation are involved. Measurements of the contractility of undamaged myocardium when other parts are infarcted have not been reported. As the net effect of contractility and other factors, the cardiac output is lowered. The low cardiac output can, however, depend on a purely mechanical factor such as bulging of the infarcted area during systole. The total peripheral systemic resistance may be increased, unchanged or decreased, a high temperature usually being associated with a decreased resistance.” The essential feature of shock is, however, the decreased cardiac output. This induces a fall in pressure and a reflex vasoconstriction. This vasoconstriction may be insufficient if there has been a rise in temperature, and in some patients it may fail. In most instances of cardiogenic shock the beneficial effect of sympathomimetic amines is attributable to their positive inotropic effect. Only drugs with that effect may thus be used. In patients with insufficient or failing vasoconstriction, there is additional advantage of the peripheral action. In most patients with shock, vasoconstriction is adequate, and further increase of the vasoconstriction is then unnecessary. A positive inotropic effect should also be achieved by digitalis glucosides, but no direct or indirect signs of such an effect were observed when patients in acute myocardial infarction were given lanatoside-C.18 A peripheral vasoconstrictive action of the digitalis glucoside was, however, observed in those acute experiments in conformity with studies using extracorporeal circulation in man.lg The reduction in heart rate produced by the sympathomimetic drug used in this study may be of special value since the need for myocardial oxygen thereby is reduced. In the experiments with digitalis there was an increase of the heart rate when digitalis was given. Metaraminol caused fewer arrhythmias in these patients than in normal subjects whose blood pressure was more increased.6 The re-
24
Malmcrona,
Schrdder
suits reported here on hemodynamic effects of metaraminol thus indicate that the drug may be useful for falling blood pressure and cardiogenic shock after myocardial infarction. SUMMARY Eleven patients with acute myocardial infarction have been studied by recordings of intraarterial pressure and determinations of cardiac output before, during and, in 7 cases, also after cessation of metaraminol infusion. The heart rate was lower and the stroke volume higher in the patients during infusion. The arterial pressure rose in all patients. In some the rise depended on a rise in cardiac output, in some on a rise in resistance, but in most patients on small rises in both output and The type of reaction was not resistance. directly correlated to the factor apparently responsible for a low blood pressure. Metaraminol seems thus a useful drug when the blood pressure decreases after myocardial infarction and may also be of value in the treatment of cardiogenic shock. REFERENCES
7.
8.
9.
10.
11. 12.
13. 14.
15.
1. HELLERSTEIN,H. K., BROFMAN,B. L. and CASKEY, W. H. Shock accompanying myocardiai infarc2.
3.
4.
5.
6.
tion: Treatment with pressor amines. Am. Heart J., 44: 407, 1952. KURLAND, G. S. and MALACH, M. The clinical use of norepinephrine in the treatment of shock accompanying myocardial infarction and other New England J. Med., 247: 383, 1952. conditions. MILLER, A. J. and BAKER,L. A. L-arterenol (Levophed) in the treatment of shock due to acute myocardial infarction. Arch. Znt. Med., 89: 591, 1952. GAZES, P. C., GOLDBERG, L. I. and DARBY, T. D. Heart force effects of sympathomimetic amines as a basis for their use in shock accompanying myocardial infarction. Circulation, 8: 883, 1953. SARNOPF, S. J., CASE, R. B., BERGLUND, E. and SARNOFF, L. G. Ventricular function. The Mechanism of circulatory effects of Aramine. action of “vasopressor” drugs in cardiogenic shock. Circulation, 10: 84, 1954. MALMCRONA, R., SCHRGDER, G. and WERK~ L.
16.
17.
18.
19.
and
Werkii
Hemodynamic effects of metaraminol in normal subjects. Am. J. Cardial., 13: 10, 1964. LIVESAY, W. R., MOYER, J. H. and CHAPMAN,D. W. The cardiovascular and renal hemodynamic effects of Aramine. Am. Heart J., 47: 745, 1954. MEIJLER, F. L., MEERSCHWAM,I. S. and KOSTER, M. De invloed van metaraminol-bitartraat op de contractiliteit van het hart. Ned&. tijdschr. Geneesk., 106: 1800, 1962. GOLDBERG,L. I., BLOODMIELL,R. D., BRAUNWALD, E. and MORROW, A. G. The direct effects of norepinephrine, epinephrine, and methoxamine on myocardial contractile force in man. Circulation, 22: 1125, 1960. MILLS, L. C., VOUDOUKIS,I. J., MOYER, J. H. and HEIDER, C. Treatment of shock with sympathomimetic drugs. Use of metaraminol and comparison with other vasopressor agents. A.M.A. Arch. Znt. Med., 106: 816, 1960. BESTERMAN,E. M. M. Treatment of cardiac shock by metaraminol. &it. M. J.,: 1081, 1959. MOYER, J. H. and BEAZLEY, L. Effectiveness of Aramine in the treatment of shock. Am. Heart J., 48: 136, 1955. STEEHEL,G. H. et al. The use of Aramine in clinical shock. Circulation, 13: 834, 1956. Clinical studies on a vasopressor WEJL, M. H. agent: metaraminol (aramine). II. Observations on its use in the management of shock. Am. J. M. SC., 230: 357, 1955. BERGLUND, E., BORST, H. G., DUFF, F. and SCHREINER,G. L. Effect of heart rate on cardiac work, myocardial oxygen consumption and coronary blood flow in the dog. Acta physiol. scandinav., 42: 185, 1958. BRAUNWALD,E., BINION,J. T., MORGAN, W. L. and SARNOFF, S. J. Alterations in central blood volume and cardiac output induced by positive pressure breathing and counteracted by metaraminol (Aramine). Circulation Res., 5: 670, 1957. MALMCRONA, R., and VARNAUSKAS,E. Hemodynamic data of patients in acute myocardial infarction. Acta med. scandinav., (in press). MALMCRONA, R., SCHRBDER, G. and WERKB, L. Hemodynamic effects of digitalization of patients with acute myocardial infarction. In preparation. BRAUNWALD, E., BLOOD~ELL, R. D., GOLDBERG, L. I. and MORROW, A. G. Studies on digitalis. IV. Observations in man on the effects of digitalis preparations on the contractility of the nonfailing heart and on total vascular resistance. J. C/in. Invest., 40: 52, 1961.
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