1. No category

Use of Drugs in Cardiogenic Shock due to Acute Myocardial Infarction
ROLF M. GUNNAR and HENRY S. LOEB
Circulation. 1972;45:1111-1124
doi: 10.1161/01.CIR.45.5.1111
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX
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Use of Drugs in Cardiogenic Shock
due to Acute Myocardial Infarction
By ROLF M. GUNNAR, M.S., M.D.,
AND HENRY S. LOEB, M.D.
SUMMARY
As a plan of therapy for shock associated with acute myocardial infarction in a
general hospital and assuming that septic and hemorrhagic shock has been eliminated
as diagnostic possibilities we would suggest the following:
(1) Pain should be relieved using morphine or pentazocine, and atropine if bradycardia is present. Oxygen by mask should be administered to bring the arterial oxygen
tension to about 100 mm Hg. The airway must be examined and, if air exchange is
poor and the artelial oxygen very low or carbon dioxide high, respiratory assistance
and occasionally intubation may be required.
(2) Blood pressure must be stabilized at an adequate level for perfusion of vital
organs, or progression may be so rapid that death will occur before proper evaluation
can be made and more rational therapy started. For this purpose we would start a
norepinephrine infusion at a rate just sufficient to keep the systolic blood pressure near
100 mm Hg. If the shock syndrome is present but arterial pressure is normal or only
slightly reduced, we would eliminate this step in therapy.
(3) Arrhythmias or heart block should be corrected by methods discussed elsewhere
in this symposium.
(4) A venous catheter should be inserted so that the catheter tip is just within the
thorax. If the central venous pressure (CVP) is below 10 cm H20 we would begin a
regimen of plasma volume expansion giving 100 cc of 40dextran over a peliod of 10
min, waiting 10 min, and if the CVP has not risen 1 cm H20 repeat the process until
shock is relieved, the CVP continues to increase or is above 15 cm H20, or 1000 cc
of 40dextran has been given. If the patient accepts more than 1000 cc of fluid
in this manner without elevating the CVP it is most likely that some other
major process causing fluid loss is complicating the myocardial infarction.
(5) If or when CVP is above 10 cm H20, and if the patient remains in shock and is
hypotensive, we would add norepinephrine infusion at a rate just sufficient to bring
the systolic pressure between 100 and 110 mm Hg. If this cannot be accomplished
with small amounts of norepinephrine then intraarterial pressure must be measured
since the discrepancy between the cuff pressure and actual pressure may be increasing
with further pressor infusion.
(6) If the patient is normotensive and has a CVP above 10 cm H20 but manifests
the shock syndrome, an isoproterenol infusion should be instituted, but to use this
regimen one must be able to measure intraarterial pressure. If CVP falls, simultaneous
plasma volume expansion may be necessary. If arterial pressure begins to fall, norepinephrine should be substituted. We would use dopamine first in this particular
situation, but this agent is not as yet generally available.
(7) With the CVP elevated and blood pressure stable, arterial oxygenation established, and arrhythmias corrected, if the patient is still in a low cardiac output state with
continued oliguria and poor tissue perfusion, digsalization with about half to two
thirds the normal digitalizing dose should be undertaken.
(8) If a further inotropic response is needed glucagon may be added at this point.
With an initial bolus injection efficacy should be established and if found helpful a
constant infusion should follow. Aminophylline should be given simultaneously to
potentiate the action of glucagon.
(9) The patient who at this point remains oliguric and with a small pulse pressure
may be benefited by cautious vasodilation with chlorpromazine or phentolamine and
simultaneous further plasma volume expansion.
(10) A patient who remains pressor-dependent or responds poorly to pressors will
probably need circulatory assistance. However, unless some definitive measure can be
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GUNNAR, LOEB
1112
undertaken to restore or replace inonfunctioninig myocardium this too will be of little
benefit.
(11) A patient wlho stabilizes well but experiences a fall in blood pressure as the
pressor infusion is being discontinued should have plasma volume expansion as the
pressor infusion is decreased. The physician must resist the temptation to restart the
infusion as the pressure falls, unless the shock syndrome accompanies the hypotension.
SHOCK IS A CLINICAL syndrome which
includes obtundation, oliguria (urine
flow<30 cc/hour), cold cyanotic extremities,
and small pulses. Blood pressure as measured
by the standard cuff method is usually low but
intraarterial pressure measured directly mav
be low, normal, or high. Since the clinical
syndrome is not dependent on a low intraarterial pressure one should classify shock as being
with or without intraarterial hypotension. The
shock syndrome associated with acute myocardial infarction has multiple factors in its
etiology,' and although ventricular dysfunction is usually the most significant component
the terms myocardial infarction shock and
cardiogenic shock must not be used interchangeably. Cardiogenic shock refers to that
portion of the syndrome which is due to
malfunction of the heart as a pump but
ignores the reflex changes in the peripheral
vascular system, the effective plasma volume
deficit, and ventilatory abnormalities which
occasionally become dominant.
Myocardial infarction results in decreased
cardiac output.2 3 The ischemic myocardium
bulges with systole4 and the remaining functioning muscle not only has to substitute for
the nonfunctioning, tissue but also must
overcome the damping effect of the expanding
infarcted area. The resultant decreased rate of
pressure rise5 activates the baroreceptors of
the carotid sinus and aorta thus calling for
vasoconstriction to maintain arterial pressure.
The surprising finding is that more than half
of the patients with myocardial infarction,
shock, and hypotension have normal rather
than elevated systemic vascular resistance."
From the Department of Adult Cardiology,
Division of Medicine, Cook County Hospital and
Hektoen Institute for Medical Research, and from the
Department of Medicine, University of Illinois College
of Medicine, Chicago, Illinois.
Agress called attention to this lack of
vasoconstriction, and by injecting beads into
the coronary arteries to produce infarction
constructed an experimental model to simulate
the clinical syndrome.7 In his animals the
cardiac output and arterial pressure fell while
the vascular resistance remained constant. If,
in addition, the animals had dorsal sympathectomy and vagotomy, the decrease in
cardiac output was accompanied by vasoconstriction and arterial pressure was maintained.
He attributed the inhibition of vasoconstriction to a reflex arising in the coronary arteries
but differing from the Jarish-Bezold reflex in
not being abolished by vagotomy. More
recently, it has been postulated that ischemia
activates receptors in the ventricular myocardium causing inhibition of the vasoconstrictor
response.Y These receptors may be stretch
receptors activated when the ischemic muscle
bulges during systole.9 The afferent fibers
have been located as being vagal10 or
sympathetic" and cause central inhibition of
sympathetic tone. In addition to these studies
in the experimental animal, it has recently
been demonstrated that patients with acute
myocardial infarction have decreased vasoconstriction during head-up tilt, again indicating inhibition of normal sympathetic responses.'12
The lack of vascular response to a fall in
cardiac output seen in the patient with acute
myocardial infarction is not easily recognized
clinically.'3 14 Such patients without generalized vasoconstriction demonstrate the best
recovery rate with pressor infusion, have
higher cardiac outputs, and may have lesser
amounts of myocardial damage.15 Since longterm survival is most likely to occur in the
patients with the least myocardial destruction,
identification of the patient in shock with
normal resistance is important.
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DRUGS IN CARDIOGENIC SHOCK IN MI
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Myocardial infaretion is in general associated with diffuse disease of the coronary
arteries.'6 Partial occlusion of a vessel causes a
pressure gradient over the narrowing and,
therefore, a significant pressure difference may
exist between aortic diastolic pressure and the
perfusion pressure at the level of the arterioles. It is probable that vessels distal to areas
of partial occlusion as well as vessels in the
ischemic zone will be maximally vasodilated.17
For these reasons very significant amounts of
the myocardium may have a blood supply
which is pressure-dependent and no longer
able to adjust by autoregulation.18 This same
situation may also pertain to cerebral and
renal blood flows if there is partial occlusion
of the major arteries to these organs.
Hypovolemia may be a significant factor in
shock associated with myocardial infaretion.19
A loss of intravascular volume may occur not
only as a result of reduced fluid intake but also
due to prolonged vasoconstriction, vomiting
associated with the pain of infarction or
medication, sweating, or the use of potent
diuretic agents which can reduce intravascular
volume precipitously. Circulatory arrest may
produce such profound acidosis at the capillary level that vascular integrity is lost, fluid
rapidly leaves the intravascular compartment,
and dilatation of the capacitance vessels
occurs. Since the injured myocardium needs a
higher filling pressure to maintain an adequate
cardiac output the reduced filling pressure
associated with hypovolemia may result in
shock in a patient with acute myocardial
infarction even though the extent of myocardial damage is only moderate. Sudden loss of
intravascular volume in acute myocardial
infarction therefore may set off a chain of
events (hypotention -* use of pressor agents ->
further loss of intravascular volume -> decreasing cardiac output) which will increase the
extent of myocardial damage.
The appearance of clinical shock in a
patient with acute myocardial infaretion
should not preclude considering noncardiae
causes of shock such as sepsis or hemorrhage.
The clue may not be obvious but a low
central venous pressure (CVP), a fever out of
proportion to the myocardial necrosis, a
sudden fall in hematocrit, shock in a patient
lacking electrocardiographic changes of transmural infaretion, or shock associated with a
normal or high cardiac output should all
initiate a search for additional nonmyocardial
causes of shock.13
Plasma Volume Expansion in Shock
of Myocardial Infarction
Most patients with shock and myocardial
infaretion have severe myocardial damage and
have an elevated CVP. However, there are
some patients who, as noted above, have an
inadequate effective blood volume. If the CVP
is below 10 cm H20, fluid challenge should
precede all forms of therapy unless hypotension is so profound that immediate stabilization of arterial pressure is mandatory. Langsjoen et al. reported a reduced mortality rate in
patients treated with low molecular-weight
dextran after acute myocardial infarction.20
Although the therapy was designed to decrease intravascular sludging, the authors
postulated that correction of undetected hypovolemia might have contributed to the improved survival. Nixon et al. pointed out the
need for fluid to elevate the cardiac filling
pressure of patients in shock with myocardial
infaretion and advocated infusion of dextrose
solution as initial therapy of all patients with
this syndrome.21 Allen et al. reported hypovolemia to be present in 20% of patients with
cardiogenic shock and advocated initial dextrose infusion as therapy.22
Normal or slightly reduced blood volumes
have been reported in patients with shock and
myocardial infaretion.23 However, without
knowing the individual's normal blood volume
prior to shock it is difficult to use blood
volume measurements in adjusting fluid therapy. For this reason Weil et al. have
advocated fluid challenge and careful monitoring of the CVP for diagnosis and treatment of
hypovolemia.24 The information needed to
monitor fluid infusion in myocardial infarction, in order to be certain that pulmonary
edema is not precipitated, is the left atrial or
pulmonary venous pressure. At the same time
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GUNNAR, LOEB
a measure of left ventricular end-diastolic
pressure (LVEDP) must be known in order
to assure that the left ventricle is working at
peak performance on the function curve,
utilizing the Frank-Starling mechanism.
Scheinman et al. used pulmonary artery enddiastolic pressure as an equivalent of mean
left atrial pressure.25 Swan and Ganz have
constructed a catheter with a balloon cuff near
the tip. This catheter can be floated into the
pulmonary artery and by inflating the balloon
the pulmonary artery is occluded and pulmonary venous pressure as transmitted through
the pulmonary capillaries can be measured
from the tip of the catheter distal to the
balloon.26 Both of these methods assess
pulmonary venous pressure and fulfill the
requirements for monitoring to avoid the
danger of pulmonary edema, but neither
method gives a measure of the pressure which
is a determinant of ventricular function
(LVEDP).
We have been impressed with the ease of
measuring left ventricular pressure directly by
passing a small catheter retrograde across the
aortic valve under fluoroscopic guidance.
Cohn has used a coiled catheter inserted
without visual guidance.27 Ventricular irritability occurs less frequently than with right
heart catheterization. We have measured
pulmonary artery diastolic pressure (PADP)
simultaneously with left ventricular diastolic
pressure in 10 patients with acute myocardial
infarction who had LVEDP in excess of 20
mm Hg (fig. 1). PADP underestimated
LVEDP by an average of 11 mm Hg. PADP
appears to give a good estimate of LV
pressure just prior to atrial contraction and
thus can be used to predict the onset of
pulmonary edema. However, to determine the
functional state of the myocardium and be
certain peak performance has been achieved it
would appear necessary to measure left
ventricular pressure directly, and this becomes
particularly urgent when considering therapy
by mechanical circulatory assistance or emergency cardiac surgery.28 If the LVEDP is less
than 20 mm Hg, plasma volume expansion
should be attempted before classifying the
Hg
40
mm
35
30_
251
201
151v
105
0
PADP
LVDP
before AC
LVDP
at ED
Figure 1
Pulmonary artery diastolic pressure (PADP), left ventricular diastolic pressure (LVDP) before atrial contraction (AC), and LVDP at end-diastole (ED) are
shown for each of 17 patients with uncomplicated
acute myocardial infarction. In some patients large
increases in LVDP occur coincident with AC and
elevate LVDP at ED.
severity of the myocardial lesion and committing the patient to a drastic therapeutic
intervention.
Recognizing that measurements of pulmonary artery or left ventricular pressures are at
present not feasible in most hospitals, we have
compared CVP and LVEDP in a large group
of patients in shock and found that as a static
measurement there was poor correlation. With
addition of plasma volume, however, both
values tended to rise proportionately and
therefore the CVP seemed to be valuable for
monitoring fluid infusion (fig. 2). However,
during infusion of norepinephrine (fig. 3),
isoproterenol, or dopamine this relationship
between the CVP and LVEDP was inconsistent and the LVEDP could rise while the CVP
was falling. This limits the usefulness of the
CVP as a means of monitoring changes in
LVEDP to periods of plasma volume infusion
when no pressor agent is being given or if
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DRUGS IN CARDIOGENIC SHOCK IN MI
2 5)
1115
Changes in CVP and LVEDP following Infusion of Low Molecular
Weight Dextran in 17 Patients
* = Pre LMWD
o = Post
LMWD
m
E
0
30
15
LVEDP mm. Hg
Figure 2
Central venous pressure (CVP) and left ventricular end-diastolic pressure (LVEDP) before
and after infusion of low molecular-weight dextran (LMWD) in patients with various types
of shock. Although the CVP and LVEDP did not correlate well before LMWD, with
LMWD infusion LVEDP and CVP showed parallel changes.
Changes in CVP and LVEDP during Infusion of Norepinephrine
in 12 Patients
25r
* = Pre - norepi neph r ne
o=During norepinephrine
20p
'P
I
5
E
E
> 10
0
5
I
5
5
10
10
20
15
LVEDP
mm.
25
30
Hg
Figure 3
CVP and LVEDP before and during norepinephrine infusion in 12 patients with shock. No
clear relationship between changes in CVP and LVEDP is apparent during infusion of
norepinephrine.
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GUNNAR, LOEB
pressors are being infused to periods when
the rate of pressor infusion is not altered.
We have used 4"dextran as the agent for
volume expansion as have Cohn et al.29
This agent has the advantage of dispersing
red-cell aggregates and preventing platelet
clumping. Nixon et al. have advocated the use
of 5% dextrose solution21 as have Swan et al.0
who suggested monitoring pulmonary artery
pressure and giving 20 cc/min of 5% dextrose
for 5-15 min or until the pulmonary artery
diastolic pressure increased more than 4 mm
Hg. Dextrose solutions, if used, must be given
rapidly so that they challenge the extent to
which the intravascular compartment is filled.
When dextrose solutions are given slowly the
fluid may leave the intravascular compartment
as rapidly as the infusion adds volume and
thereby edema may develop and the cardiac
filling pressure not rise. A 3.5% solution of
serum albumin would also be an adequate
substitute for dextran and might not leave the
intravascular compartment as rapidly as either
dextrose or dextran. We have used a modification of Weil's method for volume challenge
by giving 100 cc of 40dextran over a 10-min
period, waiting 10 min, and then if CVP has
not increased by more than 1 cm of H20
repeating the process. This is continued until
the CVP continues to increase, exceeds 15 em
H1,0, or shock is relieved, or 100 cc has been
given. With treatment of 10 patients in this
manner we witnessed recovery from shock in
seven and long-term survival in five.19 A 50%
survival is so remarkable in this illness that it
suggests that myocardial damage in these
patients was only moderate and that hypovolemia was the added complication which
produced the shock syndrome.
Norepinephrine
Using a definition of shock in myocardial
infarction which includes systolic blood pressure below 80 mm Hg, Binder et al. found the
survival rate without vasopressors to be about
10%.31 If patients with volume depletion are
excluded, the survival rate with the use of
pressor agents in most series has been between
20 and 30%.32 Pure vasoconstrictors such as
methoxamine, neosynephrine, or angiotensin
are not of value in the treatment of shock with
acute myocardial infarction.15 Increasing afterload merely increases the work of the heart,
and since these agents are without inotropic
effects the ventricle dilates. As this increases
wall tension and oxygen needs, the ventricle is
thereby required to work from an even greater
mechanical disadvantage.
The first hemodynamic studies of response
to pressors were by Malmcrona, Schroder, and
Werko who reported on nine patients with
recent myocardial infarction, five of whom
had periods of systolic blood pressure below
100 mm Hg.33 They showed increases in
cardiac output during metaraminol infusion in
seven of the nine patients. Smulyan, Cuddy,
and Eich studied seven patients in shock with
myocardial infarction measuring the effects of
norepinephrine in five and metaraminol in two
patients.34 Cardiac output increased in only
two patients although in most of the patients
systemic arterial pressure was brought above
110 mm Hg during treatment. Shubin and
Weil treated 10 patients with either norepinephrine or metaraminol and demonstrated an
increase in cardiac output and arterial pressure.35 They made the very important observation that when the arterial pressure was
brought above 90 mm Hg there was a
decrease in cardiac output and an increase in
systemic vascular resistance. We have reported on the use of norepinephrine in 33 patients
in shock with acute myocardial infarction and
all except one had control mean arterial
pressure below 75 mm Hg.' Cardiac output
increased an average of 18%, arterial pressure
increased 43%, and systemic vascular resistance
increased 37%.
We have reviewed our experience with the
use of norepinephrine in patients with various
forms of medical shock (table 1) and have
confirmed the observations of Weil and
Shubin36 that increasing the arterial pressure
above levels just adequate to perfuse the vital
organs (brain, heart, and kidney) merely
increases the work of the heart at the expense
of a decrease in blood flow. Laks et al. have
demonstrated in the intact dog that at very
small infusion rates norepinephrine increases
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DRUGS IN CARDIOGENIC SHOCK IN MI
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Table 1
Response to Norepinephrine Infusion in 122 Patients with Shock of Various Etiologies
Control
MAP
(mm Hg)
Mean A CO (%)
< 30
30 70
> 70
+32
+16
+0.3
After norepinephrine
-
-
34.0
26.3
13.7
cardiac output with little effect on systemic
vascular resistance.37 Much of the animal
experimental work that shows the detrimental
effects of norepinephrine has been at infusion
rates which elevated mean arterial pressure
above 120 mm Hg.
One can block the vasoconstriction caused
by norepinephrine by adding alpha-blocking
agents such as phentolamine (Regitine) or
chlorpromazine but it is our impression that
this is best done as a separate therapeutic
maneuver after arterial pressure has been
stabilized (vide infra).
Isoproterenol
Isoproterenol is a potent synthetic activator
of beta-receptors and thereby is an active
inotropic and chronotropic agent increasing
the force and rate of contraction as well as the
myocardial oxygen consumption. It increases
renal blood flow but the proportion of the
cardiac output going to the kidneys is
reduced.
This agent has been used with success in the
treatment of shock due to sepsis and trauma
and in cardiogenic shock following cardiac
surgery.38 Smith et al. advocated its use in
patients with myocardial infaretion and demonstrated it to be a better agent than
metaraminol.39 However, in patients with
"driving pressures" less than 80 mm Hg it
appeared to be of no benefit. Morse, Danzig,
and Swan used isoproterenol in conjunction
with volume expansion and thought it a
valuable agent,40 but did not compare it to
small amounts of norepinephrine. We compared isoproterenol infusion in amounts of
1-7,gg/min to norepinephrine infusion in 13
patients with hypotension and shock following
acute myocardial infarction.41 None of the
MAP
(mm Hg)
Mean A HR (%)
+14.7
-
+5.7
-
+1.3
-
16.8
12.3
8.1
73.6
82.9
97.7
-
-
13.0
11.9
11.6
patients showed clinical improvement during
isoproterenol infusion. There was rapid clinical deterioration in four patients on switching
from norepinephrine to isoproterenol, and this
was reversed by reinstituting norepinephrine
in one.
The most conclusive report negating the
usefulness of isoproterenol in shock and
hypotension due to coronary disease has been
that of Mueller et al.42 3 They demonstrated
that isoproterenol increased myocardial lactate production in all patients given this agent
while with norepinephrine infusion lactate
production shifted to extraction or extraction
increased. This metabolic deterioration during
isoproterenol infusion in spite of an increase in
coronary blood flow may represent the "coronary steal syndrome" described by Sharma et
al.17 The maximally dilated vessels surrounding an infarct and behind areas of fixed
obstruction have blood flow which is pressuredependent. An agent such as isoproterenol
which drops perfusion pressure and decreases
coronary resistance in uninvolved areas would
divert blood away from the ischemic areas
while increasing the oxygen needs of the
ischemic myocardium. Bing et al. have shown
that in ischemic muscle isoproterenol enhances
peak tension but that deterioration occurs
more rapidly than in ischemic muscle not
exposed to isoproterenol.44 This increased rate
of deterioration could be slowed but not
reversed by the addition of glucose. The
authors proposed that isoproterenol causes
rapid depletion of high energy stores. Thus
isoproterenol not only diverts blood from the
ischemic areas but enhances myocardial deterioration in the ischemic area.
Despite these arguments against its use,
isoproterenol may be an effective agent in the
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GUNNAR, LOEB
presence of the shock syndrome when intraarterial pressure is normal. Under these circumstances, isoproterenol should be given in small
amounts of 0.5-2.0 gg/min and discontinued if
arterial pressure falls or if arrhythmias appear.
In patients with severe mitral insufficiency
and acute myocardial infarction any increase
in systemic vascular resistance only enhances
the regurgitant flow and, therefore, isoproterenol is the catecholamine to be used first.
Isoproterenol can also be used after atropine in the presence of bradycardia but in
most instances this will be a temporary
measure while placing a pacing catheter.
Idioventricular rhythms should not be brought
much above 60 beats/min with this drug
because of the danger of inducing ventricular
tachycardia or fibrillation.
Dopamine
Dopamine is a precursor of norepinephrine
and activates both the beta- and alphaadrenergic receptors.45 In addition this drug
has vasodilator effects on the renal and
mesenteric vessels not mediated through
adrenergic receptors.46 Dopamine, by increasing myocardial oxygen consumption, reduces
coronary vascular resistance.4 A direct effect
of dopamine on the coronary circulation has
not as yet been demonstrated. Because its
action on the adrenergic receptors is intermediate between norepinephrine and isoproterenol and due to its renal vasodilator properties,
dopamine has been considered a useful agent
in the treatment of various shock states.48
Dopamine has been shown to improve hemodynamic abnormalities caused by experimental myocardial infarction as it tends to reverse
the depression of myocardial function that
follows coronary artery ligation.49 MacCannell
et al. reported improvement in urine flow as
well as arterial pressure and cardiac output
during dopamine infusion in patients with
shock of several etiologies.50 Talley et al.
reported seven patients who had a better
hemodynamic response to dopamine than to
isoproterenol.51
We have reported on the effects of dopamine on 62 patients with shock.52 In 13
patients, five of whom had acute myocardial
infarction, the shock was primarily cardiogenie. In patients with cardiogenic shock
dopamine increases cardiac output and
LVEDP and can increase mean arterial
pressure if it is reduced. Systemic vascular
resistance tends to fall as cardiac output
increases in those who are initially vasoconstricted. When compared to norepinephrine
and isoproterenol, dopamine increases cardiac
output more than norepinephrine and less
than isoproterenol and increases arterial pressure more that isoproterenol and less than
norepinephrine. Urine flow appears to improve as often with norepinephrine as with
dopamine. Comparison of the latter two
agents by therapeutic trial is often necessary if
improved urine flow is the object of therapy.
Dopamine can be infused at rates of 0.1-1.6
mg/min, and careful ECG monitoring is
necessary because ventricular arrhythmias
may be precipitated.
Digitalis
Digitalis has been used in treatment of
shock with myocardial infarction but few
studies of the hemodynamic effects have been
published. Gorlin measured cardiac output in
two patients before and after rapid digitalization and found increases in both patients.53 In
an experimental model of cardiogenic shock
Cronin and Zsoter showed that digitalis causes
an increase in blood pressure, a slight increase
in cardiac output, and a very significant
increase in stroke volume with a fall in
LVEDP.54 The increase in blood pressure
preceded the increase in cardiac output and
they suggested that the direct vasoconstrictor
effects of digitalis preceded the inotropic
action.
We have reported the effects of acute
digitalization in a group of patients in shock
with myocardial infarction and the averages
of the changes in cardiac output, arterial
pressure, CVP, and systemic vascular resistance tended to show no effect of the digitalis
on any of these parameters.' Some patients
improved but others deteriorated or continued
to deteriorate following administration of
digitalis. Morrison and Killip have stressed the
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DRUGS IN CARDIOGENIC SHOCK IN MI
increased ventricular irritability induced by
digitalis in acute myocardial infarction,55 and
therefore it should be used judiciously and
only after elevating the arterial pressure and
by ensuring an adequate filling pressure by
fluid infusion, if necessary. It should be given
in amounts calculated to be one half to two
thirds of the accepted "digitalizing" doses. The
best effects will be in the patients in overt
failure, but almost all patients with acute
myocardial infarction given digitalis will
decrease LVEDP and increase LV stroke work
and rate of pressure development.
The question remains as to whether this
effect is of benefit to the heart. The increase in
stroke work and the increase in rate of
pressure development would be at the expense
of an increase in myocardial oxygen consumption.56 However, the decrease in LVEDP, if it
represents a decrease in diastolic volume and
not just a change in myocardial compliance,
should decrease myocardial oxygen needs.
The law of LaPlace indicates that the pressure
in the ventricle varies directly with the tension
in the wall and inversely with the radius of the
cavity. Therefore, if left ventricular pressure
develops from a smaller ventricular radius,
myocardial tension, a major determinant of
myocardial oxygen consumption, could decrease even as pressure rises. It is probable
that the dilated heart benefits from administration of digitalis while the normal-sized
heart does not. The answer to whether the
effects in acute myocardial infarction are
beneficial awaits studies of changes in ventricular volume or measurements of myocardial
oxygen consumption. There is some indication
from clinical observations that changes in
ventricular volume may determine the efficacy
of digitalis in ischemic heart disease, since
patients with angina and small hearts not
infrequently accelerate their angina with
digitalization while patients with big hearts
may be relieved of angina when given
digitalis.57 Digitalis should not be given in the
presence of heart block unless a pacemaker
catheter is in place.
Glucagon
has
been noted to have an
Glucagon
1119
inotropic effect in isolated muscle preparations
and in the intact animal.58 In man it has been
shown to be effective in increasing cardiac
output, rate of pressure development, and
heart rate.59 It was first used therapeutically as
an inotropic agent by Linhart who reported
improvement in a patient with depressed
cardiac function after heart-valve replacement.60 With administration of glueagon to
this patient he noted that the blood pressure
returned to normal, heart rate increased
slightly, and further pharmacologic support
was unnecessary. Parmley reported on the
administration of this agent to 16 patients in
the first postoperative day after prostheticvalve replacement and found an increase in
mean arterial pressure, heart rate, and cardiac
index.61 There was no change in systemic
vascular resistance, although Glick had previously shown glueagon to be a mild vasodilator.62 Vander Ark and Reynolds treated 16
patients with cardiogenic shock for 1-12 days
with continuous glueagon infusions.63 They
noted improvement in 12 of the patients who
experienced increased blood pressure, decreased heart rate, and increased urine flow.
Murtagh et al. gave glueagon to eight patients
with myocardial infaretion and noted an
increase in pulmonary and systemic vascular
resistances.64 Diamond et al. treated 10
patients with acute myocardial infarction, nine
of whom had left ventricular failure.65 They
noted an increase in heart rate, cardiac output,
and arterial pressure. There was a consistent
increase in pulmonary vascular resistance, and
they attributed this to a direct effect of
glucagon on the pulmonary vasculature. They
also report the use of glucagon in treating two
patients with severe myocardial infarction and
shock, and credited survival in one of the
patients to the use of glucagon. Studies in
patients with chronic congestive failure have
been less conclusive than studies in patients
with acute failure.66 In studies of papillary
muscles from patients having mitral-valve
replacement Goldstein et al.68 found glucagon
had no inotropic effect on muscles from
patients who had prolonged cardiac failure,
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1120
GUNNAR, LOEB
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The effects of isoproterenol (ISP), phentolamine, and
glucagon in a patient with chronic congestive heart
failure. Cardiac output (CO) increased more with
isoproterenol thanz with glucagon hut urine flow (UF)
was greater during glucagon infusion. Phentolamine
infusion had little effect on either CO or UF. Changes
in mean arterial pressure (MAP), heart rate (HR),
and left ventricular end-diastolic pressu4re (LVEDP)
are also show)n.
although these same muscles responded positively to norepinephrine. Papillary muscle
from patients with mitral stenosis and no left
ventricular failure showed an inotropic response to both glucagon and norepinephrine.
This discrepancy is probably due to uncoupling or disruption of the glucagon receptor
mechanism in chronic congestive heart failure.67
Glucagon acts by activating adenyl cyclase
which converts adenosine triphosphate to
cyclic AMP ( adenosine 5'-monophosphate )
and this in turn activates the contractile
mechanism.67 Catecholamines also activate
the effects of glucagon by blocking phosphodiesterase which deactivates cyclic AMP.69
Glucagon, therefore, has the advantage of
acting through a nonadrenergic receptor
mechanism and can be effective in the patient
wvho has received beta-receptor blocking
agents. It does not cause arrhythmias and can
be used in the patient with digitalis excess. It
has also been shown to reverse the prolongation of action potential produced by quinidine.70
Administration is either by single injection
of 4-5 mg intravenously or by constant
intravenous infusion at the rate of 4-12
mg/hour. The single injection shows onset of
action almost immediately, peak action at 10
min, and action is dissipated within 30 min.71
Hyperglycemia is a constant finding, but is
usually only to levels of 140 mg% and seldom
exceeds 200 mg%. Hypoglycemia may occur,
particularly on discontinuance after prolonged
infusion. Hypokalemia occurs consistently and
should be prevented by K-' supplementation
during glucagon infusion. Glucagon infusion
should be augmented by simultaneous aminophylline infusion. Nausea and vomiting are
uncomfortable side effects and the resultant
vagal stimulation may decrease cardiac output. By limiting the infusion rate or keeping
the single injection below 5 mg this side effect
usually can be avoided.
Glucagon has a direct effect on the renal
tubules leading to diuresis and natriuresis.72 In
chronic intractible cardiac failure we have
noted marked diuresis far in excess of the
hemodynamic effect and suggest that the
direct renal effects deserve further study (fig.
4).
Chlorpromazine and Phentolamine
Chlorpromazine73 and phentolamine have
been used as vasodilators in myocardial
infarction. They can be used in conjunction
with norepinephrine to decrease the vasoconstrictor activity of the latter agent and thus
allow more inotropic activity. Both agents also
cause a decrease in venous tone and should be
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DRUGS IN CARDIOGENIC SHOCK IN MI
accompanied by volume administration unless
the vasodilator is being used in management
of pulmonary edema. Chlorpromazine is given
in amounts of 5-10 mg intravenously in a single
injection and may be repeated only once at
20-30 min. Larger amounts of this agent will
increase drowsiness and may enhance arrhythmias. Phentolamine is given as a constant
intravenous infusion at a rate of 2-4 mg/hour.
Phenoxybenzamine, although a very potent
alpha-adrenergic blocking agent, is not available for general use and its action is so
prolonged that we would not think it should
be used in acute myocardial infarction.
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