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The effects of milrinone (Win 47203) on the coronary blood flow and oxygen consumption of the dog heart-lung preparation
Baker
21.
22. 23.
24.
et al.
American
heart and great vessels. 7th ed. Boston, 1973, Little, Brown & Co, p 286. Sahn DJ, DeMaria A, Kisslo J, Weyman A: Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 60:1104, 1978. Fortuin NJ, Hood WP, Craige E: Evaluation of left ventricular function by echocardiography. Circulation 66:26, 1972. Naimark A, Wasserman K, McIlroy MB: Continuous measurement of ventilatory exchange ratio during exercise. J Appl Physiol 19:644, 1964. Leddy CL, Sutton MS, Schwartz DE, Likoff M, Reichek N, Franciosa JA: Left ventricular wall thickness and mass as predictors of survival in patients with chronic left ventricular failure (abstr). J Am Co11 Cardiol 1:593, 1983.
April, 1966 Heart Journal
25. Grossman W, Jones D, McLaurin LP: Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56:56, 1975. 26. Dodge HT, Baxley WA: Left ventricular volume and mass and their significance in heart disease. Am J Cardiol 23:528, 1969. 27. Ross J: Afterload mismatch and preload reserve: A conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis 28:256, 1976. 28. Hood WP, Rackley CE, Rolett EL: Wall stress in the normal and hypertrophied human left ventricle. Am J Cardiol 22:550, i968. 29. Baker BJ, Scovil JA, Kane JJ, Murphy ML: Echocardiographic detection of right ventricular hypertrophy. AM HEART J 105:611, 1983.
The effects of mkinone (Win 47203) on the coronary blood flow and oxygen consumption of the dog heart-lung preparation Milrinone is a new bipyridine-positive inotropic agent that is closely related to amrinone. In the nonfailing heart, coronary blood flow was increased and coronary bed resistance was decreased by milrinone, most probably by a direct action of milrinone on the coronary vasculature. Oxygen consumption was increased at the lower workloads. In the failing heart milrinone (0.1 to 0.5 mg/L of blood) increased cardiac output and coronary blood flow and reduced coronary vascular resistance. With the 0.1 mg dose oxygen consumption was reduced, especially at the high workloads, and was not significantly changed at the low work levels. With higher doses of milrinone oxygen consumption of the heart was not changed significantly while external work was increased. These data show that milrinone can increase the work of the heart with a decrease or no significant change in oxygen consumption of the isolated falling heart. The use of this drug in heart failure accompanied by restricted blood flow may thus be indicated. (AM HEART J 111:702, 1986.)
E. Kabela, L. Barcenas, and A. Farah. Mexico
City, Mexico
Milrinone (Win 47203) (1,6 dihydro-2-methyl-6oxo[3,4’ bipyridine]&zbonitrile) is a new cardiac stimulant related to amrinone. Pharmacologic data obtained in isolated heart muscle and intact animals show that milrinone is about 30 to 50 times as active as the related compound amrinone both as a cardiotonic and vasodilator.1-5 Clinical experiences with milrinone indicate that milrinone is an effective From the Department Ignacio Chavez.
of Physiology,
Received accepted
for publication Sept. 4, 1985.
Reprint Institute,
requests: Alfred E. Farah, M.D., 81 Columbia Turnpike, Rensselaer,
702
May
6, 1985;
Instituto
National
revision
received
Sterling-Winthrop NY 12144.
de Cardiologia Aug.
2, 1985; Research
positive inotropic agent and vasodilator in humans and can be given either intravenously or orally for prolonged periods without a reduction in its effectiveness.6-10 It has been devoid of the gastrointestinal, platelet, and liver side actions that were observed in some human patients receiving amrinone.7-g The effects of milrinone on cardiac contractility were not modified by beta-adrenergic blockers, antihistamines, or cholinergic blockers3 A variety of experimentally produced and natural types of heart failure, including spontaneous, pentobarbital-, nifedipine-, propranolol-, and dinitrophenol-induced heart failure, were reversed by milrinone.3-5 In the present study we have determined the effects of
Volume
111
Number
4
Milrinone:
Hemodynamics
and cardiac
milrinone on coronary blood flow and oxygen consumption of the normal and failing dog heart-lung preparation (HLP) during different degrees of cardiac preload. METHODS In 24 experiments a modified HLP described by Simaan and Fawaz” was used. In this preparation, coronary blood flow can be determined with greater precision then in the classic Starling HLP. However, the disadvantage of this new preparation is the relatively short period available for useful experimentation (60 to 90 minutes) because of its more rapid deterioration. Basically this method consists of introducing a double cannula into the pulmonary artery. One branch of this cannula is connected to the blood resevoir of the HLP and blood can circumvent the right ventricle and flow directly into the pulmonary circulation. The other cannula collects the blood from the right ventricle and accounts for about 90% of total coronary blood flow.“’ ‘* Details of the methodology and illustration of this modified HLP can be found in the article by Simaan and Fawaz.” In this preparation we measured heart rate, cardiac output, left atria1 and arterial pressure, coronary blood flow, and arteriovenous differences in oxygen content. From these values, oxygen consumption, external work, and coronary vascular resistance could be calculated before and after the administration of milrinone. The dogs were anesthetized with pentobarbital(30 to 40 mg/kg) and defibrinated blood obtained from a second dog was used to perfuse the HLP. The blood volume of the HLP was about 1000 ml, and peripheral resistance and blood temperature were kept at 80 mm Hg and 37 to 37.5” C, respectively. Under control conditions the inflow vessel was kept at 10 cm above the right atrium and systemic output was adjusted by means of a screw clamp on the inflow side to be 500 to 600 ml/min. Preload could be increased by increasing the height of the inflow vessel in increments of 5 cm. Systemic output was measured with a Stolnikof flowmeter and coronary blood flow by means of graduated cylinder and stopwatch. Cardiac output was the sum of systemic and coronary blood flow. Left atria1 and arterial pressures were measured by means of cannulae inserted into the left auricular appendage and the brachiocephalic artery, respectively, and Statham pressure transducers were used to record these pressures. Heart rate was obtained from an ECG and all parameters were recorded on a Grass polygraph. Oxygen saturations of arterial and coronary blood were measured spectrophotometrically by the method of Falholt.13 Heart failure could be induced by the administration of 60 to 140 mg of pentobarbital. In most instances enough pentobarbital was given to increase the left atria1 pressure to 50 to 75 mm of H,O. Cardiac work was increased by increasing the height of the inflow vessel in three 5 cm increments and this resulted in an increase in cardiac output and left atrial pressure.14 The external work of the two ventricles was calculated from the following equation: Left external ventricular work = [mean arterial pressure (mm Hg) - left atrial
0, consumption
703
a 0
CORONARY FLOW SYSTEMIC OUTPUT C l CONTROL F l HEART FAILURE M l AFTER MILRINONE
1
1
CFY
CFY
GFY 0.4-
O.ZSng
0.3mg
Fig. 1. Effect of milrinone (0.1 to 0.5 mg/L of blood) on cardiac output and coronary blood flow of the failing HLP (modification of Simaan and Fawaz”). Cardiac output = coronary blood flow and systemic output; q = coronary blood flow ml/min; Cl = total volume = systemic output ml/min; C = control; F = pentobarbital-induced heart failure; M = milrinone.
pressure (in mm Hg)] X [cardiac output (L/min) X 0.0136, where 0.0136 is the conversion factor for mm Hg cm3 to gram meters. Cardiac output was the sum of the systemic output and coronary blood flow. Mean arterial pressure (in mm Hg) = peak systolic arterial pressure - % (peak arterial pressure - diastolic arterial pressure). Right external ventricular work was low in this preparation since only the coronary blood was pumped by the right ventricle into the blood reservoir. Under control conditions the height of the top of the reservoir was 200 mm H,O (14.7 mm Hg). When the inflow vessel was raised to increase the preload, the pressure gradient for the right ventricle increased and this was taken into account when right ventricular work was calculated. Right ventricular work = height of reservior (mm Hg) X coronary flow (L/ min) X 0.0136; total external ventricular work = right ventricular work + left ventricular work. The modified HLP is a relatively fragile system and has a life span of about 60 to 90 minutes. It is thus imperative to follow through as rapidly as possible on the experimental procedures. We have made our readings during a control period where the cardiac work was increased over control in three increments and measurements of left atria1 pressure, systemic output, coronary blood flow, heart rate, and oxygen content of the arterial and coronary blood were determined. Similar measurements were recorded after induction of heart failure and the administration of milrinone. Statistical comparisons were performed on control,
704
Kabela,
Barcenas,
and Farah
American
Table I. The effect of milrinone (0.25 mg/L) dog HLP (average of four experiments)
Height
of inflow
Period
C
I
+5 +10
on the hemodynamics
and oxygen consumption
Coronar,y (mllmin)
Cardiac output fmllmin)
vessel
+15 Period II
c +5 +10 +15
flow
A
0 Control A Milrinone
of the nonfailing
Left
F 27.8 k 18
511 749
+ 25 ZIZ 60
118.5 136.5
-+ 16.3 _t 20
989 1190
-t 92 t 135
134.2 144
k 18.4* k 16.1*
567 863
k 33 k 71*
29 + 11* 49 i 20*
169.2 185.2
k 24* Z!T23”
1092 1323
k 84* + 123’
70 k 30* 104 k 36*
of the inflow
vessel.
height
B
0.25 mg
l Control A Miirinone
modified
atria1 pressure (mm H20i
89.7 101.5
Period I = control period; period II = after the addition of 0.25 mg/L of milrinone. All values were obtained after attainment of steady state. *Denotes significance (p < 0.05) from corresponding values obtained at the same
April, 1986 Heart Journal
46 + 8 71 + 17 100 146
* 22 t 32
0.25 mg
200 t50 100 50 I I I 0.5 1.0 1.5 L.V. WORK (Kg)
I 2.0
I I I I 10 15 20 5 O2 CONSUMPTION (ml/min) I
Fig. 2. Relationship of ventricular work (A) and cardiac oxygen consumption in the modified HLP. Cardiac work and oxygen consumption were increased the inflow vessel (preload) by 5 to 15 cm (average of four experiments).
postpentobarbital, and postmilrinone values, by paired t test analysis. p Values less than 0.05 were considered significant. The effects of milrinone were compared with the values obtained during the premilrinone period. RESULTS
Some of the effects of milrinone on the failing dog HLP have been described previously.4 In Fig. 1 we show experiments on dog HLP where an acute heart failure was induced with pentobarbital. A small dose of milrinone, 0.1 mg/L of blood, produced a significant improvement while an additional 0.5 mg of milrinone restored the heart to a normal range. Both coronary flow and heart rate were also increased by milrinone. In 24 HLPs which were prepared according to the method of Simaan and Fawaz” heart rate, left atria1
(B) to coronary blood flow by increasing the height of
pressure, coronary blood flow, cardiac output, blood pressure, and oxygen consumption of the heart were determined. External ventricular work of the heart and coronary vascular resistance were calculated from the preceding data (Tables I and II). In the first series consisting of four preparations, milrinone, in a dose of 0.25 mg/L of blood, was given to nonfailing hearts (Table I). Since these hearts were not in failure, the effects of milrinone on cardiac output and heart rate were only a 12% and 7% increase, respectively. On the other hand, coronary blood flow increased by 42%. The external work of the heart increased by 18% while oxygen consumption increased 28% (Table 1). In 20 modified HLPs, heart failure was induced with pentobarbital and this was followed by the administration of 0.1,0.25, or 0.5 mg milrinone/L of
Volume Number
111 4
Milrinone:
Hemodynamics
and cardiac
0, consumption
705
Oxygen Heart
rate
@pm)
Blood pressure (mm Hg)
Ventricular (kgmlmin)
work
consumption (mllmin)
Coronary vascular resistance
135
_t 16
73.2
f
1.9
0.498
+ 0.026
4.65
t
0.83
0.780
138 142
f f
17 17
f 1.8
0.98
15
f 0.046 + 0.116 f 0.168
f
r
0.758 1.462 1.325
6.47
145
77.2 88.2 89.5
f 1.04 + 0.56
0.709 0.682 0.577
k 0.064 f 0.059 f 0.070 * 0.083
145
2 19
147 153
f 18 k 17
74.7 78.5
+ 2.2 f 2.3
t f
0.3* 1.31*
0.535 0.520
-r 0.037* k 0.041'
155
5 17
85.7 93.2
+ 3.3 + 3.1
f 1.41 k 0.61
0.476 0.459
f 0.032* k 0.039*
f 3.1 k 3.7
Milrinone,
11.12 14.02
0.25 mg
0.585
f
0.040
1.149 1.242 1.605
+ 0.065* k 0.080 Z!I 0.150
blood (Table II). Pentobarbital, in general, decreased cardiac output and external ventricular work and increased left atrial pressure, coronary blood flow, and the diastolic volume of the heart. The administration of milrinone reversed the effects of the pentobarbital heart failure and increased external work performance of the heart (Table II). In all of these preparations milrinone increased coronary blood flow (Tables I and II) substantially and decreased the volume of the heart as observed visually. However, the increased external work performance, heart rate, blood pressure, and oxygen consumption are all factors which can cause an increase in coronary blood flow. When 0.25 mg of milrinone was administered (Table I) the heart rate increase was about 9 bpm and blood pressure changed by less then 3 mm Hg. These small changes could not have contributed significantly to the increase in coronary blood flow. The two major factors were thus the increase in external work and oxygen consumption. In Fig. 2 we have plotted oxygen consumption or external work of the ventricles against coronary blood flow. Milrinone increased coronary blood flow independently of either the oxygen consumption or external work performed, and it is thus likely that milrinone has direct dilator effects on the coronary vascular bed, thus decreasing coronary vascular resistance. Fig. 3 shows the relationship between the oxygen extraction and coronary blood flow; milrinone decreased the arteriovenous oxygen difference in the face of an increase in blood flow and this suggests a direct vasodilator effect of milrinone on coronary blood vessels. Oxygen consumption of the heart was increased during pentobarbital-induced heart failure and milrinone either decreased or did not change oxygen
6.65 9.22 11.70 14.8
. 0 A
CONTROL HEART FAILURE AFTER 0.25 m g MILRINONE
I
I
I
I
I
50
100
150
200
250
CORONARYFLOW(ml/min.)
Fig.
3. Oxygen extraction from the coronary blood of the
modified dog HLP during control period, during pentobarbital failure, and following 0.25 mg of milrinone (average of nine experiments).
consumption. However, the external work performed increased by 19 % to 40 % depending on the dose of milrinone. In Fig. 4 the relation of ventricular work to oxygen consumption is shown. Heart failure increased while 0.1 mg of milrinone decreased oxygen consumption to control levels. The data with 0.25 and 0.5 mg are not as striking as with 0.1 mg, possibly because the higher doses of milrinone increased the heart rate to a greater extent than the 0.1 mg dose (Table II). DISCUSSION
Milrinone in concentrations that produced positive inotropic effects also increased coronary blood flow. The increased work of the heart or oxygen consumption following milrinone would, per se,
706
Kabela,
Barcenas,
and Farah
April, 1986 Heart Journal
American
Table II. The effect of pentobarbital-induced heart failure and its reversal by milrinone on the hemodynamicsand oxygen consumption of the modified dog HLP Height of inflow
Period
vessel
C +5 +10 +15
Period II
Period III
Period
C +5 +10 +15
C +5 +10 +15
c +5 +10 +15
Period II
C +5 +10 +15
Period
C
III
+5 +10 +15
Period I
Period II
Period III
C +5 +10 +15
C +5 +10 +15
C +5 +10 +15
Coronary flow (mllmin)
Cardiac output (ml/mini
69.6 83.0 91.0 104.6
++ k +-
8.6 10.9 12.3 11.8
647.8 882.8 1154.4 1322.6
+ f + -+
41.9 52.7 52.1 60.7
29.8 45.0 59.6 76.4
t k T rfr
2.8 2.6 3.4 3.4
179.2 197.0 201.6 207.8
t 2 ++-
27.8* 29.6* 30.6* 32.O*
618.8 820.0 1103.0 1281.2
f f + t
30.0 49.3” 61.4 41.9
55.6 73.6 93.8 117.0
f if +
3.3* 4.1* 5.9* 8.2*
231.6 245.8 252.4 266.6
f +2 ?
32.8t 36.2t 38.7 36.6t
735.0 1002.6 1214.8 1442.4
k rt + f
33.5 52.0-f 46.7t 42.2t
38.2 54.2 70.8 89.6
+ 2 2 k
3.5t 4.lt 5.2t 6.6t
65.0 79.7 91.3 111.4
2 k 2 +
5.4 6.3 6.0 8.5
582.6 841.0 1100.7 1331.5
+ + + k
29.6 59.3 60.0 77.6
29.3 49.2 69.4 96.8
+ ++ +-
1.64 2.90 5.50 9.6
126.4 2 11.2* 137.7 + 12.5* 145.7 2 11.7* 153.8 + 12.7*
490.3 704.0 960.8 1165.7
2 k I +
31.1 50.2* 56.5* 51.4’
61.8 84.7 112.4 152.3
+ k i t-
4.8* 5.9* 9.1* 13.2*
175.5 * 17.5t 191.6 + 16.5t 208.0 k 22.3t 233.7 + 24.7t
615.6 889.1 1176.6 1433.3
k + k +
55.2 71.8 86.2 77.9
34.8 53.7 73.4 96.7
k 2 f c
4.0t 4.6t 5.9t 9.2t
76.6 97.3 115.3 145.2
* * + k
9.7 11.5 14.5 21.4
600.8 907.8 1229.5 1443.7
c i k *
48.7 85.8 101.6 114.1
28.2 43.2 63.5 90.7
+ L rt +
1.2 2.8 4.5 8.5
148.5 165.0 178.5 193.0
k + 2 +
lO.O* 11.2* 8.8* 13.3*
544.2 785.0 1081.8 1275.0
r + + ?
44.8 60.4 71.6* 79.6*
62.2 83.7 108.7 138.2
zt + -+ +
2.8* 5.1* 6.6* 10.8*
215.8 225.3 242.5 276.3
+ + + +
16.2t 15.7t 20.31 38.8t
704.2 + 49.9t 1009.3 + 65.3t 1288.2 k 91.6t 1481.5 k 107.6
22.7 37.5 51.0 64.7
+ * + +
3.3t 3.9t 4.8t 8.7t
Period I = control period; period II = after pentobarbital heart failure was induced; after attainment of a steady state. *Denotes significance (p < 0.05) of values after induction of heart failure. tDenotes significance @ < 0.05) following milrinone administration when compared
cauae an increased coronary flow, however, the data
presented suggest that milrinone has direct effects on the coronary blood vessels (Fig. 2). This conclusion was further strengthened by the observation that milrinone decreased oxygen extraction from coronary blood at a time when it increased coronary
period III = after the addition
to the values obtained
Left
of milrinone
atrial pressure (mm H20)
all values were obtained
during heart failure.
flow (Fig. 3). However, it should be kept in mind that similar data can be obtained when shunting of coronary blood flow occurs. Harris et all5 and Grant et all6 have studied the effects of milrinone on isolated canine coronary arteries. Their results show that milrinone is a potent vasodilator of dog coro-
Volume Number
111 4
M&none:
Heart rate (bpm)
147.4 149.6 151.8 153.2
k k t k
Blood pressure (mm Hs)
4.7 4.9 5.0 5.0
82.7 k 0.8 86.2 k 1.0 88.5 -t 1.3 92.8 -+ 2.2
143.6 f 5.0 144.8 + 5.1 146.6 k 5.2 148.4 k 4.9
83.8 86.5 88.8 90.5
2 2 t -+
1.4 1.7 1.8 2.1
149.8 151.4 152.8 154.0
84.8 87.8 89.7 91.8
rt t k IL
1.7 1.8 1.9 2.5
139.2 141.4 144.6 147.8
+ k f k
6.5 6.7 6.9 6.7
z!z 6.4 + 6.7 f 6.6 i 6.7
139.0 2 140.7 r 143.7 k 146.8 f
6.2 5.7 6.3 6.9
81.4 85.3 88.8 97.8
-+ -+ + -+
1.4 1.7 1.7 3.5
81.7 84.5 87.5 91.4
-t f r k
1.3 1.5 1.7 2.4
147.8 149.8 152.7 154.7
F 2 f k
6.0 6.0 5.8 5.6
83.5 86.0 90.3 96.9
i + t rt
1.4 1.7 2.2 3.3
139.5 140.2 143.0 145.2
* + i +
4.7 4.5 4.3 4.5
82.8 85.9 88.8 100.6
-c r r -+
1.5 1.8 2.0 3.8
134.0 f 136.5 + 138.2 f 140.8 f
4.8 4.8 4.5 4.6
81.8 85.6 89.3 93.0
f -c +2
1.6 1.3 1.6 2.2
150.0 154.8 159.0 161.8
4.5 3.9 4.5 4.8
85.0 88.0 90.8 95.8
++zt-t
1.2 1.5 1.8 4.0
f f + rf
-
Ventricular (kglmin)
nary arteries (1.8 to 3.6 pg/ml) and it is more active against the vascular constrictions induced by prostaglandin F, and serotonin then those produced by 40mM KCl. Milrinone in a concentration of 0.1 to 0.5 p/ml of blood increased coronary blood flow and the work of the failing heart without increasing oxygen consumption. With the lowest dosage of milrinone used (0.1 mg/L) oxygen consumption actually declined
Oxygen
work
0.1 mg 0.723 f 0.04 .9624 Z!E0.07 1.340 + 0.5 1.604 f 0.08 Pentobarbital 0.707 f 0.06 0.962 + 0.05 1.290 f 0.08 1.498 -t 0.09* Milrinone, 0.866 * .04y 1,202 t .08f 1.454 k 0.6t 1.765 k O.lt 0.25 mg 0.623 + 0.04 0.951 + 0.08 1.282 f 0.07 1.677 k 0.12 Pentobarbital 0.539 * 0.05 0.774 k 0.06* 1.043 * 0.8* 1.323 k 0.08* Milrinone, .721 + .07t 1.041 * .09t 1.344 f .12t 1.834 k .16t 0.5 mg 0.675 k 0.07 1.046 k 0.14 1.442 k 0.12 1.894 k 0.26 Pentobarbital 0.602 f 0.06 0.889 f 0.06* 1.247 f 0.09* 1.490 * 0.12* Milrinone, 0.892 k 0.08t 1.236 f 0.07t 1.622 f 0.12t 1.883 f 0.14t
Hemodynamics
and cardiac
consumption (mllmin)
0, consumption
707
Coronary vascular resistance
No.5 6.26 7.56 8.20 9.00
k 0.15 k 0.91 k 0.91 iT 0.77
1.16 0.99 0.93 0.83
iz k + +
0.069 0.060 0.058 0.077
failure 5.88 8.80 11.40 12.28
f
0.60 1.28 z!c 1.83* 2 0.99*
0.44 0.41 0.40 0.39
t k -t k
0.096* 0.052* 0.040* 0.038*
5.92 7.82 9.22 10.96
+ A -+ k
0.467 0.340 0.335 0.320
k
+
0.040 0.031 0.33 0.029
6.20 k 0.36 7.83 -+ 0.43 9.43 -+ 0.49 11.60 -t 0.95
1.223 + 1.025 k 0.917 t 0.814 F
0.054 0.059 0.052 0.047
6.93 7.63 9.39 10.70
0.68 0.44 0.49 0.64
0.611 0.568 0.544 0.521
f
0.041' 0.46* 0.40* 0.037*
7.57 I 0.84 8.80 k 0.48 9.69 + 0.68 11.22 f 0.71
0.462 0.428 0.408 0.384
k
6.45 AZ 0.59 8.20 + 0.91 10.80 i 1.13 12.55 -t 1.47
1.061 0.850 0.729 0.647
k
7.57 +-0.63 9.10 +- 0.95 11.20 +- 0.75 13.13 ‘- 0.88
0.520 0.482 0.455 0.430
f
8.9 10.25 11.65 13.4
0.286 0.379 0.360 0.330
k
+
0.1 mg 0.42 0.77 0.88t l.OOt
f *
No. 9
failure + k + f
2 * k
0.25 mg 0.031 0.037 + 0.040 z!z 0.032
AZ
No. 6 0.061 0.050 f 0.093 + 0.044
f
failure 0.041* 0.037* 2 0.039* k 0.034 +
0.5 mg + + + -c
1.42 1.25 1.80 1.36
0.033t r 0.036t k 0.039t f 0.031t
significantly. With the higher dosages (0.25 and 0.5 mg/L) this decline was not as striking, possibly because of the greater increase in heart rate produced by these higher doses. Milrinone increased the contractile force of the heart. This being a major determinant of cardiac oxygen consumption, some opposing factors must have been operative to produce the minimal changes in oxygen consumption observed. In these experi-
708
Kabela,
Barcenas,
and Farah
American
A. . CONTROL 0
NE&NT
6.
FAILURE
4 AFTER YILRINOHE
~~I~,
.
0 o., “EWTRlCuAN
C.
.
GONTROL
0
NE&NT
0 CONTROL 0 HELNT FItLURE 4 AFTER YILRINOME
FAILURE
4 AFTER YlLRlNONE
;Ip
t.0 l.5 e.0 WORK K9 rnhb
April, 1966 Heart Journal
ii”~
4 0 0.1 “ENTRlCUlN
4 1.0 I.0 e.0 Nom Kg.m,min
0 0.0 1.0 9.3 L.0 VEHTRlCULlR WORK K~mlmln
Fig. 4. Oxygen consumption of the dog HLP during control period, induction of pentobarbital heart failure, and therapy of heart failure with milrinone. Ordinate = oxygen consumption ml/min; abscissa = work of the heart in kg . m/min. A. Effect of 0.1 mg milrinone (averageof five experiments). B, Effect
of 0.25 mg milrinone (av&age of nine experiments).?, Effect of 0.5 mg of milrinone (average of six experiments).
ments, cardiac diastolic and systolic volume were decreased by milrinone, thus causing a reduction in left ventricular wall stress. This reduction in wall stress is an important factor in reducing oxygen consumption.17~ l8 The increase in oxygen consumption produced by the positive inotropic effect of milrinone was most likely offset by the reduction in the diastolic and systolic volume of the ventricles produced by the drug. These findings suggest that milrinone may be useful in the therapy of heart failure accompanied by a restricted coronary blood flow as may be observed in patients with multiple coronary artery stenosis. Benotti et al. lg have observed that amrinone in a dosage that increased cardiac work and dpfdt did not increase oxygen consumption of the heart. Bairn et ahzo and Monrad et a1.21have studied the effects of milrinone in cardiac hemodynamics and energetic9 in 18 congestive heart failure cases. Here milrinone administration increased left ventricular work by 42 % without an increase in oxygen consumption, resulting in a 45% increase in the calculated left ventricular external efficiency. The decline in left ventricular diastolic pressure and the direct coronary vessel dilation could improve coronary perfusion which would be another beneficial effect for congestive heart failure patients whose coronary flow is limited by arterial disease. REFERENCES
1. Alousi AA, Helstosky A, Montenaro MJ, Cicero FS: Intravenous and oral cardiotonic activity of Win 47203 a potent amrinone analogue in dogs (abstr). Fed Proc 40:663,1981. 2. Alousi AA, Canter JM, Montenaro MJ, Fort DJ, Ferrari R: Cardiotonic activity of milrinone, a new and potent cardiotonic bi-pyridine on the normal and failing heart of experimental animals. J Cardiovasc Pharmacol 5:792, 1983b. 3. Alousi AA, Stankus GP, Stuart JC, Walton LH: Characterization of the cardiotonic effects of milrinone, a new and potent
4.
5.
6.
7.
8.
9.
10.
11. 12.
13. 14. 15.
16.
cardiac biphyridine, on isolated tissues from several animal species. J Cardiovasc Pharmacol 5:804, 1983b. Pastelin G, Mendez R, Kabela E, Farah A: The search for a digitalis substitute. II. Milrinone (Win 47203) its action on the heart-lung preparation of the dog. Life Sci 33:1787, 1983. Kittleson MD, Pipers FS, Knauer DM, Keister DM, Knowlen GG. Miner WS: Efficacv of milrinone in naturally occuring heart failure in dogs. “In Braunwald E, Sonnenblick Ey Chakrin L, Schwartz R, editors: Milrinone: Investigation of new inotropic therapy for congestive heart failure. New York, 1984, RavenPress,p 77. Maskin CS, Sinoway L, Chadwick B, Sonnenblick EH, LeJemtel TH: Sustained hemodynamic and clinical effects of a new cardiotonic agent, Win 47203, in patients with severe congestive heart failure. Circulation 67;1065, 1983. Sinoway LS, Maskin CS, Chadwick B, Forman R, Sonnenblick EH, LeJemtel TH: Long-term therapy with a new cardiotonic agent, Win 47203: Drug-dependent improvement in cardiac performance and progression of the underlying disease. J Am Co11 Cardiol 2:327, 1983. Bairn DS, McDowell AV, Cherniles J, Monrad ES, Parker JA, Edelson J, Braunwald E, Grossman W: Evaluation of a new bipyridine inotropic agent-milrinone-in patients with severe congestive heart failure. N Engl J Med 309:748, 1983. Monrad ES, McKay RG, Bairn DS, Colucci WS, Fifer MA, Heller GV, Royal HD, Grossman W: Improvement in indexes of diastolic performance in patients with congestive heartfailure treated with milrinone. Circulation 70:1030,1984. McDowell AV, Bairn DS, Monrad ES, Cherniles J, Braunwald E, Grossman W: Chronic oral milrinone therapy in patients with refractory congestive heart failure (abst). Circulation 66:III-374, 1983. Simaan J, Fawaz G: The mechanical efficiency of the Starling heart-lung preparation. Pflugers Arch 302:123, 1968. Rodbard S, Graham CR, Williams F: Continuous and simultaneous measurement of total coronary flow, venous return and cardiac output in the dog. J Appl Physiol 6:311, 1953. Falholt W: Blood oxygen saturation determined spectrophotometrically. Stand J Clin Lab Invest 15:67, 1963. Krayer 0: Versuche am insuffizienten Herzen. N Sch Arch Exp Path Pharmakol 162:1, 1931. Harris AL, Wassey ML, Grant AM, Alousi AA: Direct vasodilating action of milrinone and sodium nitrite in the canine coronary artery. (abstr). Fed Proc 43:3819, 1984. Grant AM, Harris AL, Alousi AA: Selective dilation by milrinone and amrinone in coronary arteries (abstr). Fed Proc 44:716, 1985.
Volume Number
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Milrinone:
17. Braunwald E: Control of myocardial oxygen consumption. Am J Cardiol 44:722, 1971. 18. Weber KT, Janicki JS: The metabolic demand and oxygen supply of the heart: Physiological and clinical considerations. Am J Cardiol 44~722, 1979. 19. Benotti JR, Grossman W, Braunwald E, Carabello BA: Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease. Circulation 62:28, 1980. 20. Bairn DS, Monrad ES, McDowell AV, Smith HS, Lanone A,
Hemodynamics
and cardiac
0, consumption
Braunwald E, Grossman W: Milrinone therapy in patients with severe congestive heart failure: Initial hemodynamic and clinical observations. In Braunwald E, Sonnenblick E, Chakrin L, Schwartz R, editors: Milrinone: Investigation of new inotropic therapy for congestive heart failure. New York, 1984, Raven Press, p 143. 21. Monrad ES, Bairn DS, Smith HS, Lanone A, Braunwald E, Grossman W: Effect of milrinone on coronary hemodynamics and myocardial energetics in patients with congestive heart failure. Circulation 71:972,1985.
Can the technique for Doppler estimate of pulmonary stenosis gradient be simplified? Although Doppler echocardiography has been demonstrated to accurately predict the pressure drop across the pulmonary valve in patients with pulmonary valve stenosis, prior reports have stressed the need to correct for beam-flow intercept angles, to use simultaneous imaging, and to utilize the subcostal approach. The purpose of this study was to determine the accuracy of estimating the pressure drop in pulmonary stenosis patients by means of nonimaging Doppler applied without angle correction from precordial examination. Pressure drop estimated by Doppler was compared to that measured by strain gauge manometry at catheterization. Data for 39 patients (21 simultaneous measurements; 18 nonsimultaneous) were evaluated. Results for the entire group showed a good correlation (r = 0.94; SEE = 7.9 mm Hg). The correlation for simultaneous measurement improved somewhat (r = 0.95; SEE = 5.9) but the difference was not significant. Comparison of the slope and intercept of data of this study to those of prior studies, which advocated more complex methodology, indicated that results were essentially similar and that use of the additional steps did not confer a significantly improved result. We conclude that the simplified methodology utilized in this study provides accurate Doppler estimates of pressure gradient in patients with pulmonary stenosis. (AM HEART J 111:709, 1986.)
Stanley J. Goldberg, M.D., Susan D. Vasko, M.D., Hugh D. Allen, M.D., and Gerald R. Marx, M.D. Tucson, Ark.
The ability of Doppler echocardiography to estimate quantitatively the pressure gradient across stenotic valves has been well established.‘e5 Correlation of pressure gradient by strain gauge manometry at catheterization and Doppler in patients with isolated pulmonary stenosis has been previously reported. Lima et al.,4 in an early article regarding pulmonary stenosis, utilized continuous-wave Doppler with imaging and angle correction of velocities. Later, Johnson et al., utilizing similar equipment and From the Department Center. Received accepted Reprint University
for publication Sept. 4, 1985.
of Pediatrics, May
University 6, 1985;
requests: Stanley J. Goldberg, of Arizona Health Sciences
revision M.D., Center,
of Arizona received
Health Aug.
Sciences 2, 1985;
Department of Pediatrics, Tucson, AZ 85724.
technique without angle correction, reported similar results. The latter group emphasized the necessity for both subcostal and precordial examinations because alignment of the poststenotic jet with the ultrasonic beam during imaging from the precordium was not always possible. These reported methodologies produced high correlations with manometry performed at catheterization, but the incorporation of imaging with reported techniques is difficult because the coupling end of imaging transducers is usually large and this size sometimes impairs the transducer manipulation necessary for alignment with the jet. Further, Hatle and Angelsen have indicated that imaging may be a liability because jets may be eccentric and may not be where the examiner thinks they should be locat709
21.
22. 23.
24.
et al.
American
heart and great vessels. 7th ed. Boston, 1973, Little, Brown & Co, p 286. Sahn DJ, DeMaria A, Kisslo J, Weyman A: Recommendations regarding quantitation in M-mode echocardiography: Results of a survey of echocardiographic measurements. Circulation 60:1104, 1978. Fortuin NJ, Hood WP, Craige E: Evaluation of left ventricular function by echocardiography. Circulation 66:26, 1972. Naimark A, Wasserman K, McIlroy MB: Continuous measurement of ventilatory exchange ratio during exercise. J Appl Physiol 19:644, 1964. Leddy CL, Sutton MS, Schwartz DE, Likoff M, Reichek N, Franciosa JA: Left ventricular wall thickness and mass as predictors of survival in patients with chronic left ventricular failure (abstr). J Am Co11 Cardiol 1:593, 1983.
April, 1966 Heart Journal
25. Grossman W, Jones D, McLaurin LP: Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56:56, 1975. 26. Dodge HT, Baxley WA: Left ventricular volume and mass and their significance in heart disease. Am J Cardiol 23:528, 1969. 27. Ross J: Afterload mismatch and preload reserve: A conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis 28:256, 1976. 28. Hood WP, Rackley CE, Rolett EL: Wall stress in the normal and hypertrophied human left ventricle. Am J Cardiol 22:550, i968. 29. Baker BJ, Scovil JA, Kane JJ, Murphy ML: Echocardiographic detection of right ventricular hypertrophy. AM HEART J 105:611, 1983.
The effects of mkinone (Win 47203) on the coronary blood flow and oxygen consumption of the dog heart-lung preparation Milrinone is a new bipyridine-positive inotropic agent that is closely related to amrinone. In the nonfailing heart, coronary blood flow was increased and coronary bed resistance was decreased by milrinone, most probably by a direct action of milrinone on the coronary vasculature. Oxygen consumption was increased at the lower workloads. In the failing heart milrinone (0.1 to 0.5 mg/L of blood) increased cardiac output and coronary blood flow and reduced coronary vascular resistance. With the 0.1 mg dose oxygen consumption was reduced, especially at the high workloads, and was not significantly changed at the low work levels. With higher doses of milrinone oxygen consumption of the heart was not changed significantly while external work was increased. These data show that milrinone can increase the work of the heart with a decrease or no significant change in oxygen consumption of the isolated falling heart. The use of this drug in heart failure accompanied by restricted blood flow may thus be indicated. (AM HEART J 111:702, 1986.)
E. Kabela, L. Barcenas, and A. Farah. Mexico
City, Mexico
Milrinone (Win 47203) (1,6 dihydro-2-methyl-6oxo[3,4’ bipyridine]&zbonitrile) is a new cardiac stimulant related to amrinone. Pharmacologic data obtained in isolated heart muscle and intact animals show that milrinone is about 30 to 50 times as active as the related compound amrinone both as a cardiotonic and vasodilator.1-5 Clinical experiences with milrinone indicate that milrinone is an effective From the Department Ignacio Chavez.
of Physiology,
Received accepted
for publication Sept. 4, 1985.
Reprint Institute,
requests: Alfred E. Farah, M.D., 81 Columbia Turnpike, Rensselaer,
702
May
6, 1985;
Instituto
National
revision
received
Sterling-Winthrop NY 12144.
de Cardiologia Aug.
2, 1985; Research
positive inotropic agent and vasodilator in humans and can be given either intravenously or orally for prolonged periods without a reduction in its effectiveness.6-10 It has been devoid of the gastrointestinal, platelet, and liver side actions that were observed in some human patients receiving amrinone.7-g The effects of milrinone on cardiac contractility were not modified by beta-adrenergic blockers, antihistamines, or cholinergic blockers3 A variety of experimentally produced and natural types of heart failure, including spontaneous, pentobarbital-, nifedipine-, propranolol-, and dinitrophenol-induced heart failure, were reversed by milrinone.3-5 In the present study we have determined the effects of
Volume
111
Number
4
Milrinone:
Hemodynamics
and cardiac
milrinone on coronary blood flow and oxygen consumption of the normal and failing dog heart-lung preparation (HLP) during different degrees of cardiac preload. METHODS In 24 experiments a modified HLP described by Simaan and Fawaz” was used. In this preparation, coronary blood flow can be determined with greater precision then in the classic Starling HLP. However, the disadvantage of this new preparation is the relatively short period available for useful experimentation (60 to 90 minutes) because of its more rapid deterioration. Basically this method consists of introducing a double cannula into the pulmonary artery. One branch of this cannula is connected to the blood resevoir of the HLP and blood can circumvent the right ventricle and flow directly into the pulmonary circulation. The other cannula collects the blood from the right ventricle and accounts for about 90% of total coronary blood flow.“’ ‘* Details of the methodology and illustration of this modified HLP can be found in the article by Simaan and Fawaz.” In this preparation we measured heart rate, cardiac output, left atria1 and arterial pressure, coronary blood flow, and arteriovenous differences in oxygen content. From these values, oxygen consumption, external work, and coronary vascular resistance could be calculated before and after the administration of milrinone. The dogs were anesthetized with pentobarbital(30 to 40 mg/kg) and defibrinated blood obtained from a second dog was used to perfuse the HLP. The blood volume of the HLP was about 1000 ml, and peripheral resistance and blood temperature were kept at 80 mm Hg and 37 to 37.5” C, respectively. Under control conditions the inflow vessel was kept at 10 cm above the right atrium and systemic output was adjusted by means of a screw clamp on the inflow side to be 500 to 600 ml/min. Preload could be increased by increasing the height of the inflow vessel in increments of 5 cm. Systemic output was measured with a Stolnikof flowmeter and coronary blood flow by means of graduated cylinder and stopwatch. Cardiac output was the sum of systemic and coronary blood flow. Left atria1 and arterial pressures were measured by means of cannulae inserted into the left auricular appendage and the brachiocephalic artery, respectively, and Statham pressure transducers were used to record these pressures. Heart rate was obtained from an ECG and all parameters were recorded on a Grass polygraph. Oxygen saturations of arterial and coronary blood were measured spectrophotometrically by the method of Falholt.13 Heart failure could be induced by the administration of 60 to 140 mg of pentobarbital. In most instances enough pentobarbital was given to increase the left atria1 pressure to 50 to 75 mm of H,O. Cardiac work was increased by increasing the height of the inflow vessel in three 5 cm increments and this resulted in an increase in cardiac output and left atrial pressure.14 The external work of the two ventricles was calculated from the following equation: Left external ventricular work = [mean arterial pressure (mm Hg) - left atrial
0, consumption
703
a 0
CORONARY FLOW SYSTEMIC OUTPUT C l CONTROL F l HEART FAILURE M l AFTER MILRINONE
1
1
CFY
CFY
GFY 0.4-
O.ZSng
0.3mg
Fig. 1. Effect of milrinone (0.1 to 0.5 mg/L of blood) on cardiac output and coronary blood flow of the failing HLP (modification of Simaan and Fawaz”). Cardiac output = coronary blood flow and systemic output; q = coronary blood flow ml/min; Cl = total volume = systemic output ml/min; C = control; F = pentobarbital-induced heart failure; M = milrinone.
pressure (in mm Hg)] X [cardiac output (L/min) X 0.0136, where 0.0136 is the conversion factor for mm Hg cm3 to gram meters. Cardiac output was the sum of the systemic output and coronary blood flow. Mean arterial pressure (in mm Hg) = peak systolic arterial pressure - % (peak arterial pressure - diastolic arterial pressure). Right external ventricular work was low in this preparation since only the coronary blood was pumped by the right ventricle into the blood reservoir. Under control conditions the height of the top of the reservoir was 200 mm H,O (14.7 mm Hg). When the inflow vessel was raised to increase the preload, the pressure gradient for the right ventricle increased and this was taken into account when right ventricular work was calculated. Right ventricular work = height of reservior (mm Hg) X coronary flow (L/ min) X 0.0136; total external ventricular work = right ventricular work + left ventricular work. The modified HLP is a relatively fragile system and has a life span of about 60 to 90 minutes. It is thus imperative to follow through as rapidly as possible on the experimental procedures. We have made our readings during a control period where the cardiac work was increased over control in three increments and measurements of left atria1 pressure, systemic output, coronary blood flow, heart rate, and oxygen content of the arterial and coronary blood were determined. Similar measurements were recorded after induction of heart failure and the administration of milrinone. Statistical comparisons were performed on control,
704
Kabela,
Barcenas,
and Farah
American
Table I. The effect of milrinone (0.25 mg/L) dog HLP (average of four experiments)
Height
of inflow
Period
C
I
+5 +10
on the hemodynamics
and oxygen consumption
Coronar,y (mllmin)
Cardiac output fmllmin)
vessel
+15 Period II
c +5 +10 +15
flow
A
0 Control A Milrinone
of the nonfailing
Left
F 27.8 k 18
511 749
+ 25 ZIZ 60
118.5 136.5
-+ 16.3 _t 20
989 1190
-t 92 t 135
134.2 144
k 18.4* k 16.1*
567 863
k 33 k 71*
29 + 11* 49 i 20*
169.2 185.2
k 24* Z!T23”
1092 1323
k 84* + 123’
70 k 30* 104 k 36*
of the inflow
vessel.
height
B
0.25 mg
l Control A Miirinone
modified
atria1 pressure (mm H20i
89.7 101.5
Period I = control period; period II = after the addition of 0.25 mg/L of milrinone. All values were obtained after attainment of steady state. *Denotes significance (p < 0.05) from corresponding values obtained at the same
April, 1986 Heart Journal
46 + 8 71 + 17 100 146
* 22 t 32
0.25 mg
200 t50 100 50 I I I 0.5 1.0 1.5 L.V. WORK (Kg)
I 2.0
I I I I 10 15 20 5 O2 CONSUMPTION (ml/min) I
Fig. 2. Relationship of ventricular work (A) and cardiac oxygen consumption in the modified HLP. Cardiac work and oxygen consumption were increased the inflow vessel (preload) by 5 to 15 cm (average of four experiments).
postpentobarbital, and postmilrinone values, by paired t test analysis. p Values less than 0.05 were considered significant. The effects of milrinone were compared with the values obtained during the premilrinone period. RESULTS
Some of the effects of milrinone on the failing dog HLP have been described previously.4 In Fig. 1 we show experiments on dog HLP where an acute heart failure was induced with pentobarbital. A small dose of milrinone, 0.1 mg/L of blood, produced a significant improvement while an additional 0.5 mg of milrinone restored the heart to a normal range. Both coronary flow and heart rate were also increased by milrinone. In 24 HLPs which were prepared according to the method of Simaan and Fawaz” heart rate, left atria1
(B) to coronary blood flow by increasing the height of
pressure, coronary blood flow, cardiac output, blood pressure, and oxygen consumption of the heart were determined. External ventricular work of the heart and coronary vascular resistance were calculated from the preceding data (Tables I and II). In the first series consisting of four preparations, milrinone, in a dose of 0.25 mg/L of blood, was given to nonfailing hearts (Table I). Since these hearts were not in failure, the effects of milrinone on cardiac output and heart rate were only a 12% and 7% increase, respectively. On the other hand, coronary blood flow increased by 42%. The external work of the heart increased by 18% while oxygen consumption increased 28% (Table 1). In 20 modified HLPs, heart failure was induced with pentobarbital and this was followed by the administration of 0.1,0.25, or 0.5 mg milrinone/L of
Volume Number
111 4
Milrinone:
Hemodynamics
and cardiac
0, consumption
705
Oxygen Heart
rate
@pm)
Blood pressure (mm Hg)
Ventricular (kgmlmin)
work
consumption (mllmin)
Coronary vascular resistance
135
_t 16
73.2
f
1.9
0.498
+ 0.026
4.65
t
0.83
0.780
138 142
f f
17 17
f 1.8
0.98
15
f 0.046 + 0.116 f 0.168
f
r
0.758 1.462 1.325
6.47
145
77.2 88.2 89.5
f 1.04 + 0.56
0.709 0.682 0.577
k 0.064 f 0.059 f 0.070 * 0.083
145
2 19
147 153
f 18 k 17
74.7 78.5
+ 2.2 f 2.3
t f
0.3* 1.31*
0.535 0.520
-r 0.037* k 0.041'
155
5 17
85.7 93.2
+ 3.3 + 3.1
f 1.41 k 0.61
0.476 0.459
f 0.032* k 0.039*
f 3.1 k 3.7
Milrinone,
11.12 14.02
0.25 mg
0.585
f
0.040
1.149 1.242 1.605
+ 0.065* k 0.080 Z!I 0.150
blood (Table II). Pentobarbital, in general, decreased cardiac output and external ventricular work and increased left atrial pressure, coronary blood flow, and the diastolic volume of the heart. The administration of milrinone reversed the effects of the pentobarbital heart failure and increased external work performance of the heart (Table II). In all of these preparations milrinone increased coronary blood flow (Tables I and II) substantially and decreased the volume of the heart as observed visually. However, the increased external work performance, heart rate, blood pressure, and oxygen consumption are all factors which can cause an increase in coronary blood flow. When 0.25 mg of milrinone was administered (Table I) the heart rate increase was about 9 bpm and blood pressure changed by less then 3 mm Hg. These small changes could not have contributed significantly to the increase in coronary blood flow. The two major factors were thus the increase in external work and oxygen consumption. In Fig. 2 we have plotted oxygen consumption or external work of the ventricles against coronary blood flow. Milrinone increased coronary blood flow independently of either the oxygen consumption or external work performed, and it is thus likely that milrinone has direct dilator effects on the coronary vascular bed, thus decreasing coronary vascular resistance. Fig. 3 shows the relationship between the oxygen extraction and coronary blood flow; milrinone decreased the arteriovenous oxygen difference in the face of an increase in blood flow and this suggests a direct vasodilator effect of milrinone on coronary blood vessels. Oxygen consumption of the heart was increased during pentobarbital-induced heart failure and milrinone either decreased or did not change oxygen
6.65 9.22 11.70 14.8
. 0 A
CONTROL HEART FAILURE AFTER 0.25 m g MILRINONE
I
I
I
I
I
50
100
150
200
250
CORONARYFLOW(ml/min.)
Fig.
3. Oxygen extraction from the coronary blood of the
modified dog HLP during control period, during pentobarbital failure, and following 0.25 mg of milrinone (average of nine experiments).
consumption. However, the external work performed increased by 19 % to 40 % depending on the dose of milrinone. In Fig. 4 the relation of ventricular work to oxygen consumption is shown. Heart failure increased while 0.1 mg of milrinone decreased oxygen consumption to control levels. The data with 0.25 and 0.5 mg are not as striking as with 0.1 mg, possibly because the higher doses of milrinone increased the heart rate to a greater extent than the 0.1 mg dose (Table II). DISCUSSION
Milrinone in concentrations that produced positive inotropic effects also increased coronary blood flow. The increased work of the heart or oxygen consumption following milrinone would, per se,
706
Kabela,
Barcenas,
and Farah
April, 1986 Heart Journal
American
Table II. The effect of pentobarbital-induced heart failure and its reversal by milrinone on the hemodynamicsand oxygen consumption of the modified dog HLP Height of inflow
Period
vessel
C +5 +10 +15
Period II
Period III
Period
C +5 +10 +15
C +5 +10 +15
c +5 +10 +15
Period II
C +5 +10 +15
Period
C
III
+5 +10 +15
Period I
Period II
Period III
C +5 +10 +15
C +5 +10 +15
C +5 +10 +15
Coronary flow (mllmin)
Cardiac output (ml/mini
69.6 83.0 91.0 104.6
++ k +-
8.6 10.9 12.3 11.8
647.8 882.8 1154.4 1322.6
+ f + -+
41.9 52.7 52.1 60.7
29.8 45.0 59.6 76.4
t k T rfr
2.8 2.6 3.4 3.4
179.2 197.0 201.6 207.8
t 2 ++-
27.8* 29.6* 30.6* 32.O*
618.8 820.0 1103.0 1281.2
f f + t
30.0 49.3” 61.4 41.9
55.6 73.6 93.8 117.0
f if +
3.3* 4.1* 5.9* 8.2*
231.6 245.8 252.4 266.6
f +2 ?
32.8t 36.2t 38.7 36.6t
735.0 1002.6 1214.8 1442.4
k rt + f
33.5 52.0-f 46.7t 42.2t
38.2 54.2 70.8 89.6
+ 2 2 k
3.5t 4.lt 5.2t 6.6t
65.0 79.7 91.3 111.4
2 k 2 +
5.4 6.3 6.0 8.5
582.6 841.0 1100.7 1331.5
+ + + k
29.6 59.3 60.0 77.6
29.3 49.2 69.4 96.8
+ ++ +-
1.64 2.90 5.50 9.6
126.4 2 11.2* 137.7 + 12.5* 145.7 2 11.7* 153.8 + 12.7*
490.3 704.0 960.8 1165.7
2 k I +
31.1 50.2* 56.5* 51.4’
61.8 84.7 112.4 152.3
+ k i t-
4.8* 5.9* 9.1* 13.2*
175.5 * 17.5t 191.6 + 16.5t 208.0 k 22.3t 233.7 + 24.7t
615.6 889.1 1176.6 1433.3
k + k +
55.2 71.8 86.2 77.9
34.8 53.7 73.4 96.7
k 2 f c
4.0t 4.6t 5.9t 9.2t
76.6 97.3 115.3 145.2
* * + k
9.7 11.5 14.5 21.4
600.8 907.8 1229.5 1443.7
c i k *
48.7 85.8 101.6 114.1
28.2 43.2 63.5 90.7
+ L rt +
1.2 2.8 4.5 8.5
148.5 165.0 178.5 193.0
k + 2 +
lO.O* 11.2* 8.8* 13.3*
544.2 785.0 1081.8 1275.0
r + + ?
44.8 60.4 71.6* 79.6*
62.2 83.7 108.7 138.2
zt + -+ +
2.8* 5.1* 6.6* 10.8*
215.8 225.3 242.5 276.3
+ + + +
16.2t 15.7t 20.31 38.8t
704.2 + 49.9t 1009.3 + 65.3t 1288.2 k 91.6t 1481.5 k 107.6
22.7 37.5 51.0 64.7
+ * + +
3.3t 3.9t 4.8t 8.7t
Period I = control period; period II = after pentobarbital heart failure was induced; after attainment of a steady state. *Denotes significance (p < 0.05) of values after induction of heart failure. tDenotes significance @ < 0.05) following milrinone administration when compared
cauae an increased coronary flow, however, the data
presented suggest that milrinone has direct effects on the coronary blood vessels (Fig. 2). This conclusion was further strengthened by the observation that milrinone decreased oxygen extraction from coronary blood at a time when it increased coronary
period III = after the addition
to the values obtained
Left
of milrinone
atrial pressure (mm H20)
all values were obtained
during heart failure.
flow (Fig. 3). However, it should be kept in mind that similar data can be obtained when shunting of coronary blood flow occurs. Harris et all5 and Grant et all6 have studied the effects of milrinone on isolated canine coronary arteries. Their results show that milrinone is a potent vasodilator of dog coro-
Volume Number
111 4
M&none:
Heart rate (bpm)
147.4 149.6 151.8 153.2
k k t k
Blood pressure (mm Hs)
4.7 4.9 5.0 5.0
82.7 k 0.8 86.2 k 1.0 88.5 -t 1.3 92.8 -+ 2.2
143.6 f 5.0 144.8 + 5.1 146.6 k 5.2 148.4 k 4.9
83.8 86.5 88.8 90.5
2 2 t -+
1.4 1.7 1.8 2.1
149.8 151.4 152.8 154.0
84.8 87.8 89.7 91.8
rt t k IL
1.7 1.8 1.9 2.5
139.2 141.4 144.6 147.8
+ k f k
6.5 6.7 6.9 6.7
z!z 6.4 + 6.7 f 6.6 i 6.7
139.0 2 140.7 r 143.7 k 146.8 f
6.2 5.7 6.3 6.9
81.4 85.3 88.8 97.8
-+ -+ + -+
1.4 1.7 1.7 3.5
81.7 84.5 87.5 91.4
-t f r k
1.3 1.5 1.7 2.4
147.8 149.8 152.7 154.7
F 2 f k
6.0 6.0 5.8 5.6
83.5 86.0 90.3 96.9
i + t rt
1.4 1.7 2.2 3.3
139.5 140.2 143.0 145.2
* + i +
4.7 4.5 4.3 4.5
82.8 85.9 88.8 100.6
-c r r -+
1.5 1.8 2.0 3.8
134.0 f 136.5 + 138.2 f 140.8 f
4.8 4.8 4.5 4.6
81.8 85.6 89.3 93.0
f -c +2
1.6 1.3 1.6 2.2
150.0 154.8 159.0 161.8
4.5 3.9 4.5 4.8
85.0 88.0 90.8 95.8
++zt-t
1.2 1.5 1.8 4.0
f f + rf
-
Ventricular (kglmin)
nary arteries (1.8 to 3.6 pg/ml) and it is more active against the vascular constrictions induced by prostaglandin F, and serotonin then those produced by 40mM KCl. Milrinone in a concentration of 0.1 to 0.5 p/ml of blood increased coronary blood flow and the work of the failing heart without increasing oxygen consumption. With the lowest dosage of milrinone used (0.1 mg/L) oxygen consumption actually declined
Oxygen
work
0.1 mg 0.723 f 0.04 .9624 Z!E0.07 1.340 + 0.5 1.604 f 0.08 Pentobarbital 0.707 f 0.06 0.962 + 0.05 1.290 f 0.08 1.498 -t 0.09* Milrinone, 0.866 * .04y 1,202 t .08f 1.454 k 0.6t 1.765 k O.lt 0.25 mg 0.623 + 0.04 0.951 + 0.08 1.282 f 0.07 1.677 k 0.12 Pentobarbital 0.539 * 0.05 0.774 k 0.06* 1.043 * 0.8* 1.323 k 0.08* Milrinone, .721 + .07t 1.041 * .09t 1.344 f .12t 1.834 k .16t 0.5 mg 0.675 k 0.07 1.046 k 0.14 1.442 k 0.12 1.894 k 0.26 Pentobarbital 0.602 f 0.06 0.889 f 0.06* 1.247 f 0.09* 1.490 * 0.12* Milrinone, 0.892 k 0.08t 1.236 f 0.07t 1.622 f 0.12t 1.883 f 0.14t
Hemodynamics
and cardiac
consumption (mllmin)
0, consumption
707
Coronary vascular resistance
No.5 6.26 7.56 8.20 9.00
k 0.15 k 0.91 k 0.91 iT 0.77
1.16 0.99 0.93 0.83
iz k + +
0.069 0.060 0.058 0.077
failure 5.88 8.80 11.40 12.28
f
0.60 1.28 z!c 1.83* 2 0.99*
0.44 0.41 0.40 0.39
t k -t k
0.096* 0.052* 0.040* 0.038*
5.92 7.82 9.22 10.96
+ A -+ k
0.467 0.340 0.335 0.320
k
+
0.040 0.031 0.33 0.029
6.20 k 0.36 7.83 -+ 0.43 9.43 -+ 0.49 11.60 -t 0.95
1.223 + 1.025 k 0.917 t 0.814 F
0.054 0.059 0.052 0.047
6.93 7.63 9.39 10.70
0.68 0.44 0.49 0.64
0.611 0.568 0.544 0.521
f
0.041' 0.46* 0.40* 0.037*
7.57 I 0.84 8.80 k 0.48 9.69 + 0.68 11.22 f 0.71
0.462 0.428 0.408 0.384
k
6.45 AZ 0.59 8.20 + 0.91 10.80 i 1.13 12.55 -t 1.47
1.061 0.850 0.729 0.647
k
7.57 +-0.63 9.10 +- 0.95 11.20 +- 0.75 13.13 ‘- 0.88
0.520 0.482 0.455 0.430
f
8.9 10.25 11.65 13.4
0.286 0.379 0.360 0.330
k
+
0.1 mg 0.42 0.77 0.88t l.OOt
f *
No. 9
failure + k + f
2 * k
0.25 mg 0.031 0.037 + 0.040 z!z 0.032
AZ
No. 6 0.061 0.050 f 0.093 + 0.044
f
failure 0.041* 0.037* 2 0.039* k 0.034 +
0.5 mg + + + -c
1.42 1.25 1.80 1.36
0.033t r 0.036t k 0.039t f 0.031t
significantly. With the higher dosages (0.25 and 0.5 mg/L) this decline was not as striking, possibly because of the greater increase in heart rate produced by these higher doses. Milrinone increased the contractile force of the heart. This being a major determinant of cardiac oxygen consumption, some opposing factors must have been operative to produce the minimal changes in oxygen consumption observed. In these experi-
708
Kabela,
Barcenas,
and Farah
American
A. . CONTROL 0
NE&NT
6.
FAILURE
4 AFTER YILRINOHE
~~I~,
.
0 o., “EWTRlCuAN
C.
.
GONTROL
0
NE&NT
0 CONTROL 0 HELNT FItLURE 4 AFTER YILRINOME
FAILURE
4 AFTER YlLRlNONE
;Ip
t.0 l.5 e.0 WORK K9 rnhb
April, 1966 Heart Journal
ii”~
4 0 0.1 “ENTRlCUlN
4 1.0 I.0 e.0 Nom Kg.m,min
0 0.0 1.0 9.3 L.0 VEHTRlCULlR WORK K~mlmln
Fig. 4. Oxygen consumption of the dog HLP during control period, induction of pentobarbital heart failure, and therapy of heart failure with milrinone. Ordinate = oxygen consumption ml/min; abscissa = work of the heart in kg . m/min. A. Effect of 0.1 mg milrinone (averageof five experiments). B, Effect
of 0.25 mg milrinone (av&age of nine experiments).?, Effect of 0.5 mg of milrinone (average of six experiments).
ments, cardiac diastolic and systolic volume were decreased by milrinone, thus causing a reduction in left ventricular wall stress. This reduction in wall stress is an important factor in reducing oxygen consumption.17~ l8 The increase in oxygen consumption produced by the positive inotropic effect of milrinone was most likely offset by the reduction in the diastolic and systolic volume of the ventricles produced by the drug. These findings suggest that milrinone may be useful in the therapy of heart failure accompanied by a restricted coronary blood flow as may be observed in patients with multiple coronary artery stenosis. Benotti et al. lg have observed that amrinone in a dosage that increased cardiac work and dpfdt did not increase oxygen consumption of the heart. Bairn et ahzo and Monrad et a1.21have studied the effects of milrinone in cardiac hemodynamics and energetic9 in 18 congestive heart failure cases. Here milrinone administration increased left ventricular work by 42 % without an increase in oxygen consumption, resulting in a 45% increase in the calculated left ventricular external efficiency. The decline in left ventricular diastolic pressure and the direct coronary vessel dilation could improve coronary perfusion which would be another beneficial effect for congestive heart failure patients whose coronary flow is limited by arterial disease. REFERENCES
1. Alousi AA, Helstosky A, Montenaro MJ, Cicero FS: Intravenous and oral cardiotonic activity of Win 47203 a potent amrinone analogue in dogs (abstr). Fed Proc 40:663,1981. 2. Alousi AA, Canter JM, Montenaro MJ, Fort DJ, Ferrari R: Cardiotonic activity of milrinone, a new and potent cardiotonic bi-pyridine on the normal and failing heart of experimental animals. J Cardiovasc Pharmacol 5:792, 1983b. 3. Alousi AA, Stankus GP, Stuart JC, Walton LH: Characterization of the cardiotonic effects of milrinone, a new and potent
4.
5.
6.
7.
8.
9.
10.
11. 12.
13. 14. 15.
16.
cardiac biphyridine, on isolated tissues from several animal species. J Cardiovasc Pharmacol 5:804, 1983b. Pastelin G, Mendez R, Kabela E, Farah A: The search for a digitalis substitute. II. Milrinone (Win 47203) its action on the heart-lung preparation of the dog. Life Sci 33:1787, 1983. Kittleson MD, Pipers FS, Knauer DM, Keister DM, Knowlen GG. Miner WS: Efficacv of milrinone in naturally occuring heart failure in dogs. “In Braunwald E, Sonnenblick Ey Chakrin L, Schwartz R, editors: Milrinone: Investigation of new inotropic therapy for congestive heart failure. New York, 1984, RavenPress,p 77. Maskin CS, Sinoway L, Chadwick B, Sonnenblick EH, LeJemtel TH: Sustained hemodynamic and clinical effects of a new cardiotonic agent, Win 47203, in patients with severe congestive heart failure. Circulation 67;1065, 1983. Sinoway LS, Maskin CS, Chadwick B, Forman R, Sonnenblick EH, LeJemtel TH: Long-term therapy with a new cardiotonic agent, Win 47203: Drug-dependent improvement in cardiac performance and progression of the underlying disease. J Am Co11 Cardiol 2:327, 1983. Bairn DS, McDowell AV, Cherniles J, Monrad ES, Parker JA, Edelson J, Braunwald E, Grossman W: Evaluation of a new bipyridine inotropic agent-milrinone-in patients with severe congestive heart failure. N Engl J Med 309:748, 1983. Monrad ES, McKay RG, Bairn DS, Colucci WS, Fifer MA, Heller GV, Royal HD, Grossman W: Improvement in indexes of diastolic performance in patients with congestive heartfailure treated with milrinone. Circulation 70:1030,1984. McDowell AV, Bairn DS, Monrad ES, Cherniles J, Braunwald E, Grossman W: Chronic oral milrinone therapy in patients with refractory congestive heart failure (abst). Circulation 66:III-374, 1983. Simaan J, Fawaz G: The mechanical efficiency of the Starling heart-lung preparation. Pflugers Arch 302:123, 1968. Rodbard S, Graham CR, Williams F: Continuous and simultaneous measurement of total coronary flow, venous return and cardiac output in the dog. J Appl Physiol 6:311, 1953. Falholt W: Blood oxygen saturation determined spectrophotometrically. Stand J Clin Lab Invest 15:67, 1963. Krayer 0: Versuche am insuffizienten Herzen. N Sch Arch Exp Path Pharmakol 162:1, 1931. Harris AL, Wassey ML, Grant AM, Alousi AA: Direct vasodilating action of milrinone and sodium nitrite in the canine coronary artery. (abstr). Fed Proc 43:3819, 1984. Grant AM, Harris AL, Alousi AA: Selective dilation by milrinone and amrinone in coronary arteries (abstr). Fed Proc 44:716, 1985.
Volume Number
111 4
Milrinone:
17. Braunwald E: Control of myocardial oxygen consumption. Am J Cardiol 44:722, 1971. 18. Weber KT, Janicki JS: The metabolic demand and oxygen supply of the heart: Physiological and clinical considerations. Am J Cardiol 44~722, 1979. 19. Benotti JR, Grossman W, Braunwald E, Carabello BA: Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease. Circulation 62:28, 1980. 20. Bairn DS, Monrad ES, McDowell AV, Smith HS, Lanone A,
Hemodynamics
and cardiac
0, consumption
Braunwald E, Grossman W: Milrinone therapy in patients with severe congestive heart failure: Initial hemodynamic and clinical observations. In Braunwald E, Sonnenblick E, Chakrin L, Schwartz R, editors: Milrinone: Investigation of new inotropic therapy for congestive heart failure. New York, 1984, Raven Press, p 143. 21. Monrad ES, Bairn DS, Smith HS, Lanone A, Braunwald E, Grossman W: Effect of milrinone on coronary hemodynamics and myocardial energetics in patients with congestive heart failure. Circulation 71:972,1985.
Can the technique for Doppler estimate of pulmonary stenosis gradient be simplified? Although Doppler echocardiography has been demonstrated to accurately predict the pressure drop across the pulmonary valve in patients with pulmonary valve stenosis, prior reports have stressed the need to correct for beam-flow intercept angles, to use simultaneous imaging, and to utilize the subcostal approach. The purpose of this study was to determine the accuracy of estimating the pressure drop in pulmonary stenosis patients by means of nonimaging Doppler applied without angle correction from precordial examination. Pressure drop estimated by Doppler was compared to that measured by strain gauge manometry at catheterization. Data for 39 patients (21 simultaneous measurements; 18 nonsimultaneous) were evaluated. Results for the entire group showed a good correlation (r = 0.94; SEE = 7.9 mm Hg). The correlation for simultaneous measurement improved somewhat (r = 0.95; SEE = 5.9) but the difference was not significant. Comparison of the slope and intercept of data of this study to those of prior studies, which advocated more complex methodology, indicated that results were essentially similar and that use of the additional steps did not confer a significantly improved result. We conclude that the simplified methodology utilized in this study provides accurate Doppler estimates of pressure gradient in patients with pulmonary stenosis. (AM HEART J 111:709, 1986.)
Stanley J. Goldberg, M.D., Susan D. Vasko, M.D., Hugh D. Allen, M.D., and Gerald R. Marx, M.D. Tucson, Ark.
The ability of Doppler echocardiography to estimate quantitatively the pressure gradient across stenotic valves has been well established.‘e5 Correlation of pressure gradient by strain gauge manometry at catheterization and Doppler in patients with isolated pulmonary stenosis has been previously reported. Lima et al.,4 in an early article regarding pulmonary stenosis, utilized continuous-wave Doppler with imaging and angle correction of velocities. Later, Johnson et al., utilizing similar equipment and From the Department Center. Received accepted Reprint University
for publication Sept. 4, 1985.
of Pediatrics, May
University 6, 1985;
requests: Stanley J. Goldberg, of Arizona Health Sciences
revision M.D., Center,
of Arizona received
Health Aug.
Sciences 2, 1985;
Department of Pediatrics, Tucson, AZ 85724.
technique without angle correction, reported similar results. The latter group emphasized the necessity for both subcostal and precordial examinations because alignment of the poststenotic jet with the ultrasonic beam during imaging from the precordium was not always possible. These reported methodologies produced high correlations with manometry performed at catheterization, but the incorporation of imaging with reported techniques is difficult because the coupling end of imaging transducers is usually large and this size sometimes impairs the transducer manipulation necessary for alignment with the jet. Further, Hatle and Angelsen have indicated that imaging may be a liability because jets may be eccentric and may not be where the examiner thinks they should be locat709