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Pathogenesis of cardiogenic shock. II

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 Cardiogenic Shock
Recent advances in pharmacologic
management (I)

Recent advances in pharmacologic

management {II)

RICHARD J. KONES, M.D.

Pound R1dge, New York

Reprinted from NEW YORK STATE JOURNAL OF MEDICINE, Vol. Ia, Nos. 14, 15, July 15 and August 1, 1973
 Reprinted from NEW YORK ~TATEJotJR;>ALOf'Mr:J?lC!NE, \lul73, Nos. 14, 15, July I and August I, 1973
Copynght 1973 by the MedH~ai!Soctety of the Stat-e of ~ew 'ork and repr:mted by pe-rroi$$iM of the oopyrlght owner~
Cardiogenic Shock
Recant advances in pharmacologic
management (I)
RICHARD J. KONES, M.D.
Po~md Aidge, New York
ASS$tant Profe$$0f of Cl:tmc.al Medlt:!O.e {CatdiO!ogyL New
York Med1cal College-. New Vorl!: Cttv
Recent advatWeli in the understanding of the
pathogenesis of cardiogenie shock has had a pro·
found effect on the management of such patients.'
A critical re·examination of the present treatment
program of patients with cardiogenic shock there·
fore appears appropriate.
General care 1 •
Although there is little doubt that enviromnen·
tal and risk factors contribute to the incidence
and course of acute myocardial infarction and car·
diogenic shock, a discussion of the preventive as·
pects is beyond the scope of this review. '·• The
beneficial effect of resting the heart, via bed rest,
in part probably due to diminution in myocardial
oxygen oonsumption, has been appreciated for
some time.•- 11 Attention should be given to both
environmental temperature and humidity, for ex·
cesses have been shown to increase heart work
and, hence, myocardial oxygen consumption."'"
Early relief of pain is important and may par-
tially reverse hypotension in itself. Morphine sui·
fate: in li·mg. increments, or dihydromorphinone
hydrochloride (Dilaudid), 2 to 4 mg., injected in·
travenously over a two-minute period, is usually
efficacious. Among other actions, morphine sui·
fate blocks sympathetically medicated venous
constriction in the "capacitance bed" to reduce
preload, and all act to reverse pulmonary edema.
Blood pressure is not unduly affected by mor-
phine," and myocardial contractility is unal-
tered.,. Naw.ea and emesis may be minimi~ed
with the use of dimenhydrinate, 25 to 50 mg., or
hydroxyzine, 25 to 50 mg. Diazepam, 2 to 5 mg.,
intravenously may be the tranquilizer of choice,
since recent work suggests a positive inotropic
property of this agent.
Tachy- or bradyarrhythmias should "''"'ive
1886 New Yori< State Journal of Medieine I July 15.1973
prompt attention.!?-~> Arrhythmias may have a
profound deleterious effect on cardiac output and
coronary blood tlow. "'·" Although not completely
settled, lidocaine administration intravenously, 1
to 3 mg. per mmute after an initial bolus of 50 to
100 mg., has gained wide acceptance. 22-24 This
agent, which may also be administered intramus-
cularly!'·'• does not excessively depress myocar·
dial contractility, alter afterload, or elevate myo.
cardia! oxygen consumption slgnit"wantly when
used in low doses."'"' Procalnamide, quinidine,
and diphenylhydantoin, now used less frequently
in the acute tachyarrhythmi...,, may also depress
contractility to a greater extent than does lido·
caine, although simultaneously decreased after·
load may lessen the net effect of these agents on
cardiac index. 119 ' " All of these substances appear
to act by reducing the maximum rate of depolar·
ization of cardiac muscle. ao
Bretylium tosylate is a unique antiarrhythmic
agent because of its positive inotropic proper·
ty. 33' 34 lt decreases aiterload, an action due solely
to the release of norepinephrine from sympathetic
nerve endings. Although presently experimen-
tal," bretylium tosylate is most useful in treating
refractory ventricular arrhythmias. 36-3•
Arterial catheterization
The relative inaccuracy of blood·pressure mea·
surement with the cuff technique in patients with
cardiogenic shock is now aceepted. Peripheral
vasoconstriction renders cuff blood pressure lower
than true arterial pressure. When vasopresaor
drugs are used, this difference is ncL"E!ntuated.
When vasodilator drugs are employed, peripheral
blood flow may improve, and cuff pressure becomes
measurable, even though true arterial pressure
may fall. Therefore, insertion of a small catheter
into either the femoral or brachial artery, connect-
ed to a suitable transducer for direct recording of
pressures, is becoming routine in many centers.
Arterial samples for oxygen tension determinations
may be easily obtained; the catheter may also be
used for measurement of cizculation time and
cardiac output.'""'
Acid-base and electrolyte balance
Abnormalities in serum electrolyte activities
and their ratios may alter both the membrane po-
tentials of myocytes, their cable properties, and
contractility. An adverse effect on contractility
may be considered a true metabolic cardiomyopa-
thy. Alkalosis increaaes myocardial contractiii·
ty," while acidosis markedly diminishes contrac·
tility ." Possible mechanisms of these actions will
be discussed further. Changes in pH may also
alter the responses to cardio-active drugs and,
therefore, should be corrected forthwith.
Survival of patients with cardiogenic shock is
inversely proportional to the extent of lactic ad~
doois. During therapy, it is important to recog·
 nil:e that arterial pH may paradoxically fall due to
mobilizatkln of lactic acid from pooled blood in
peripheral areas. ••
Anemia and blood viscosity
A higher mean hematocrit in patient< with
acute myocardial infarction than in control
subjects w1111 (l.l'St noted by Burch and DePas-
quale.<>·•• In male patient< with "stress erythro-
cytosis," chronically contracted plasma volume
may cause the measured hematocrit to he higher
than expected. Such patients probably have a
higher incidence of myocardial infarction. The
prognosis of patients with higher or lower admis-
sion hematoerits and cardiogenic shock remains
unknown. Diagnostic phlebotomy may account
fot" a substantial fall in hematocrit levels during
the course of illness. •• Blood viscosity increases
with hematocrit, especially in the range 4S to 65.""
Perhaps equally as important, the pressure head
required to begin blood flow after it bu stopped,
known 1111 the yield shear stress, increases 115 the
third power of the hematocrit and square of the fi.
bri.nogen concentration. A reductkln in viscosity
incre1111es coronary blood flow.
Conversely, byperviscosity, fur example, 115 in
mac:roglobulinemia, may considerably reduce
coronary blood flow.
To decNase blood viscosity, infusions at 37•c.
of either albumin, 3.0 to 3.5 Gm. per 100 ml. in
saline, or of low molecular weight dextran may be
employed. Dextrans with molecular weights in
exc- of 60,000 AMU increase yield shear stress,
whereas dextrans with molecular weights much
less than 60,000 AMU are rapidly cleared by the
kidneys.
Reported mortality rates in acure myocardial
infarction are said to be reduced in patients treat-
ed with low molecular weight dextran. However,
whether the beneficial effect claimed is due to de-
cressed viscosity or incressed preload remains un-
proved.."
Anemia directly reduces the oxygen-carrying ca-
pacity of the blood, and correction of a red-cell
mass def.~eieney may improve myocardial oxygen
supply. Excessive infusion of erythrocytes, bow-
ever, may raise blood viscosity and, hence, reduce
coronary blood flow. Mild anemia may influence
the determinants of myocardial performance;
heart rare, preload, and contractility all inc.rease,
while afterload decreases. Net myocardial Ol(ygen
consumption is probably diminished, but this
question is debated." Further, the effects of ane-
mia on the performance of diseased myocardium
are even more unclear. For instance, when hemo-
globin is severely reduced below a critical level,
compensatory mechanisms may fail, and symp-
toms of congestive heart failure may appear. The
variation in such a critical level in patient.• with
scure myocardial infarction and cardiogenic shock
is unknown.
July 15. 1973 I New Vorl< Stat., Journal of Medicine
VarioU$ modes of treatment f()l' cr:trdwgelli.c shock
ond myocardial infarction tm: discus•ed in. this re-
port, which appeiJrs in two parts. Pllrt I d!!.U. with
general ctm: of patients su/{erl."'J from co.rdi<lgelli.c
shock, includi"'J agent. u.ed for early relkf of pain..
MOO<!s of treatment include arterial catheterization,
.ac•d· base and electrolyte b«l<mce, treatment for
anemia and altered blood uisc<NJity, numitori"'}
technique•, treatment for myocardial ond 8)18temk
hypoxio, ond oxygen therapy. Part li diacU88es
treatment through tlu! we of therapeutic Q~ents
and procedu.res. Cate<:JwJamiMs have recently
appetm:d as therapeutic agent. in tlu! treatment of
cardiagellic shock. The•e otJIIOI>Ctiue amities in-
clude isoprotereM~ dopamine, no"'pin.t:phrine, and
metaraminol. Digitalis acticn, glucagon, ond cor-
tic<14'teroids are <Jlao considered in. detaiL
Monitoring techniques
Myocardial perfurmanee may be adequately 115·
sessed by means of biplane cineangiography and
roentgen techniques,"-" which may provide semi·
continuous monitoring of ventricular dynamics ...
Since such methods are invasive and laborious,
recent attention bas focused on noninvasive evalu-
ation of left ventricular function, so using
radarkymograpby,"" scintillation counting,•• or ul-
trll50und.•2·64 While promising, these methods
are generally unavailable and, on a practical level,
either central venous pNSSure, pulmonary artery
end-diastolic pressu..., pulmonary "wedge" pres-
sure, or even left-ventricular end-diastolic pres-
sure are monitored.
In addition to a source for obtaining blood sam-
ples and administering drugs, the central venous
catheter permits continuous measurement of cen-
tral venous pNSSure, which bllll been regarded as a
useful guide to venous return and fluid replace-
ment...... Care must be taken to insure correct
placement of the catheter tip which should be
identified radiographically."' Respiratory varia-
tion in central venous pNSSure indicates an
intrathoracic location of the catheter tip; paten·
cy of the catheter is assumed if free blood with-
drawal is possible. Respiratory assist devices
must be disconnected befQN a reliable central ve·
nous pNSSure may be recorded. In the presence
of pulmonaey hypertension, chronic obstructive
lung disease, or pulmonary emboli, central venous
pressure values are expected to be higher than in
their absence.
Although most patients with cardiogenic shock
have an elevated central venous pressure, a con·
siderable number have inadequate relative intra-
vascular volumes. MoNover, peripheral venous
capacitance may be enlarged, rendering "effective
blood volume" inadequate... Decreased venous
return and relative hypovolemia are more fre-
quent in cardiogenic shock than is generally ap-
1$87

OIAS'1'0t..IC ~SCU: LENGTH OR
V(HTR!ClJUR E'-D"' DIA$TO!.JC VOl.UME
WALL
TENSION
~----~----~~~-.-<---~ Po
A. NORMAL
S. DEPRESSED HEART
C. INCREASED PRELOAD
0 POSITIVE INOTROPIC AGENT
FIGURE 1 iA) Effecr of tncreasmg preload
positive moJrople agent m c:ardtogenu:: shock,
on !ength~teruHon d•agram (5) Effect of
preload and usutg posibve inotropic agent.
on force~ve:Joclty diagram.
preciat<ld.•" 7" Under such circumstances, infusion
of fluids would evoke a favorable response .11
Accordingly, if the central venous pressure is
below 10 em. of water in a patient with cardiogen-
ic shock, intravascular volume should be expand-
ed with the administration of 100 mi. dexnan-40
over a ten-minute period. If the central venous
pressure increases more tban 5 ml., tbe infusion is
discontinued. If central venous pressure does not
exceed the control pressure by more than 1 em. of
water at the end of ten minutes. additional incre-
ments of 100 ml. dextran-40 should be infused
until the syndrome improves. central venous pres-
sure is above 16 to 18 em. of water of 1,600 mi. of
dextran-40 has been given (Fig. 1). Additional
fluids most be chosen and administered if compli-
cations involving fluid balance coexist. 1f central
venous pressure rises more than 5 em. during a
challenge, incremental phlebotomies should be in·
stituted.
As discussed in the section on hemodynamic al-
terations11 central venous pressure monitoring is
not ideaL When used primarily to judge intra-
vascular volume expansion. pulmonary edema
may be produced, since left atrial and pulmonary
venous pressures remain unknown. Last, central
venous pr-essure need not reflect variations in ef~
1888 New York State Journal of Medicine I July 15. 1973
fective blood volume. When used as an index of
left ventricular function, central venous pressure
~orrelates poorly with left ventricular end-diastol·
1c pressure and/or left ventricular end-dilllltoH<:
volume.72-79
The Swan-Ganz catheter can be floated into the
pulmonary artery and, with ~he cuff deflated, re-
cords pulmonary artery end-diastolic pressure. Jn.
A flation of the cuff occludes the pulmonary artery,
and pulmonary venous pressure is recorded. Pul-
monary artery end ·diastolic pressure or "wedge
pressure" may thus be monitored continuously.n
Although technically more demanding than cen·
tral venous pressure monitoring,,. the use of a
Swan-Ganz catheter appears sufrJCiently reward-
ing to justifY the additional effort.,. While the
static correlation between central venous pressure
and left ventricular end-diastolic pressure values
is indeed poor,"·'" when intravascular volume is
expanded, both variables tend to rise proportion-
ally. However, this is not true when pressors are
being administered.
Direct measurement of left ventricular end-dia·
stolic pressure through a catheter passed retro·
grade across the aortic valve has also been em-
ployed,•'·•• but unless a satisfactory wedge pres·
sure cannot be recorded, its value has been ques-
8 tioned. &'1- 87
and usmg Continuous measurement of pulmonary artery
1Uustrated end-diastolic pressure as an index of left ventricu-
mcreas;ng lar end-diastolic pressure has met with increasing
illustrated popularity. u.aa Clinical situations in which pul-
monary artery end-diastolic pressure fails to re·
fleet left ventricular end-diastolic pressure include
pulmonary vascular disease, right bundle branch
block, aortic regurgitation, mitral stenosis, pulmo-
nary venous obstruction, and left atrial pressure
lower than pulmonary capillazy "critical closing
pressure:··~ Specifically, in patients with isch-
emic heart disease, agreement between pulmonary
artery end -dilllltolic pressure and left ventricular
end-diastolic pressure, in the absence of the afore.
mentioned clinical entities, is reportedly best im-
mediately before the inscription of the "a" wave
on the left ventricular pressure tracing.'"'
Incremental fluid expansion may be undertak-
en, as described previously with the central ve-
nous catheter, for left ventricular filling pressures
less than 15 rom. Hg. When ventricular perfor-
mance is assessed by plotting a "conventional"
ventricular function curve, survivors of cardiogen~
ic shock usually respond favorably to low molecu-
lar weight dextran infusion (Fig. IA). Cardiac
index is increased more per change in pulmonazy
artery end-diastolic pressure or left ventricular
end-diastolic pressure than in nonsurvivors."' In-
creased cardiac output derived from moving the
patient "along" his ventricular function curve to a
more optional position rnay not be as costly in
terms of myocardial o.xygen consumption as other
methods of improving left ventricular perfor-
 I CMON.lftY 8LOOO FLOW
•
lll'OCAROIAt. ISCH£11fA/AftOXIA
• HYPOTENS!OII
AIIAEROB!t GLYCOlYSIS
• \
?UR~
T!IOPONIN SARCOPLASIIIC RETICULUM
PIIOTON COIIPETITION lHCREAS£11 AFFINITY
FOR co••&INOIIII SIT£$ FOR c.++
""/
DECRWEO ACTIVATOR Co+>
TO £FFECT CONTRACTION
•
CUli!CAL CONSEQUENCES
OF IIIPA!R£0 COIITIIACTlliTY
FiGURE 2. Acute reduction !n contractility from dt·
mir»shed cOtQnary blood flow probably due to mtracei-
h.dar acidosis. In turn, excess hydronium ion results m
competitiOn wlth calc•um for blnttin:g s•tes on tro,:x:mi-n.
Affinity of sarcoplasmic rettcu!um for caJclum may also
be reduced in actdie environment. Oimirushed activator
calcu.;~m ton reduces actomyosin siidi:ng and hence con-
tractility IS 1mpair-ed.
mance. If left ventricular end-diastolic pressure,
as measured directly or with the Swan-Ganz cath-
eter, exceede 20 mm. Hg, diuresis or phlebotomy
is indicated to reduce pulmonary venous pressure.
Overzealous use of potent diuretics may adversely
alter potassium balance acroes myocellular mem-
branes and contractility, and, hence, phlebotomy
may be preferable, especially if the patient is si-
multaneously receiving a short-acting digitalis
glycoside.»
Myocardial and systemic hypoxia
Advances in the understanding of pulmonary
physiology-<lxygen intake, transport, and periph-
eral delivery-have demanded that traditional
concepts of oxygen "replacement" therapy be
re-examined.>'- In addition, oxygen must also
be regarded as a pharmacologic agent, since oxygen
iteelf produces direct effects on several organ sys-
tems."' For example, oxygen may cause arterial
constriction to raise blood pressure..,·"
As previously mentioned, myocellular hypoxia,
secondary to diminished coronary blood flow, is
the event from which all sequelae of cardiogenic
shock arise (Fig. 2}. 100 _,.,.
Biochemically, intracellular accumulation of
hydronium ion may increase the affinity of sarco-
plasmic reticulum for calcium ion and may com-
pete for calcium-binding sites on troponin, the
calcium receptor protein of actomyosin, Since
myocardial contractility directly depends on local
Jutv 15, 1973
MYOCARO!AL PULIIOHARY
(NECROSIS\ (COII.PLICATION\
MYOCARDIAL 'ARTERIAL
JIA\. c~~~
ICORONAII!/" METABOLIC/
FJGURE 3.
BLOOD
FLOW
CONSEQUENCES
"Vtcious cycles" of cardiogenfc shock.
Myocellular hypoxia impairs left ventricular perfor.
m.arn::e and affects pulmonary function. Oxygenation
disturbed m lung, thus ~owerlng arterial oxygen content
to cbrectly decrease oxygen available to myocardium.
calcium ion activity surrounding actomyosin,'""
deprivation of calcium from the contractile fila-
ments, caused by intracellular acidosis, ultimately
reduces contractile strength.
In addit:ion to myocardial hypoxia, distal to cor·
onary occlusion, systemic hypoxia, (whether re-
sulting from pulmonary complications of cardi-
ogenic shock or another etiologic cause) adversely
influences all organ systems including the myocar-
dium.''"' Thus, a "vicious cycle" may be encoun-
tered (Fig. 3), Further, myocardial hypoll:ia may
cause intracellular potassium loss, with attendant
changes in membrane potential and excitability,'""
Finally, the response to such commonly used posi-
tive inotropic agents as the digitalis glycosides
and pressors may he significantly depressed in the
hypoxic heart. 1011
Clinical hypoxia is a common finding in pa-
tients with acute myocardial infarction and is
even more striking in cardiogenic shock.9s..ur.-ns
The decrease in arterial oxygen tension is in·
versely proportional to the elevation in left ven·
tricular filling pressure.'"-"· 11 • In addition, the
extent of arterial oxygen tension deficiency is pro-
portional to infarct size, since the alveolar-arterial
O$ygen tension difference is directly related to ere·
atine phoaphokinase levels. H 6
Three mechanisms have been proposed to ex-
I New York State Journal of Medicine 1889

"''
:
/ ..•
.. '
"" .-.-·~
car, nt/00mqJ.fll!(!
FIGURE 5. \Al In carrnogenic shock. correlation between myocardial oxygen consumption !MVO:t) and coronary
blood flow iCBFJ •• poor. IBI Myocardial oxygen extraction. IA·CS) Q,. i• clos.,ly related to myocardial oxygen con-
$u.mptu::m {MV02'} m shock tonowmg myocarchal mfarction. 11'
plain the hypoxia of cardiogenic shock: ventila-
tion-perfusion imbalance, true venoarterial shunt-
ing, and diffusion abnormalities. Venoarterial
shunting appears quantitatively more important
than the other mechanisms and may be estimated
clinically during 100 per cent oxygen breath-
ing.'w.m Under such conditions, the alveolar-ar-
terial oxygen difference reflects nonventilation of
perfused alveoli.
Arterial carbon dioxide tension following acute
myocardial infarction is frequently normal or de-
creased, arguing against alveolar hypoventilation
as a cause of the hypoxia.'" Wide differences he-
tween alveolar·arterial carbon dioxide tensions in
cardiogenic shock imply persistent ventilation of
nonperfused units, resulting in alveolar dead
space. no The relative importance of abnormal
diffusion in cardiogenic shock remains unsettled.
but when the formal shock-lung syndrome super-
venes, abnormal diffusion is undoubtedly signifi-
cantly decreased.
Normally, myocardial oxygen extraction, or ar-
terial~coronary sinus oxygen difference, increases
as arterial oxygen content increases (Fig.
4).'"'·"' "" In addition, under physiologic cir-
cumstances, elevated myocardial oxygen con-
sumption i£ met by variation in coronary blood
flow rather than by differences in myocardial oxy-
gen extraction. As mentioned previously. coro·
nary blood flow is probably fixed and low m card•-
og<mic shock. Therefore. it is not surprising that
the correlation between myocardial oxygen con·
sumption and coronary blood flow. while good in
normotensive patients, is poor in patients w.ith
cardiogenic shock (Fig. SA).'" However, artetlal-
coronary sinus-oxygen tension difference may be
notably correlated with myocardial oxygen con-
sumption in cardiogenic shock {Fig. 5B). '"'
Oxygen therapy
The administration of 100 per cent oxygen by
nasal catheter at 5 to 6 L. per minute flow rate to
patients with acute myocardial infarction is wid-e-
1890 New York State Journal of Medicine
ttv-:;,t, lfiiJJ\'X'.vl!!YI
!<h ~~~.
•2j
~·I
!
..
I
·:
,, h• ~ ?!io
'1
I
.. ~·19'·. 0.411
,, 81 "< 00' •! f<.~4 p~().
00 100 •? •6 fj l2 It)
b A (A·CSJo1 , ~'~~~'lOOm o- S
ly practiced. Moderate rises in arterial oxygen
tension may effect incr<l)ased oxygen delivery to
the ischemic zone surrounding a myocardial in-
farction."" Moreover, 100 per cent oxygen
breathing may benefit myocardial ischemia by
elevating coronary arterial oxygen tension, reduc·
ing myocardial o~ygen tension, and reducing myo-
cardial oxygen consumption, 123• 1« although the
latter issue is far from settled.'" Unfortunately,
however, because of tbe extent of arteriovenous
shunting in patients with cardiogenic shock, ac·
ceptable arterial oxygen-tension values may not
be attainable with oxygen delivered by nasal cath-
eter alone.
For these reasons, most patients with cardl-
ogenic shock should be intubated and receive as-
sisted ventilation if the arterial o>Cygen tension
cannot b!? maintained well above 70 mm. Hg
using a catheter or mask alone. A volume-cycled
respirator is preferable to a pressure-cycled ma-
chine, since pulmonary compliance is frequently
decreased, and airway resistance is increased.
lJse of a volume-cycled respirator may insure
against atelectasis, prevent pulmonary edema, de-
crease pulmonary blood volume, permit access to
the bronchi for suctioning, and decrease the work
of breathing.
Continuous positive-pressure breathing has
been advocated for use in patients with the
"shock ~ung'f syndrome. since alveo)aT collapse
may be prevented by raising expiratory pressures.
lJnless pulmonary compliance is significantly re-
ducedt however, large inc·reases in transthoracic
pressure may decrease preload and, hence, com-
promise cardiac output.llt'J
There is a serial improvement in arterial oxyge-
nation during recovery from cardiogenic shock
(Fig. 6). The arterial-alveolar oxygen gradient
dec.reases, reflecting reduced arteriovenous shunt·
ing of blood. A sharp difference between arterial-
oxygen tension during ambient air and 100 per
cent oxygen breathing will he noted.
Hyperbarlc oxyge-n therapy is used in some cen~
ters to overcome the pulmonary complications
1 July 15. 1973
 600
""e"'e
\ 6th <d. New York, McGraw Hill. 1970, p. 1221.
\
500 \ 3. Weil, M. H, end Shubin, H.: Diagnasis and Tre<rt·
\ ment of Shock, Baltimore, The Williams Md Wi!ki~· n,
~ \
0
..... 400 '' \
a:: \ 5. ShiUi'l!lfool. J. P.: Power falhn of the heart in
:::>
',
"'"'""
g:
300
.....
""
>=
zoo
"'jf 100
0 9. llur<:h, G. E .• and O.Posquale, N. P.: On
TIME 2:
CLINICAL Card•o<J••ie PulmoMry M•ld NoCHf
STAT£ Shock Edemc CHf
FiGURE tl Serial improvement in arterial·oxvgen ten-
sions and alveotaNJrterial oxygen gradient foUows ctiru~
cat recovery after complicated myocard1at infarction_ t:s
previously discussed. ""Hz> After experimental
coronary occlusion in laboratory animals, hyper·
baric oxygen reportedly protected against ventric·
ular fibrillation and may have reduced infarct
si:re.'"'- 127 Excess myooardial lactate production
may have also been revecsed, presumably reflect·
ing improved myocardial oxygenation. ' 28 On the
other hand, other investigators failed to show a
decrease in infarct size nor any beneficial effect on
myocardial oxygen balance with the use of hyper-
baric ozygenation.'""''"' ln addition to the re-
ported conflicting data deriW!d from laboratory
animal work, available clinical data in man do not
permit a conclusion concerning the efficacy of
hyperbaric oxygen therapy.
Recent reports of oxygen toxicity in man have
caused concern about oxygen therapy fullowing
myocardial infarction .., In critically ill patients,
increased arteriovenous shunting may protect
against oX)Igen toxicity."' At conventional pres-
sures of 760 rom. Hg, 100 per cent oxygen via vol·
ume-cycled respiratol'S should not be withheld for
fear of oxygen toxicity.'" The subject of oxygen
toxicity has recently been reviewed in detail else·
where.l» Of specific interest, however. are re·
ports that oxygen therapy adversely affects lactate
metabolism in man. •:w is negatively inotropic. {ii:>
and fails to increase intramyocardial oxygen ten·
sion measured directly.'"' Based on the latter ob-
servation, it has been suggested that oxygen may
reduce myocardial capillarity, which, if confirmed,
is of far-reaching significance.
Pound Ridge, New Y()rk 10576
References
L J{.:),tWs, R J,: Pathogenesis of cardiogenic shock,
New York State J. Med" 73; 1662 <Junt' 15!·, 73; 1793 {,iu!y 1)
19iS.
2. a-. ,R: ls<bem~ heart diaeaae. in Wintrobe, M.
M., et ol., Eds.: Harrison • Principles of Intemal Medicine
'
!967. - ~..
4. Thai. A. P., et <U.: Shock, Chicago The Yeor Book
Medical Publi.U...., 1971. '
acute: my~ial infs.rctiun: mechanisms and management
',, Card1ov...,, ChniCil h 155(191!9).
6. Kuhn, L. A.: Changing treatment of shook followillf
'
----
'"' ........ A"'O GRA01ENT
~~
'•.
acute tnY«ardial i:nfan:ti.on. a critical evaluation Am J Qu-.
dioUII! 757 (1967).
7. Carver, S. T.: Eooioay of coronary heart ~-
New York StateJ. Mlld.71: 1065 !.M•r 15) 1971.
' . .
ll. Katz,_ L. N.: H .. knowledge of atber,..lerooio ad·
'
ROOIII AIR
vanced _suirKle1:1.dy to warrant it& app!icatkm to a pl'$Ctlc.al
preventton ProgrAm? The 1970 G. L)'n:tiUl Duff M~ntorial
~ture, Coundl on Atffll.rosclerosis, CU'CUlation U: 1 {Apr.)
1972.
hum"" heart, Am. Hem J. 71: 422 (19<;6),
,..,ingthe
5 4 1\l. Bureb. G. E., Walah, J. J., and Black, W. C.: Value
of proloned bed: 'ffl$t ln managentent Q{ cardiom•.raly.
J.A.M.A. f83: 8! (191>3).
U. Dub. M.: Bed rest in aeuw myocardial in!aroti,;m:
a study <>i physician prll<ltiC<!II, Am. a..llrt J. 8~: 486 (Oct.)
!971.
_ 12.. Ansari, A,, and Bu.reb, G. E.: CUmatie factan in
ll«:bemlc heart d......,, South. M. J. 62: S79 (1969).
13. Butch, G. E., and Giles1 '!'. D.: The bu:rden of a hot
and bu!Did environment on the neart, Mod. Concepts Card\Q...
..... n... u: as (1970).
t4. &t.aniemi, E.: Environments.! temperature and the
incidence of m)f<>C8tdial inforotinn, Am. a...rt J. 82: 723
(0...) 111'11.
15, Mille-t, R, L .• et tzl.~ The ~ective t::hanges in region·
al blood~ produet>d by morphine, Clin. !los. 18: 34,1 (1970).
16, Zehs. R., et al.: The inotropic and peripheral drcU·
t.~tot:Y eff~tsofmmphi.Min man, ibid. 18: ass {1:170).
17. Rotman, M.. Wagner, G. S., and Wallace. A.
G.: Bra<lyarJ'bithmi.. ln '""'"' my<>m~zdial infaretion, Circu·
lation 4$: 703 (Mar.) 1!!72.
18. KapHnaky, E.. Yahini, J, H,~ 4nd Neufeld. H.
N.: On the mechan.Utm oC sustained ventri-cular arrhythmias
asaociated with S(;ute myocaniial infarction, Cardiovasc. Res..
6: 135 (Mar.) 1!!72.
19. De&ncti&, R. W., Block_, P., and Hutter, A. M .•
Jr,: Tachyatthythm:ins in myocardial infarction, Cireula.tion
411: 681 !Mar.) ll!72.
20-. Senehim.ot A.. et al.; Phasic eoronM')f arterial flow
velocity during atrb.ythmias in :m.an. Am. J, Catdiol. 39: 604
(May) 1972.
2L Kuhn, L. A.: A~ift management of cardiac arw
rhythroias in acute m)f«ardial infarction, in Ru&&ek, H. I.,
and Zobman, B. L., Eda.: CO!"()ll8.cy Heart Disewse, Philadet-
phio,J. B. Lippincott, 1971. p, 395.
'2'2. Chopra, M. P,, et <U.; Lignocaine therapy fOl" ventric·
ular ectopic activity after acute m)'Q(:aniial infarction: a dou·
bl•·blind trial, Brit. M. J. 3:688 (Sept.) 1971.
23. Tho"""'"· P. D.• Rowland, M .. and Melmo.n, K. L.:
The influence of heart failure, livet dl.&ease, and renal failure
on the disposition of lidocaine in man, Am. Heart. J. 82: 411
(S.pt.) 197!.
24. Pitt, A., Lipp. H., and Audersont S. T.: ~ocaine
given prophyiactieally to patienb with acute myocardial in·
Uu'ct\fin, Lanl.'let h812(Mu,) 1971.
25. BeHet. S., et Q/..~ Intramuacular lidocaine in the ther-
apy of ventricular arrhythmias, Am. J. Catdio!. 27: 2'9i (Mar.}
!971.
26. Bernstein, V.• et al.: Lid(.!Caine intramuscularly in
ac-u~ myocardial :infarction, J.A.M.A. 2:1t: 1021 (Feb. 21}
1972.
27. Nayler, W. G.• et at.: Effect of lignocaine on myocar~
dial functkm, high energy pho&phate stores, and ()Xygen con-
l Westchester Avenue sumption: compariSOn with propranolol, Am. Heart J. 78: 338
(1969).
28. Rahimtoola, S. H .• et al.: Lidocaine infusion in acute
myocardial inf~xeti<m. Eff:eea on left Vi:!ntricuiar functioo,
Arch. Int. Med. l2fl: 416 (Sept.) 1971.
29. Nuyler. W. G., et aL Some effects of dipbenylhy~
de.ntoin and ptQPran<>IDt on the cardiovascular system, Am.
H.tart J. 75: S3 ( 1968).
July 15, 1973 I New Yori< StateJoumal of Medicine 1891
 SO, Dreifus. L. S., and Watana.be, Y.: Curtt:nt statu.4; of
diphenylhydantoin. ibid. 80: 700: { 1970),
3l. Puri, P. S.: The effect of diphenylhydantoin ~ium
(Dil~ntin) on myocardia.t t»ntractthty and hemodynamws,
ibid. 82:62 (July) 197L
32. Singh, B. N., and Williams, E. M.; Effect of altering
potassium concentration on th~ acticn of !itkx:-aine and diphe-·
nylhydantoin on rtlbbit atrial and v~ntrkutar mu$Cie-, Cir<:uia-
tion Re-s;. 29~ 286 tSept.) 1971.
33. Cooper, J. A., and Frieden, J.; B~yhum tCffyl:ate,
Am. HeartJ. 82; 703 {:-.iov.} l97L
34. Marki£. J. E.. and Koch-Weser, J.: Charactertstic~>
and mechanism of inotropic and chronotropic actions of brety·
hum tos.vlate, ,l Pharmacoi. & Expet. Therap. 118: 94 {July}
!971.
35. Allen. J. D.. et aL: The effects of bmylium on ex·
p:erimental cardiac dysrhythmia;;, Am. J. CardioL 29: 04I
(May} 1972.
36. Siggff, J. T"' and Jaffe. C, C.; The eff~et of bretyl-
ium tosylatt an the electropbysiologic: properta:s of ventricuhtr
musde and Purkinj~ fibers, ibid. 21:82 tJan.) 197L
37. Day, H. W.. and Bacani:-", M.: Use of bretyHum tos~
y{ate in the managem:ettt of acute myocardial J:nfa:rltion, obid.
27: 171 (Feb.J 197L
38. Romhlit, D. W., et aL Evaluation .()( bretytlum to~'"
y!ate fQf' the treatment or premature \'Cntricuiar cont.rac!J()ns.,
Cittuiation 45: 800 (Apr.} l972.
39. Bernsttin, J. G .• and Koch~Wescr, J.: Effectiveness
or bretylium tosyiate agaim>t refractory vent;.\t;ular Atthyth·
mias, ibid. 45: 1024 (May) 1972.
40. Weit M. H., l}nd Sh~lbin. H.: Symposium un shock
and sync<t):*. introduction and general ~oncepts. Am. J. Car-
diel, 26:: 55:}! 1970/.
41. Weii. M. H, and Shubin, H.: Cardiogenic shock:
pathogeru:-sis and. rationalt' of therapy, Cardiovasc, Clinics b
165 I !91>9).
42. Lorkovi~. H,: tnfluence of changes in pH on the me·
chankal act:vity of cardiac muscle, Circulation Res. lt: 71 1
{[966).
4:'\.S;e-geL .J. H .. o>l al. · A rn<>thod of quantifym~ ~he n~ed
for surgical therapy in chnical myvc:a:rdial lnfarctltm shoek.
Am. J. Cardia!. 29: 292 (Feb.} 1972. {Comments. Am. Coll~i!:~
CardioL, ~1st Annual Se:ss-lon, Chicag<t, Mar. 3, 19n}.
44. Don Michael, T. A., et al.: ld.:ntificatkm of chnkal
subsets in cardiopnic shock, ibid. 29: 280 1972,
45. Clancv. R L., et at.: influeuce of sodium bh::arbonate
o:t myocardial performance. Am ..J. Phy!>1ol. :.!12! 9t7 ~ 1967L
46. Sriussadaporn. S .. and Cohn, J. ~,: Lactate m:etabo·
bsm m dimcal and experim~ntal s.hock, C!.io. Res. IS: 519
09681
47. Burch. G E , and DePMqua!e. :-..;: P The hemato-·
crit in pac.(mts wlth myocarrlnl mfarcuon, J A M A 180! 63
{1962).
48. OePa:squah~:, St. P., and Burch. G. E.: Hematocn1 in
women w1tb m-..·ocardial infarction, 1btd. 183-: 142 {i96Jl.
4'9. Hershherg, P. L Wells, R E., and McGanrly, K B.:
Hematocrit and PrognO:Si$. in patients with acute myocardi-al
infarction, tbid. 2lt: 8$ (Feb. i4J l972:.
50. Rubinow, S. L, and KeUer, J. B.: J:o1ow of a vi.soous
fluid through an elasti<:: tube with ~pplic.ations to blood fl:<:~w,
J_ Thoor. BioL 3$; 299 (May .I 19?::.t
51. Langs;oen, P. H., et at: Observationf, Itt treatment
of aeutt.' myocardial Infarction u.-·ith lnw mclleeuhu wmght dex·
tran, Angioiogv U: 465 (196-I;}.
52. Vtu•at: M.A., Adolph, R J .. and Fowler,~. 0 :_ Car:
dlnvascular 'Jffecn of a~mia, Am. Heart J. 83: 415 {Mar./
19i:!.
53. Ross J. Jr.: The at\Sessment nf myocardial perfor·
mance in m3n by hemodynamtc and tinean;glog:raphic tech·
nics, Am. J. Cardif!t 23: 511 {19691.
M. Dodge-. H. T .. and Baxley. W. A.: l...eft vent-ricular
volume and mass and their sigmftca:nce in heart di!!>ease, 1ind
23, szs 09691.
55. Kong, Y., Morri~ J, J_, Jr,, and Mclntooh, H. 0.:
Assessment of regi<mal my()Cardln~ performance fmm h~plane
eor-oruu)' dneang:iograms, iind. 27! 529 (Mayj 1911.
56. Bov~. A, k: Radiographic JtVJJ'iuatton of dynami.c ge--
ometry of the ldt ventricle, J. Appl. PhysioL 31: 221 IAur;:.)
1971.
57. MaN:'us, M. L.. ~t ai.: An amomatf'd methnd for lhe
mcasuremt-nt ot v(>ntncular ~·o!ume, Ctrculation 45: f)."> lchm 1
19:72:.
58 Ha\~th<Hn€, E. W,, Hunter. F S., and Walker, L ·
1892 New York State Jo\irnal of Med1cine 1 July 15, 1973
Use of continu-o-usly monitored left ventricular dimemKmal
changes in evaluating ventricular dynamics. Cardiovaac. Res.
l•upp. 3) 4: 36 (1970),
59'. Sonnenblick, E. H.: Non-invasive evaluation of re-
gio-nal vtntrkular dysfunction, Ne:w England J. Med. 285:: 114
(July l!) 197L
60, ~auu~ias, T. ~·· et al.: Detection of left ~tricular
waH motmn dit'Orden~ m coronary artery dJsea'Se by radarky-
mogra_phy. Lbtd 2.85: t;3 {JulyS} 1971.
tL ls.hii, Y,, and Macintyre, W. J.: Measurement of
heart chamber volQmes by analysis of dilution eurvel.i simulta~
neoualy recorded by scintiHatlon catn£-ra, Circulation 44: 37
!Julyll97L
62. Horwitz, [., D,. and Bishop, V. S,: Left ventricular
preswre-dimE'nsion relationships m the conscious dog, Cardio-·
vase. Res. 6: !63 {Mar.) 1972:.
63. Troy. B. L.. Pombo, J., and Rackley, C. E.' Mea,
s.uremem of ~e(t ventncuhu watl th.icknes6 and mass by
echocardtugraphy, Ciret.dation 45: 6021Mar.) 1972.
64, Kootcke, L. L., et al.: Echoca:rdi-ographk l:Wi.es$tnent
of left ventricular diastoHc pressure. Ann. Int. M.ed. 1$: 865
(May} 1972.
65. Cohn, .J. N.; M-onit.urlng-wchniques in shock, Am .•L
CardtoL at;, 565! 1970),
66. CoHius, J, V., ttt of.: Central venous pressure in
acutt> myocardial iofaretion, Lancet t; 373 (Feb.} lSiL
67, Thomas. T. V. ~ Loc-ation Qf catheter Up and its im.·
pact on <t:ntral ~nOll$ pre>s!Jre, Che$t 61: 668 (June) 1972.
68. Weil. M. H,, and Shubin, H.: Changet~ in v¢nous ea-
ptu:::ttance during cardiogenK: shock; a search for the third di·
fuemnon, Am. J, Cardiot 26:613 (1970L
00. Alten, H. M,, Danz-ig, R., and Swan, H. J. C.: Inei·
dence and signMieance of relativ~ hypovolemia as a -cause of
shock associated wlth acute myocardial infatctron, Circulation
\supp. 2) 36' 50 I !967).
f1J Shuhin, H., and Wei!, M. H.: Cardiovascular, meta·
bolic and blood volume observ,atiu:ns in myoc.atdil'tl infMction
and shock. Cardiovasc. Res. {s.upp. 3) 4~ 285 {1970).
71. Coltart, D. J., and Hamer, J,: Response to rapid
lrd'usinn ot diuresis. :in acute cardiac infarction, BriL Heart J.
33~ 72 {Jard t97L
72. Kones, R J., and Phillips, J. H,: Ne~'.E!r inotropic
agents tOr card'iQgenic sho-ck, South. M. J. 65: 329 tMar.} 1972.
'73. Ganz, W. W., et a.L A new flow~direct~d catheter
technique for me-asurement of pulmonary artery and capillary
wedge pressure without fluoroscopy, Am. J. Catdiol. 2$: 96
{1970).
74. .Las.sers. B. W .• et al.: Left v~ntriculat failure In
acutf' myocardial infarction. ibid. 25: SI 1 (1.970),
75. Cohn, J. N .• Tristan!, F, E., and Khatri, L M.:
StudleR In dinkal shock and hypotension. VI. Relationship
hetween left and right ventricular function. J. Clin. Invest. 48:
:1008 !2969)
76. Forrester, J. S., Diamond. G., McHugh, T. J., and
Swan, H. J, ~ Fining pressure in the right and ieft .sides of the
heart in acute myocardial infarction. A reappraisal of e~n­
tral·vtnOU$-pressure monitoring, New England J. Med. 285:
1!\0 (July 2'2) 197L
17. Swan, H. J., t>t aL: Catheteriutioo of the heart in
man with use of a flow-directed balloon-tipped catheter, ibid.
283: 447 (lg70L
18. Forr-ester, J., et at.: Right and left heart pres~uru in
the acutely Bl patient. Clin. Res, 18: 306 {1970),
79. Herbert, W. H.: Limitations of pulmonary artery
<.•nd--dl$loUc pressurn; as the reflection d left ventricular
tonrl-diastolic pressure, New York State J" Med. 72: 229 (Jan.
15! 1972.
.00 Gold, H, K., LcinbiJi;;h, R. C., and Dunkman, W. B.:
Wedg-e presl'l<l.lte monitoring in my~ardial infarction, New
EnglandJ. Med. 28.5:230 (July 22) 1971,
SL Hamosh, P., and Cohn, J. N.: Left ventricular func·
tion in acut.e myocardial infarction. J. Clin. Invest. SO:; 523
Hv1ar.) lfnL
82. R.usseH, R 0., ,Jr .. et at.: Quantitative d:ultacteriza-
tion of left ventr1cut.ar function in ac<,IU myocardial infar-ction,
C!in. Res. Ui: 327 ( 1970).
83. Parmley, W. W., e-t aL: Clinical evaluation of left
ventrku!ar pressures in myocardial infarctiOn, Circulation 45-:
;~;;.s {Feb.} 1972.
84 Diamond., G .• et at.: Ca.thet('tiz:ation of the left ven·
!nc!e in acutely iH patitmW.J?~it. Heart~· 33~ 489 \July) .1971.
81). Bhubm, i:L and Wetl. M, H.. Hemodynam1c aiter·
actiQnS w patients after mvocardiallnfarction, m !\i:iHs, L. C.,
an-d: Ma-yer. J. H., Ed.s.: Sh<ock and Hypotension: Puthog~n·
esla and Treatment. a Hahltemann Sympo&ium, New York,
Grune and Stl'lltton, 1965. p. 499.
86. Braunwald, E,: Topics in clinical .medi<:ine: the
pat~n§is and tl'Q.tment of shock in myocardial infarction,
Jolmsll<>Pkina M. J. ttl: <121 11967!.
~- Ayre>, S. M .. and Groc<>r:y. J. J.: Cotdiology: A
CHnicopbyslologie App.l"'B.Ch,. N~w York, Appleton-Century¥
Crofts, 1971, p. 252.
8lt Rotman1 M.. Oavi<:l&on, R. M.. and Hawley, J.: Pul-
monary arttry (liastoJ:ic pttl'118Ute in acute myocardial tnfarc~
tion. Ann.lnt. Med. ?&: 867 (May) 1972.
89, Bal...,, R., Bonnett, E. D.. and Sowt<m, G. E.:
Com~n of pulm<>nary arte:y diastolic and left ventricu·
)a.r and diastolic p_tesaUTt$ in 1)4tiente: with iscMmic heart di&·
..... cotdlov...,.l!es. 6: l72(Mar.l1972.
90, Ratshin, R. A.. IIAckl<)', C. E .. and Rtl$1iol, R. 0., J<.:
Hemodynamic evaluation of Jeft ventricular function in shock
compli.<:ating: myocardia! infarction.. Cin:::ulati<m 4$: 127 {Jan,)
1972.
9L Seller~ R H .• et ai.: The myocardial effect of diuretM:
drugo, Clin. Reo. 13: 669 (1970).
92. Finch. C. A.• and Ltniant, C.: Oxygen transport in
man, New England J. Med. 336: 400 {F<>b. 2<1) 1972.
93. Pilper, J.~ and Scheid, P.: Re&pitatlon: alveolar gu
exchanp, Ann. Rev. Physiol. 33: 131 (1971).
94. Mitchell, J. H., and Blom.qvia~, G.: Muimal o<y&en
upt,Oke, New Eru:land J. Med.ll84: 1018 (May) 1971.
95. We&t, J. B.: Reapiration, Arm. Rev. Pby$iol. 34: 91
(1972).
96. s.idel, G. M., Militano, T. C., and Cbeawr, E. H.:
M,..._halance model of pul""""'-"J' OXY&<n transport, IEEE
TrMS. Biomed. Eng. lt: 205 (May) 1972.
97. camer, 0., Walker, J. R .. and Guytnn. A. C.: The
role of oxypn in autoregU)&tion o£ bl-ood llow in i&olated v~...
oels, Am. J. Pb)'lliol. 206: 951 !1964).
96. K~r&. S. K.; Ox:.Ypn in ischemit beart disease,
Am. H_..Ll2: 269(AU(.) 1.97!.
99. Tbnmaa. M .. Malmerona, R .. and Shillin&ford, J.:
Hemodynamic effects of oxygen in patients with acute myo-.
cordial iofarctina, Brit. HeartJ.'J:T: 4(>1 (1965).
100. Kat•, A.M., and Hecht, H. H.: The early "pump"
C•llureofthe is<hemicbeart, Am. J. Med. 41:497 (1969).
101. K•tz, A.M.: Contractile proteim of the heart, Phys-
iol. Rev. SO: S3 !197<.\).
102. Katz, A. M.; Effects of interrupted coronary flow
upon myoclU'dial metabolism •ud rontractillty, Progr. Cardio-
v...,, Dis. 10: 450 il669l.
103. Cdem: Effect& of ischemia and hyp<»;ia uPQn the
my()(;Ald\u.m, in Ru:ssek, H. l., and Zohm.an, B. L., Ed&.: Cor·
nnary Heart Disease, Philadelphia, J. B. Lippinoot.t, 1971, p.
411.104 Nakhjava.n, F. K, ~ al..; Effect& Qt ··--·
nr..,......l3, reoxyge-
nati®, and tempet9tun on cat papill4f:Y muscl~. Am.. J.
Ph)'lliol. :120: 1289(Mayl 1971.
105 Wi.Uehr~cb A. F., and VanderVeen, K. J.: tnnu-
enu Or substrate on' oxygen consu.mptic)n of Wo.lated perfused
... heart, ibid. 21%: 1529 (l9il'1). . eutation Res. lf: 499 (1965-) .
100. KonH, R. J.: The molecular and ionic baaw fot at~
tered myocan.Hal «:~ntrac:tility, Res. Commun. CM.m. Path.
Pbarmaoot (•upp. l) li: l \M.,,) 1973.
1\)7, Freed, s. C., and Meunier, A. M.: Effect of. hypntla
ona.tterial mWIClet<mo, Alljliology23: 1 (Jon.) !972.
108. Syhem, H. D., Helmer, P. R., and Murphy, Q. R.:
Eff«t4 of hypo:tia on myooardi& potasstum balance, Am. J.
Phy•iol. :120: 2047 (June)197l. . . . England J. Med.ll83: 1473 {1970).
109. Kent, K. M., et o.J..; lnotro:p.~;C ~ents .tn by~w cat
,myocardium: depression and pot.enttatwn. CU'(:Watton ~-
;It! l96(l'•b.) 1972. J 1971.
1Ht Ayres., S. M., et al.: Tbe lung: in $h<;ek, Am. . Car~
dial. 2$: 588 {1970). nr>.. R. H
llL Borden., Cr W., Ellett,, R. v_., !J.nd. nlUMJn., .:
A.no:~.la in tn)'OC.ardial ltlfarctwn: irubeati.G:M f.or osygen
therapy J.A.M.A. 148: 1370(1954).
112. 'Vitale, A., Dumke, P.R., and Comroe, J. H.;. 4ck of
correlation between rales and arterial oz:ypn sa.t~auon. m pa-
tients with pulmonary congestion and edema. Ctt(ulattan 10:
July 15.1973 i New York StateJoumal of Medicine
81 (1964).
11-3. MacKenzie, G. J., et al.: Cir<::ularoty and respiratory
studies in myocardial infarction and ca.rdiogenic shock, Lancet
2: 820 !1964).
114. l(ey!oun, V. E., Ayre>, S. M .. and Gr11ee, W. J.:
HypoXemia in acute myoe;;rdial infarction, Clin, Re$, l$; 450
(1867).
ll5. Fillm...., S. J.1 et al.: Blood-g.. chang.. and pul!l><l-
nary heroodynam.ics tOUowing acute myocardial infaredt;n,
Circulation 45: 583 (Mar.) 1972.
116. Hardy, W., et <xl.: Canxes of hypo>em!o and alk·
aiemia in acute myoca:tdial infu<:tion. ibUL (supp. 6) 38: 94
(1!168).
!!7. Fillmore, S. J., Shapir<>, M .. and Killip, T.: ~risl
oa.ygen tension in acute myOCArdial infarction; serial ana~ysi:s
ol clinical £tate and blood g.. ehang... 1\m. Heart J. 79: 620
(1970).
118. Mue:U•r. H. $.., et rd.: Hemodynamics. coronary
blood flow .00 myoceudial metaboli&m in eoronary sbock, J.
Clin.lnveot. 4$: 1!185 {!970).
119. Mueller, H., et aL: Effect of ieop,.....,ol, 1·"""'1>1·
nephrine, and intraaortic oounte:rpulsation on hemodynanncs
and myocardial ~etaboli.sm in shock !oikrwing acute myocar~
diallofar<tion, Circulation 45: 335 (Feb.) 1972.
120. Ayn:s, S. M., and Gregory, J. J.: Cardio!<JJ)': A
CJinicophys:iQlogie Approach. New York, Appleton~Century·
Cro!bi, 1971, p. 139.
121. Mueller, H .• et aL: Canliac pe:rfmDl.Anee and metab.-
otism in shock d\le to- .acute n:lyocardial infarction in man: re-
sponee to eatecholaminea and mechanical cardUJe assist,
Tums. N.Y. Aead.Se.M: 309!Apr.)l972.
122. Asbbangh, D. G., et aL Continuo® .J)O$itive preuure
breathing (CPPB) in adult respiraW.ry distress syndrome, J,
Thonlc. Cordiovasc. Suzc. 57: 33 (1969).
123, Smith. G., and l..aW$0n, {). A.: Experimental C(}J'(}--
nary arterial occlusion; e-ffeeta oft~ .ed:m.inistratlon of oxy-
gen under p,...ure, Scm~i$h M. J. 3: 346(1958).
124. Idem/ The protective effect (}{ o:xygen at tW\.1 atrno-.-
apherea pn~Mtrre in acu~ coronary occlusion, Surg. Gynctc. &
Obst. 114: 320 (1962).
125. Thurston, J. G.: A wntroUed trial of hyperbaric oxy·
pn in acl.ltt' myocardial infarction, Circulation (supp. 3) 40:
203 (1969).
126. Cbardack, W. M., et al.: &ductioo by hyperbaric
oz:y~ation cf th~ mortality from ventricular fibrillation fol-
lowing ~ artery ligation, Circulation Res. 15; 49'1
(1964).
127. Tra·pp, W. G., and CnJ:}&hton, R.: Experimental
atudt. of increued atmQiphetic preasure on m,voeardial i:sch~
emia. after coronary ligation, J, Tbt>rac. Cardlovasc. Surg. 41!
68'/ (1964).
128. Kline, H. J .• et 4.&.: Hemodynamic and tnet&bolh: ef·
Cects of hyperbaric oxygenation in myoc.fll'dial i~tiun, J.
Appl. Physiol. 2$: 256 {1970).
129. Kulm, L. A. et at.: Htmodymunic effects of hypel'-
baric OJ;)'Ietl in e:rperiment-al acute myocardial infar<:tion. Cit·
130. t..eding:ham, 1. M.~ et at.: Haemodynamic and mycr
cJ;~rdia! effeets <1f hyperbaric ot:Y)'I;en in dogs subj~ to haem·
orrhtlge, Cardiovase. Res. 5: 277 (July} 197L
131. Winttr. P. M.,. et al.: Modif'lCS.tion of hyperbatie
o.ygen toxicity by uperimental venous admixture, J. Appl.
Physiol. 23: 954 ( 1867).
132. Singer, M. M., et at.: Oxygen to:tleity in man, New
13a. Clark, J. M .• and L.ambertsen, C. J.: Pulmonary
oxygen to.xidty: a review, Pharmacol. Rev. 23t 37 (June)
134. Bourassa, M. G,, et .at.: 'I'M eff~s of inhalation of
100 per C(l:nt ~gen on myocardial lactate metabolism in corow
naey heart disease, Am.J. Cardiot. Ul 17'2 (1969),
135. Waxman, M., et al.: The negative inotropic t;ffec~ of
oxyg>n, Clin. Reo. 1$: 1!6 (1970).
136. M06S, A. J., and JohM()n, J.~ Effects of U¥ygen inha-
lation on intramyocardial tension. Cardio'Vasc. R.es. -4: 4.36
(1970).
1893
 l
Cardiogenic Shock
i
11!
Recent advances in pharmacologic
management Ill)

RICHARD J. KONES. M.D.

Pound R•dge. New York

AsStstaot Professor of Chmcal Med!CJOe !Can::.bolog;t}. New

I
York Mifdlcal Cot!e-gt. New Yo~k Ctty

In Part I of this report, which appeared in the

July 15 issue of the Journal, the author discussed
various modes of treatment for patients with car~
diogenic shock. Preventive aspects were beyond
the scope of this review. but a number of agents
used in the general care of myocardial infarct.ion
and cardiogenic shock, inc! uding those used fnr
early relief of pain, were mentioned. Included in
the modes of treatment discussed were arterial
catbet.erization, acid-blll!e and electrolyte balance,
treatment for anemia and altered blood viscosity,
monitoring techniques, treatment for myocardial
and systemic hypoxia, and oxygen therapy. Part
II will further discuss treatment for cardiogenk
shock through the use of therapeutic agents and
procedures.

Catechola mines
Among the clinician's armamentarium of thera- J
peutic agents and procedures for cardiogenic
shock, use of one or another of the vasoactive
amines is perhaps the most prevalent (Fig. 7).
Several comprehensive reviews of the funclamen~
tal actions of the catecbolamines have recently
appeared and therefore will not be discussed fur·
I
~
ther bere. 1 Vfl.H~ U!.l A spectrum of vasoactive
agents are ava,Habie to the physician who must $e-
lect one or those most appropriate to his patient's
need lFig. 8).
l.
The clinician must be mindful of the metabolic "'"
changes which accompany cardiogenic shock fol-
lowing acute myocardiat infarction in relation to
those alterations effected by the catecbolamines
and other pharmacologic agents (Fig. 9). Beta-
receptor :;,timulation results in metabolic a1ter·
ations of potential concern: glycogenolysis in the

August1,197l 1 NawYorkStatecJourna1ofMedicine 1967

 VASOACTIVE DRUG SPECTRUM concentrations (Fig. 10). For instance, high
serum free fatty acid concentrations may depress
ALP!IA eontractility140 and may 1' 1 or may not 1\2,1 43 raise
ANGIOTENSIN the likelihood of arrhythmias."'
METHOXAMINE The seareh for the ''ideal" vasoactive drug for
patients with cardiogenic shock has somewhat
PHENYLEPHRINE abated since the recent appreciation of the hemo·
LEVARTERENOL dynamic heterogeneity of the syndrome. Even
METARAMINOL cyclic adenosine 3',5' -monopbosphate itself has
been advocated for use in patients with severely
EPINEPHRINE compromised left ventricular performance. as
DOPAMINE Before considering each vasoactive amine indi-
vidually, a conceptual diagram of the effects of
MEPHENTERMINE treatment with volume expansion and positive
ISOPROTERENOL inotropic agents may oo usefuL Since volume
CYCLIC AMP work is lea expensive in terms of oxygen con-
sumption than pressure work, the clinician may
PHENTOLAMINE attempt to increase cardiac output initially by
PHENOXYBENZAMINE volume expansion. An ideal manipulation is il·
lustrated on the length-tension curve in Fig. lA.
BETA At point 0 a patient suffers myocardial infarc-
FlGURE 8. Speettum of vasoact1ve drugs ranges from tion. His stroke volume falls to point 1, which
''pure" alpha agonist methoxamine to "pure" beta ago~ lies on a ventricular function curve associated
nist tsoproterenot. with reduced contractility. Expansion of intra-
vascular volume and filling volume improves
stroke volume to point 2 on the same ventricular
liver to raise blood glucose and in skeletal muscle function curve, A positive inotropic agent is then
to produce lacticacidemia, and lipolysis resulting administered, providing a higher cardiac output
in free fatty acidemia, presumably via increased (point 3) on an improved ventricular function
intracellular cyclic adenosine 3',5'-monophosphate curve. On tbe force-velocity relation, a similar

M[!AB<l.IC EVENT PLASMA CONCENTRATION CLINICAL

!LlPOI.YTICI
FIGURE 9. MetaboHc markers of sevEM'e myocardfal mfarcbon {AMH. Physiologic pmperty of each sub:stance Jn
first column JS included b~ow 1t. F'or ms.uulCtiL 1nsuhn. normaUy l!pogerut::, IS feduced in concentration, thus leadmg
to an increase m free·fattv ac1d tf'FA) content tn blood A-ct;ons of many hormones appear to be mediated by alter~
at1ons m mtracellv1ar com:entratu:>n of adttnosme 3', 5' ·monophosphate <cydhc AM Pi.

1968 New York State Journal of Mt~~dicine I August 1, 1973

 ATP adenyl cyclase phosphodiesterase
3' ,5'- AMP _;..,._.....__ _ _ _.,. 5'- AMP + PP 1
Mg-++ ( CJCiic AMP) Mg-t+
t
STIMULATION
t
INHtSlTtON
CATECHOI.AMINES METHYLXANTHINES
GLUCAGON OIAZOXIOE
PROSTAGLANDINS PUROMYCIN
THYROJO HORMONES CITRATE
VASOPRESSIN PYROPHOSPHATE
CHLORPROPAMIDE ATP
CHOLERA TOXIN TRICYCLIC ANTIDEPRESSANTS
HISTAMINE ETHACRYNIC ACID
?BRETYLIUM HYDRALAZINE
?NICOTINIC ACID TRIIODOTHYRONINE
?PROTEIN FACTORS
'NHtB!TION' S TtMULATtON
INSUL.IH IMIDAZOLE
PHENOTHIAZINE$ INSULIN
CLOFIBRATE
ACETYI.CHOUNE
FlOUR£ 10 Reactions of cyc-lic AMP format1on ana degradation Synthests of cyclJC AMP catalyzed by adenyl
cyclase. act1V1ty of whtch JS sttmvfated by the catecholammes. gtucagon, and a numbe-r of other agents {lett}. Only
one pathway ex~sts for degfadatton of cyclic AMP. wt-Hch >S catalyzed by the enzyme phosphodua:sterase. Thus. net
1t1traceHular concentration of cyctic AMP is determined by balance m activ1tu~s ot these two enzymes. PP 1 = inor-
garuc phosphate, cvchc AMP = adenosine 3 ', 5' -mono-phosphate

sequence may be plotted (Fig. !Bl. At point A ume as a function of preload, afterload, contractil·
the insult occurs, and the force-velocity curve ity, synergy, and heart rate may be appreciated
moves downward to the tell (curve BL An eleva· by considering alterations in each of the indepen·
tion in preload occurs (curve C), changing the in- dent variabies, The clinician must recognize that
tercept with the abscissa, and finally (curve Dl a a single intervention may simultaneously influ.
positive inotropic action is seen to change the in- ence more than one major determinant of ventrk·
tercept with the ordinate, velocity of contraction. ular performance. For instance, isoproterenol di-
As mentioned, the relation between stroke vol- minishes afterload, but stroke volume may also
increase due to augmented contractility {Fig. ll ),
An alpha agonist, such as methoxamine, may in-
crease atterload, with no effect on the contractile
state, to decrease stroke volume. Ouabain~ ad~
CARDiAC !~DU ministered intravenously, may increase peripheral
tl!mmtM 28SA} va..-.cular resistance, and despite its celebrated
positive inotropic action, may decrease stroke vol-
AfTER LOAD-
IMPEOANCE 10
ume at a point in time (Fig. 11 ).
EIIPT'f!IIG IsoproterenoL Isoproterenol, with "pure"
i mm Htfl/tnlnJ beta-receptor stimulatory properties, improves
myocardial contractility and reduces systemic
CONTRACl'll!TY vascular resistance, thereby raising cardiac output
Vmot!rnm/Uti
{Fig. 1:2). w• The positive chronotropic action of
isoproterenol is due largely to a direct effect'" but
A c may also be secondary to relatively reduced blood
FIGURE 11 Vanat1on m cardLac H1dex. as funcuon of
presr.ure. Injettion of isoproterenol into the renal
both cootracl!ilty and afterload durmg chaHenge 111!\th artery fails to cause vasoconstriction~ t.jx but be-
pharmacologic agents. Card1ac 1ndex does not always t" a use of diversion of blood elsewhere, renal blood
follow contractolny m dJrect;on and rnagn1tude ot flow is not increased when isoproterenol is given
change intravenously. 1 4' 1

August 1. 1973 I New York State Journal of Medictne 1969

 •coRONARY fCBF f PLATELET
STEAl• FOCAL
NECROSIS
AGGREGATION
IIITI!ACEllutAR
CALCIUM
OVERUlAO (?!'?
l?
....,. FOCAl
NECROSIS

FIGURE 12. Both beta ttl) and alpha ial stimulation mcrease heart work and myocardial o><ygen consumpt<on
(MV02). In addition. birt:a st1mulat10n with tsoprotarenol 1nCr$a:ses heart rate. promotes ptateJet aggregation, and is
responsible for focal myocardia£ necrosis. Coronaty btood flow 1s probably .a.ugmanted secondary to mcreased
metabohc: demand. Since this occurs unsehrct!Vety, coronary vess~s which are pliant and hence less !ikety to sup~
ply fschem1c areas may dilate to greater degree than nonphant vessels. Coronary flow may thus be diverted from
areas supplied by ngid. diseased artenes. to areas supplied by healthier artenes, so-caUed "coronary stear phenome·
non. Alpha sttmulatiof1 w;th norepfnephnne may increase coronary blood flow whe:o used to restore a mmtmum
perfusion pr$$$tire, However. aftarloa-d tncreases as wen when this agent •s employed.

Isoproterenol effects vasodilatation of tbe coro-
nary arteries in clinical situations other than car-
diogenic shock,'"" mainly affecting the arteri-
oles."' It is generally considen.d a "secondary"
coronary vasodilator, in that augmented coronary
blood !low follows metabolic demand. Distal to
an occluded coronary artery, however, vasodila-
tion of adja<:ent patent arterioles :may result in a
''coron£!ry steal" of blood flow to a marginally via-
ble ischemic zone surrounding an infarction (Fig.
12).' 52
The large increase in myocardial oxygen con-
sumption associated with the inotropic and
chronotropic properties of isoproterenol are well
known.''"·'"'-'" Myocardial demands for oxygen
are not met by available oxygen supply, hence se-
verely restricting its use. Isoproterenol has re-
peatedly been shown to increase myocardial lac-
tate production in patients with cardiogenic
shock, secondary to augmented anaerobic g!ycol-
ysi~, while myocardial lactate consumption is re-
sumed after norepinephrine treatment, reflecting
aerobic predominance. 115 ,lt1I.!Zl,J');),tllti In good part.
these adverse effects on myocardial oxygen bal-
ance may account for the relatively poor clinical
response noted by several investigators. ;s. '~'' lM
When ischemic myocardium was treated with
isoproterenol, decay of peak-developed tension oc·
curred earlier than when no isoproterenol was
used.l<'e
Focal necrosis of myocardial cells and inflam-
matory cell infiltration are a well-recognized con-
sequence of isoproterenol infusion.''"'-"" In low
doses. however, :myocytolysis may be less likely to
occur."' Catecholamine-induced myoeytolysis
may be mediated by platelet aggregation in myo-
cardial capillaries (Fig. 12). 172 In addition,
isoproterenol-induced intracellular accumulation
of calcium andfor cyclic adenosine 3',5'-mono-
phosphate, H,. may be toxic to myocytes.''"
Thus, while isoproterenol appears beneficial in
endotoxic shock and postcardiac surgery, 174 • 175
presently available evidence does not justify its
use in cardiogenic shock. Even when used to
treat the postoperative heart, the metabolic price
of augmented myocardial contractility produced
by this agent limits its usefulness.""·"'
When peripheral vascular resistance is normal
in cardiogenic shock, isoproterenol has been re-
ported to reverse the syndrome wben administered
in a continuous intrave-nous drip of 0.5 to 1.2 mi-
crograms per minute.'" If hemodynamically sig-

1970 New York State Journal of Medicine J August 1, 1973

nificant mitral regurgitation is present, for exam-
ple, after papillary muscle infarction, isoprotere-
nol may find a role in the treatment program,
since alpha-receptor agonism raises afterload and
thus would be expected to increase the regurgitant
volume of blood.
Dopamine. Dopamine, or 3-hydroxytyramine,
is the immediate metabolic precursor of norepi-
nephrine. Three quarters of administered dop-
amine is rapidly 0-methylated and deaminated. 179
Not only does this agent stimulate beta and alpha
receptors, 180• 181 but certain vasodilator effects,
such as renal 148• 182 - 187 and mesenteric 188 in particu-
lar, appear to be mediated by a specific "dop-
amine receptor." 187 While these latter actions are
not blocked by either alpha- or beta-blocking
agents, they are modified by haloperidol 18 9 and
the phenothiazines. 190 The chemical structural
requirement for dopamine-induced vasodilatation
is rigorous in vascular beds where the action is
dopamine-specific.
Dopamine exerts alpha-adrenergic vasoconstric-
tor activity in both arterial 148• 187·188 and venous
beds. 191 Dose-response curves indicate that in
higher doses the peripheral vasoconstrictor effect
predominates over the vasodilating action. Dop-
amine raises pulmonary artery pressures without a
change in pulmonary vascular resistance, suggest-
ing that it increases intramural smooth-muscle
tension in this vascular bed. 192
Through beta-receptor agonism, dopamine di-
rectly augments myocardial contractility, 193- 196 as
well as effecting an indirect positive inotropic ac-
tion through the release of norepinephrine. 196-!98
Dopamine also exerts a " mixed," direct and in-
direct, positive chronotropic action which is pro-
portionately less with respect to augmented con-
tractility than, for instance, that seen with norepi-
nephrine.199
Dopamine is a secondary vasodilator, since cor-
onary blood flow rises linearly after changes in
myocardial oxygen consumption, 200- 202 although a
direct coronary vasoconstrictor action has been
s uggested. 202
Due to dopamine's unique renal vasodilating
properties and its dose-related peripheral vasocon-
strictor effect, intermediate between norepineph-
rine and isoproterenol, it is considered a potential-
ly useful agent for the management of shock. 203
In cardiogenic shock produced by coronary mi-
crosphere injection in the dog, dopamine in-
creased cardiac output and improved indices of
left ventricular function. 204 While dopamine also
raised renal blood flow, isoproterenol failed to do
so in the same preparation. 205 Dopamine and
norepinephrine produced equivalent improvement
in aortic pressure and coronary blood flow in a
similar study. 206 After major coronary artery liga-
tion in the dog, dopamine ameliorated left ven-
tricular performance, cardiac output, renal blood
flow, coronary blood flow, and superior mesenteric
blood flow. 20i- 209
August 1. 1973 I
The unique renal and cardiac hemodynamic ef-
fects of dopamine, as previously discussed, have
been confirmed in man. 210 - 214 In patients with
cardiogenic shock, continuous infusion of dop-
amine at rates of 0.1 to 1.6 micrograms per min-
ute increases cardiac output and urinary out-
put.215-219 If peripheral vascular resistance is low,
dopamine can restore mean arterial pressure by
dose titration. 217 Total peripheral resistance de-
creases in response to dopamine's positive inotro-
pic action in t hose patients who manifest intense
peripheral vasoconstriction initially. Dopamine is
of particular value when oliguria is refractory to
other pressors, namely, epinephrine, norepineph-
rine, and metaraminol. 215 Dopamine increases
cardiac output to a greater extent than does nor-
epinephrine but less than does isoproterenol. Si-
multaneously, blood pressure increases are less
marked after dopamine therapy than after the use
·of norepinephrine but are certainly significant
when compared with those of isoproterenol.216.217
Myocardial oxygen balance is perhaps less dis-
turbed by dopamine than by either norepineph-
rine or isoproterenol.220 Dopamine, while less
positively inotropic t han isoproterenol, is still ca-
pable of inducing ventricular and/ or supraventric-
ular tachycardia.
Norepinephrine. The alpha-receptor agonists,
norepinephrine and metaraminol, have been used
commonly to increase peripheral vascular resis-
tance and cardiac output in patients with cardi-
ogenic shock (Fig. 7). 181•221 These agents are said
to shunt blood from less critical vascular beds,
skin and skeletal muscle, to more critical ones,
coronary and renal.
Norepinephrine (levarterenol) is administered
in a concentration of 8 to 16 mg. per liter of fluid,
preferably into a large upper-extremity vein to
prevent extravasation and tissue slough. Phento-
lamine, 10 mg. per liter of solution, may be added
to prevent this complication. Norepinephrine
acts on myocardial beta receptors to increase con-
t ractility,2 2"l which may or may not augment car-
diac output. 1• 119 Vasoconstriction occurs predom-
inantly in the skin, splanchnic, muscle, and renal
arterial and venous circuits, but spares the cere-
bral and coronary arteries. 13i·223·224 Although
some investigators argue against the use of pres-
sors, claiming that vasoconstriction is maximal
after acute myo-c ardial infarction when cardiogen-
ic shock supervenes, current evidence suggest s
that this may not be the case. 119·223·:m Norepi-
nephrine may thus help restore an adequate mini-
mum perfusion pressure, even when some vaso-
constriction is initially already present. Norepi-
nephrine is positively inotropic and may increase
the blood pressure solely as a result of augmented
contractility in approximately half the cases treat-
e d . 224
Greater constrictor activity in the postcapillary
vessels could increase capillary hydrostatic pres-
sure and result in net loss of intravascular vol-
New York State Journal of Medicine 1971
 ume. 220 ' '"" Acidosis reduces the desired response
to vuoaetive drop experimentally,"' which forms
the basis for attempting to restore effectiveness
with bicarbonate. Other factors, however, such
as microangiopathy, undoubtedly play a part in
clinleal pressor fMtness. An appropriate inf\lSion
rate of norepinephrine should ideally be deter-
mined by direct recording of arterial pressure, as
mentionedt since auscultatory measurements of
blood pressure may be inaccurate.""
Following acute myocardial infarction, endoge·
noJJS sympathoadrenal activation supports cardiac
output to a great extant. 8 L 233 ~ 236 In a recent
study in man, mean peripheral vascular resistance
for nons urvivors after acute myocardial infarction
was significantly higher than for survivors in the
absence of exogenously administered pressors.""
Norepinephrine has traditionally been held to in·
crease myocardial work in proportion to the elevat-
ed afterload. Other workers maintain that when
norepinephrine is used to correct hypotension, the
increase in myocardial work is no greater than
wh;m the heart normally works against the after-
load of normotensive patients. w The resolution A 8
of this problem has recently been provided in pa- FIGURE 13. Biochemical events postulated for digital·
tients with cardiogenic shock in whom hemody- IS actfon Otgitatis gtycosides tnhibit sarcolemmal en~
namics and myocardial metabolism were studied zyme Na"" K+,·ATPase. which lS respOnSible for pump~
during treatment with norepinephrine.'"·'" mg sod1um (Na -+) out of the myocardial cell ~n ex-
Mean aortic pressure increased an average of 21 change for potassium (K "''l lnhfbftion of thts pump re·
sutts m Sntracellular accumuiation of Na + and loss of
mm. Hg (range prior to treatment 40 to 65 mm. K.., from celt fntraceUuJar Na + is then exchanged for
Hg), coronary blood flow rose from a mean of 68 extracellular calcium {Ca0 f +) in greater quantity, thus
mi. per 100 Gm. per minute to 95 mi. per 100 Gm, delivering mcreased acw.rator calcium to contractile ac~
per minute. Abnormally high myocardial oxygen tomyosin fitament apparatus.
extraction remained unchanged. Mean myocar-
dial oxygen consumption rose from 8.11 mi. per
100 Gm. per minute to 10.35 mL per 100 Gm. per storage sites. Myocardial norepinephrine may
minute which was associated with a shift from be depleted in low cardiac output syn-
lactate productiun to extraction. While nurepi- dromes,'""·"'"·"' especially cardiogenie shock,'"
nephrine improved myocardial perf\lSion. cardiac and by such agents as guanethidine and reserPine.
output and peripheral perfusion were unchanged. The clinical frequency of metaraminol ineffective·
Myocardial oxygen consumption indeed incre.ased, ness due to norepinephrine depletion remains un·
but since norepinephrine effected lactate metabo- known, hut the possibility exists.
lism, overall myocardial oxygen balance was made
more favorable, although by no means normal- Digitalis
ized. These data are further supported by those Several authors have recently reviewed new in-
of other investigators who recorded an increase of formation available concerning the mechanism of
15 per cent in the time-tension index in patients digitalis action. J.G6.Nt ~. 246 While a recapitulation is.
with poor left-ventricular performance after myo- beyond the acope of this teview, it is important to
cardial infarction."' ThUll, it appean; that nor- appreciate that hy inhibition of the myocardial
epinephrine is preferable to isoproterenol in the membrane sodium (Na+), potassium (K•)·adeno-
initial management of patients wtth left ventricu~ sine triphosphatase, and intracellular sodium i;;
Jar power failure, since improved cardiac output accumulated in a stoichiometric relation to intra-
associated with the use of isoproterenol is accum- cellular potassium depletion. An enlarged intra-
panied by unacceptable deterioration of myocar- cellular calcium pool results in increased contrac-
dial oxygenation. tility of the myofilaments (Fig. 13). Altered
Metaraminol. Metaraminol, in a concentra- intracellular:extracellular, sodium:potassium ra·
tion of 100 to 250 mg. per liter in intravenous so- tins are an obligatory consequence of digitalis ac-
lutions, produces hemodynamic and metabolic ef· tion,
fects similar to those of norepinephrine. Metar- The relationship between myocardial content of
aminol is an indirect-acting vasoconstrictor, act- digitalis and the resultant inotropic activity bas
ing primarily by releasing norep,inephrin~; from been examined. ~.tt,lNJ$ Factors other than myocar-

1972 NewVorkStateJoumalo!Medicine I August 1,1973

FIGURE 14. Central role of mvocatdia! oxygen b-alance and determmams. fmbalance between oxygen supply and
myocard1al demand !eopard1Zes ttSSt..h? m lschem1C zone suuoundmg a myocardia:! lrtfarct1on. improvement of myo~
card1al oxygenatiOn mereases chance for survival of such margmally vtable tissue"

dial digitalis concentration are responsible for the
lag between myocardial digitalis levels and the
onset and peak of the inotropic effect.
A new appreciation of the metabolism of digi·
talis glyc05ides has resulted in changes in clinical
approach.'"·""' For instance, digitoxin, chiet1y
metabolized extrarenally, may be preferred for
some patients with renal failure. The concept of
the "digitalizing dose" has also been seriou>ly
questioned,:!&~'
The use of digitalis after acute myocardial in-
faretion has been much debated. Studies m !abo-
ratorv animatszr,;- J,"<;; and In man~;; 6 demonstrated
reduced tolerance to digitalis following myocardial
infarction. In experimental cardiogenic shock
produced by coronary microsphere injection. digi·
talis restored blood pressure and cardiac output
and reduced left ventricular end-diastolit pres·
sure . .:s; although these alterations may not be sus-
tained ..M:-:
The reported positive inotropic action and ex·
pected beneficial hemodynamic change associ·
atPd with digitalis administration, foHowing acute
mvocardial infarction, has been further quali-
fitid.'"· "" During the period immedtately
postco-ronary ligation in the dog, acetylstrophan-
thidin did not improve hemodynamics. whilE> one
week later in the '·healing phase." left vent rkular
performance was indeed improved by the
drug, th.t-:J:';_'f Moreover. both the extent of left ven-
tricular dysfunction and the failure of digitalis to
ameliorate this depression correlated with the
mass ofleft ventride infarcted.'"
Early studies consisting of administration of
digitalis to alternate patients with acute myocar-
dial infarction suggested that digitali• could he
tolerated in this setting and was clinically use·
ful.'''"' "" More recently, in a group of patients
with cardiogenic shock, acute digitalization was
found not to alter cardiac out put, mean arterial
pressure, central venous pressure, and peripheral
vaseular resistance . .:hl Rapid intravenous admin¥
istration of digitalis in man may cau~ peripheral
arteriolar cor.striction to increase after1oad. 26 2 ":!trl
Further, digitalis may reduce preload via periph-
eral venod.Hation and depressed venous return.">t:J
Thus.. the anticipated augmentation in stroke
volume secondary to enhanced contractility may
he masked by simultaneous elevation in afterload
and reduction in preload, both of which tend to
decrease stro.ke volume. 1
Although patients with "clinical" evidence of
congestive heart failure following acute myocar-
dial infarction (ra!es, sa gallop, and tachycardia)
have been reported w benefit hemodynamically
from acute digltaUzation."i;·l other investigators
have found a variable response to digitaHs.l6J,
suggesting a limited role for digitalis in early myo-

August 1, 1973 ! New York State Journal of Medicine 1973

cardia! infarction. Current data do not, however,
permit a conclmion regarding the efficacy of digi·
talis following acute myocardial infarction wheth·
er "clinical'' congestive heart failure is present or
not~266
Despite the traditional reluctance to use digital.
is after acute myocardial infarction, digitalis is
finding greater use in this setting.''" Digitalis
appears to he indicated after acute myocardial
infarction in the presence of atrial fibrillation with
rapid ventricular rates and/ or cardiomegaly with
or without an sa gallop, tachycardia, and rales.
The use of digitalis in uncomplicated myocardial
infan:tion is not recommended. Viewing cardio-
genic shock as a variant of acute left ventricular
failure, digitalis may have a restricted role in the
management of this syndrome.
Augmented contractility resulting from digitalis
treatment increases myocardial oxygen consump·
tion in the normal heart (Fig. 141. However, in
the failing heart, digitalis either reduces myocar-
dial oxygen consumption or leaves it nearly un·
changed. ""'"• Simultane<>us reduction in left·
ventricular end-diastolic pressure and volume and
heart size, thus decreasing myocardial wall ten-
sion. accounts for the net effect of digitalis on
myocardial oxygen consumption. In the ischemic
zone surrounding an area of necrotic myocardium,
such a beneficial effect on net oxygen balance may
contribute to the survival of tissue marginally
supplied with blood.
Since the hemodynamic alterations after acute
myocardial infaretion are a function of reduced
left ventricular contractile mass and depressed
compliance, the p<>ssible regional effects of digital·
is must also be considered. '- 270 The contractility
and compliance of infareted myocardium is un-
likely to be affected by digitalis preparations.
Surviving myocardial mw;de may already be hy-
percontractile due to increased endogenous cate-
cholamine release and, therefore, less responsive
to digitalis-induced inotropism. Moreover, in·
creasing the contractility of functioning myocar·
dium may he futile to the extent that this energy
is dissipated by areas of dyssynergy.
The hazards of digitalis excess are legion and
are well documented."".,,. Following myocardial
infarction~ patients have increased sensitivity to
the electrical manifestations of digitalis toxici·
ty_,,...,.._,,. Quantitative assay of serum-digitalis
levels has afforded an important diagnostic tool in
prevention and detection of digitalis overdos-
age."''"' As mentioned, due to digitalis-induced
mvocardial potassium loss,'" toxicity is more like-
ly· to develop in the presence of hypokalemia. m
Interestingly, the myocardium is also more seosi ·
tive to the p<>sitive inotropic property. of digitalis
when serum potassium is low."" Recently, obht·
oration of digitalis-induced arrhythmias with in·
travenous arginine was reported . .!t~l White the
mechanism for this action is unproved, glucagon,
1974 New Yotk State Joumal of Medicme ; Augusl1, 1973
with antiarrhythmic properties of its own, is se-
creted in response to arginine infusion in man and
may contribute to the genesis of these observa~
tions. "82
Glucagon
Since the initial demonstration of the direct
p<>sitive inotropic property of glucagon, great in-
terest in the cardiovascular effects of this agent
has been shown. 282• 283 In the papillary muscle
preparation, glucagon shifted the force-velocity
curve upward and to the right, which was unaf.
fected by pretreatment with beta-blocking
agents. ' 8' Glucagon-enhanced contractility was
additive with that of ouabain hut did not precipi-
tate digitalis toxicity.
Electrophysiologic actions of glucagon have also
received considerable attention. Glucagon facili·
tated atrioventricular conduction at fast pacing
rates2M and reversed depressed atrioventricular
conduction produced by propranolol hydro-
chloride.""' Not only does glucagon fail to
cause ectopic ventricular activity,28 7 ~ 28 • but also it
abolishes ouabain-induced arrhythmias, wbich
may he related to a decreased rate of rise of action
potential and conduction velocity. 2""·z••
In man, hemodynamic effects of glucagon in-
clude augmented left ventricular dpfdt, cardiac
index, and mean arterial pressure, all of which are
independent of beta blockage or administration of
digitalis. Glucagon increased the contractility of
the noninfarcted portion of the ventriclem and re-
stored arterial pressure and cardiac output after
experimentally produced myocardial infan:tion in
the dog.'"'"''"
Glucagon administration to patients with myo-
cardial infarction has yielded inconclusive data.
On the one hand, three studies thus far do not
confinn the beneficial hemodynamic actions of
glucagon in cardiogenic shock when injected as a
single bolus {3 to 5 mg.).'""-"' Other investiga·
tors, using a continuo\111. intravenous drip of gluca-
gon, have noted both hemodynamic improvement
and favorable clinical results in patients with
p<>stmyocardial infarction with and without cardi-
ogenic shock (Figs. 15 and 16), 237•2 ""·'""·3\l• The
heterogeneity of the syndromes themselves con·
tribute to the difficulties in resolving this issue.
In contrast with digitalis, which is of greater
clinical usefulness in patients with cardiomegaly
both pre· and p<>stinfarction, glucagon appears
less likely to be of benefit in patients with heart
disease of long duration. 28'-'89 The reasons for this
remain unclear, but chronic myocardial dL•ease
may he accompanied by a change in the glucagon
receptor or in its coupling to adenyl cyclase.
Glucagon increases coronary blood flow, but
myocardial oxygen consumption rises proportion-
ately, thus classifying this agent as a secondary
coronary vasodilator. :.:sz,v.H In ischemic heart dis¥
 \~red preload.'"' In addition to the lowered pe-
npheral vascular resistance, it appears that gluca-
gon augments renal blood flow to a greater extent
than norepinephrine, isoproterenol, and dop-
amine.:«Jti
In conclusion, glucagon's additive inotropic ef-

-f'""'' fect with that of digitalis, antiarrhythmic proper-

ties, failure of propranolol hydrochloride to block
inotropy, absence of tachyphylaxis, longer biologic
half-life than isoproterenol, secondary coronary
.J vasodilatation, and relatively favorable hemooy-

-l ClAY OF PftC1'fOCOL
s
,. 8 ~ Qt~ •
FIGURE 15, Beneficia~ effecrs of gfucagon mfus1on m
patients wuh tow cardiac output syndromes mclude s1g>
nrficant natnufesis
ease, when coronary blood flow is fixed and can-
not accommooate great myocardial oxygen de-
mands, use of a positive inotropic agent may
tentially precipitate angina or extend an infarc-
tion. Such adverse effects of glucagon have been
reported in man.'"·"' In comparison with norepi-
nephrine, however, glucagon proouced the same
increase in cardiac output without any significant
change in the time-tension index. This was chief-
ly attributed to the mooerate decrease in aftcrload
effected by glucagon, in conjunction with una!-
nam•c effects are among the desired clinical prop-
erties of glucagon. However, the use of high doses
of this agent may produce small pulmonary emboli
of chemicophysical nature similar to in vitro gluca-
gon gels. More investigation is necessary to fully
characterize this phenomenon.
Corticosteroids
Attention has recently focused on the visceral
microcirculatory abnormalities manifest in shock
which include initial arteriolar and venular con-
striction followed by relative diminution of arteri-
olar tone, increased capillary permeability and
po~ loss of anatomic integrity of capillaries and ven-
ules, and, finally, intravascular thrombosis and
coagulation defects. In isolated canine forepaw
and in intact forelimb preparations, massive doses
of corticosteroids stabilized capillary membranes,
thus preventing pathologically increased perme-
ability.·"''· ""' In addition, transmission of sympa-
thetic nervous impulses may he slowed by cortico-
steroids. Both of these effects would tend to

-·... ----. ....... .., .... --

.;... • .::=,. ! "'T "t" ~

k •

..•• ........
,.
.. .. .. --·.. ..r!.,
.,. -
- -
•• • •

--- ... ., = - ---

' •• !J • ••
,. . •
••
. . 10\011 "'
- f t:
'I -
••
•
-
" . - ""
•'I -
•• I... .
="--·
....
- -
• " •
... .• ~·I •
, . . ro

"
• •• •U , . . ,

., 1- ..
.... 'I
~ ~f'
-
•
- L-
-
- -
=•"
•• !toe -
., ""
'f

...::~I!
• •
.. "
"
.
.
.,
••
-
I
•.o :uM

-!~ ,, ,
•II I
I
-lf -
! -
.
..
'
" I
~ tt ... j ., ~~ j tOO
+ ..Ill! .. I •
,
I . :;o.-
_,_~
! _ _L..,_ _,e___,L,

FIGURE 16 Summary of data dunng contmuous in!ravenous mfus10n of glucagon 1r1 patients w1!h card1ogemc
shock ATN = acut-e tubular rHaCIOSJS. VT =
ventncular tacnvcardm

A11gust 1, 1973 I New York State Journal of Medicine 1975

 lower peripheral vascular resistance and be re-
flected by an augmented stroke volume.
Large doses of corticosteroids "stabilize'' lysoso-
mal membranes and thus prevent tL•sue dam-
age/10 although myocardial and skeletal muscle
lyS(lSOmal enzyme activity is unaltered by gluoo-
corticoid pretreatment."' There is substantial
evidence that myocardial hypoxia reduces intra-
cellular pH. Lysosomal enzymes become more
active in this lower pH environment and are cur·
rentlythought to initiate myocellular death.
In the heart-lung preparation, large doses of
corticosteroids increased stroke work while mini~
mizing stroke oxygen consumption so that corow
nary sinus oxygen tension rose.att As with two
other reports concerning the positive inotropic ac-
tion of high-dose corticosteroids, complete and
conclusive data have not been presented,'"u"
The experimental circumstances under which
these data are collected are varied, and the posi-
tive inotropic effect is short-lived."'"' Such a
property, however, if verified, may he related to
the similarity in chemical structure of the cortico·
steroids to digitalis,
After experimental myocardial infarction in the
dog, massive doses of corticosteroids reduced total
peripheral resistance and improved animal surviv·
al.:ns Since intra-arterial infusions of corticoids
were not vasodilating,"' the question of whether
lowered afterload was secondary to improved car·
diac output or the result of a primary change in
peripheral blood vessels remained unanswered.
Earlier reports that in cortisone-treated dogs the
size of myocardial infarction was smaller, there
was a decrease in fibroblastic proliferation and an
increase in vascular anlllltomoses, and the mortali-
ty rate was diminished had not been confirmed
for some time.sl8-S22 Recently, however, the re·
duction in tbe extent of experimental myocardial
infarction by corticosteroids administration has
been established using a s;msitive epicardial
mapping technique.'""
Some experimental evidence suggests that c<>rti·
costeroid administration may be harmful after
myocardial infarction. Enlargement of infarct
size and delayed healing attends steroid pretreat·
ment and sensitizes to catecholamine,induced
myocardial necroois, ''-' Changes in serum and tis-
sue electrolytes, such as the loss of potassium,
magnesium, and hydronium ions, may adver:sely
affect the coronary vascular bed, thus impairing
myocardial oxygen balance, perhaps in the face of
increased stroke work.""""'" lt is important to
recognize, however, that such prolonged adminis-
tration of corticoids is unlikely during the treat-
ment of cardiogenic shock,
In man~ acute myocardial infarction is accom~
penied by metabolic markers, including elevated
cortisol levels, the e•tent of which reflects the se·
verity of the infarction."2 ' ·J.H In cardlogenk
shock, catecholamine levels are the highest of all
1976 New Vorl< State Journal ol Medicine I August 1. 1973
subgroups of patients with acute myocardial in-
farction (Fig. 9).
To achieve the desired effects previously dis-
cussed, proponents of corticosteroid therapy for
cardiogenic shock have repeatedly stressed the
importance of massive "pharmacologic" doses,
given intermittently by vein.w7~~ai6.332~3Jlil. For
this reason, objection could be raised to the con-.
elusion of independent investigators and the coop-
erative study of the Scottish Society of Physicians
thnt glucocorticoid therapy did not benefit pa-
tients with severe myocardial infarctions."'-l:><.m
In these trials, tbe doses used were varied and
smaller than those required to achieve a ''pharma-
cologic" effect.
Hemodynamically, such massive doses of gluco-
corticoids lower after!oad and secondarily increase
cardiac output.·m•.Jl~>,J:JS Urine output and skin
and rena) perfusion are said to improve. so 7.s.1.s
Much of this work was done in low-output syn-
dromes following cardiac surgery and in endotoxie
shock, during which the reduction in coronary
blood flow is not necessarily the initiating factor
in the ensuing shock syndrome. Other investiga-
tors have, in fact, used lJUISSive doses of corticoids
and noted the vasodilatino to be transient and un-
sustained or inconsistent, and concluded that
their data did not enable them to advocate steroid
therapy in cardiogenic shock.""-'"'
Arteriolar responsiveness to sympathomimetic
pressors is restored when treating patients with
adrenal insufficiency with corticosteroids. How-
ever; as menti-oned, very few patients with cardi ..
ogenic shock manifest this difficulty; the opposite
is usually the case. The widely held concept that
corticosteroids restore or potentiate pressor re-
sponse in cardiogenic shock is not supported by
the data currently available.""
Recently, a myocardial depressant factor has
been identified in "shock plasma" 341 which plays a
role in the pathogenesis of cardiogenic shock,'"'""'
Plasma levels of a myocardial depressant factor
are elevated in cardiogenic shoc-k, 343 and, in fact,
survival may correlate with the plasma level as
welL A preliminary report suggests that methyl-
prednisolone administration reduces plasma myo-
cardial-depressant factor levels and is associated
with improved survival.,.,
The question of the routine administration of
corticosteroids after myocardial infarction repre-
sents a somewhat different problem from their use
in cardiogenic shock. Since the majority of pa·
tients with myocardial infarction do not manifest
depressed left ventricular performance to the ex-
tent seen in cardiogenic shock, other variables af.
feeted by corticosteroids must be considered.
Quantitatively, tbe actions of the glucocorticoids
on the initiation and maintenance of arrhythmias
are probably of greatest importance.'"
The routine use of corticosteroids in patients
wlth myn<:ardial infarction without ca:rdiogenk
shock has been debated and investigated since
1963, but with ineondusive results."" "' A clini-
cal impression of a more favorable course of pa-
tients treated with corticosteroids"" is supported
by a recently reported clinical trial in 466 pa.
tients. 3"' The mortality rate was reduced in those
patients receiving 500 mg. hydrocortisone intrave-
nously daily for the first three days after their in-
farction. While not conclusive, these data should
be given due consideration until randomized dou-
ble-blind trials follow.
I W~tcJ~ester Avenue
Pound Ridge, New Vork W576
Acknowledgment: I wish to thank Mrs_ C'arnle {Jeffen ft~:r
her -exceli{!tH s~cn:nari.ai h-e!p and Mre, Pat born for her :m·alu·
able library aid
References
13.7, Aviad.,. D. M., and Dripps, R 0,~ Sympathomimet-
ic drug:;., Springfield, IHinois, Charles C Thomas, 197fL
13tt MarshalL R. J., and: Shepherd. ,J. T.: Cardiac funt>
tion in Health and Disease. Philadelphia, W. R Saunrlel'l-- Co ..
1968. p. l4L
139. Robison, G. A., Butcher, R W.. and SutherLand, E.
W.: The- <:att>cho!amines. in Litwak. G . Ed.. Biochemi<:a!
Actions of Hormones, New York, Academic ~s, vot 2, t972,
p. 81.
140. H~nders<m, A. H" l!( a{: Fre-e fatty a~;ul& and myo.
cardia! function in perfus-ed rabbit hean;;, Cardiovasc Res. 4:
466{t9i0).
l4L Oliv~r, M. F., and Kurien, V. A: Arrhythmogemr
aetiC>n ¢{ free fatty-acids In myocarduJ hypoxia. tbrd. \supp.
3)4: 240 { l970).
142. ~elsup, P. G.: Effect uf bepartn on serum ftetdatty·
adds, plasma catecholarnlnes. and the incidence of arrhylh·
mi4lfi foUowing acuu.• myocardial infarction, Brit. M. J. 3: 7:15
(!970).
l43, Opie, L. H., et at: Failure <:Jf h.if(}l reom·erttraoon:. of
clrcutaHng ffW' fatty .a:cuis to provoke arrhythmia~ m upen·
mental myocardial infarction, Lancet t~ 8l8 \Apr. J :.97!
144. Editorial: Free- fatty addft and heart·attad;;, Ibi-d. !:
843 {Apr.ll97l.
145. Gtrdcr, M. M .. aod SalusttL E.: The treatment ot'
refractory ~ongestive heart failure with 3'.5'-ade-nusiM moM·
phosphate, Cardiovat;<:. &$. (sup}.:L 6) 4:47 { i97fl.).
146. Krasnow, X.: Bi«hemicai and physmlngic respon:-..;
to isoproterenol in patients with left ventricular f.aihJre, Am,
J. Cardiol. 'l"/; 73 {Jan. I !971.
147. Kassebaum. D G" and Van Dyke, A. R.
E:lectrophysiologkal effects of isoproten?rwl on Porkmjt! fihe"
of the heart. Cir-c-ulatwn R!?b. Hi! 94011966L
248. Mi':~av, ,L L .. and Goldberg. L. L Cmnpansnn of
effects t;f dt>}>arnine, lS<•proter"'noL nnreprinephr!M'. and
b:adykinm on canine renal and femoral blood t"h<w, J. PhM"
ma<"OL & E-~per, Therap 151: Zl i 1966).
149. Roo-enblum. R.. Berkowitz, W_ IL and Law!«m, D,
Effeet of scutt. intravenous <tdmlt'li.">tratim; of iiwpmtert'no:
on eardl:orena! hemodvnamicl' in man. ( 'irru!al ion :t8: l ;~<.;,
!l968L - 62":957 iDt-t'.) i9iL
1.">0. Krasnnw, ;-..;_, t't at; t~lproterenul ttnd r;u-d;nvHH'u!ar
p£>rformance,Am.J.Ml'd 37:5H09641
15L Winbnrv, ~t t.L Hm\'tL B. IL anrl Hefner. \1. A
Effect of nitrat'es and other coronar\' dllaH.,n- <rn lMt!f' rind
smaU ccm.m4J:n: ve?J.IM!I>·. an hypothe;;il< l'm rhc m{;>:h<>m~m ot
acr\on of nit;<U~- .1, PharnHlCI\L & Expe-r. Thtnlp t6X: i'U
iH1691
l:JZ. :"'\harma. G \'.ai: Corrma.rv ,..a•al: regional myo-
t>f
cardial blood fioW :O:tUdie~ durin~ i!<t)pro!fitent>i i!liU'tiiHn In
a:;utf' and hea!m? myncatdial mfart·tin!'l, CJin H.~;';-. 19; ;lN
(:\-1a·n19'7L
;:;:t. Clant'\, R. L. t>t t1f: lmotropir .au).!memdtl<ltl d mvn·
eardia! oxygen.con.<.umptknL Am .L Ph,v,.;ioi li2; ;il;\.-": 1 l%7 J
;n..t_ R0."~ ,J, ,Jr.: Clirncal implicaoun~ t>l rard>fH' .:~dn:n
en::nc medumisrM. C'urdwva.M:. Hi>s. l'-'tlPP \)J 4: -Ill i !,9";\l)
Lli.". . .\1ue-H<:t- H .. f'l af; Cnrnnar. flo,.,-pr~t~;.un· rda11on
and it-- mle for mvcx·ardia: me;ahoH~m 1!'1 hurn;w comnM\
shn.:k. ;\:J1 "J. f'atd!OL 26: ti;)I I 197<)\
156. Ku_hry., h. A,: Shock in myocardial infarction-medical
treatment. Jbld 26! 578 ( l97Q_L
i57 ::i.m1th. H. J ., el al.: Hemodynamic studi~ in car-di~
o~.;>ruc ~~ode treatm~nt wi.th isoprotere-MI and metaraminol,
Cm:;uiatmn 35; WS-4 0967} .
. ~S$.. Mo-roe, ~· W .. Danzig, R., and Swan, H. J,; Effects
9! IS(_JP«}(_eronoJ 1n shock associated wlth acute myocardial in-
farction. lbui. {~-upJ:L 2136: 192 ( 1967)
159 .. J:iraunwald, E., f(t al.; Eff~ts- of drugs and of coun-
terpu:isanon on myoc~r<hal oxygen consumption ibid.. (supp.
4 ItO: 220 (!009l. '
!6~). Mar?ko, P.R., et at.: Thi: cotrelation betw~en myo--
t:ardtal creatm~ phosphoklnasti' actlvitv and ~pkatdiai c-hanges
foHowing experimental myocardia\ irifar<:tmn Ciin. Res. 18·
t 16 (1970}. ' •
, 161. Gunrwr, R-.. M., £t at.: lne-ffecti,.·enes:o; of isoprottrenol
m :;hoc-k du~ to flC'Ute myocardial inlarction, J.A.M.A. 202;
ll24(t9681
16_2. Kuh, L. A.. f:_~t ut.: C-ompanson of the hemodynamic
a_nd cardiac ~etabohc effects of isoproterenol and noreplneph~
r!~lf m expenmenta~ aeu:te myocardia! infarction with shock.
Ctrctdatmu (supp. 2) 36: 166 {1967).
16_3. DanitliL H. B .• Bagwt:'H, E. E .• and Walto-:n, R. P.:
LinHtatton of .myocardial funct}on by .reduced coronary hlood
tlow dunng !!iOptotercnol a.ctwn, CtN:ulatton Res. 21! 85
0%7L
1134" Kuhn, L. A., et «l.: Effects pf isoproterenol on hema--
dynamic alteration~. m,_v{l(;ardial metabolism and coronarv
flow in experimental myocardhtl infar<:tion with shock, AID.
Heart J, 77:772-09691.
I65. Welt M, H., and ShubirL H.: Isoproterenol for the
treatmomt of c1reuJ.atory shock. Ann.lnt. Med. 70; 638 {1969).
1!ffi Kuhn. L. A" .:•t at:. Po~entiation of inotropic effects
0f mopwterenol by mechantcai mcrease of (:t>ronan.t flow in
myocardial infarctiun w;th shock, c.r~llltion \~upp-. 3) 4(); 127
1[969)
167. Cunnar, R. M .. et at.: Ineffectiveness of ffi.opr~rt:n.ol
in the treatment of shock due tO myocardial infarction,
J.A.M.A. 202: 11240967;.
168. Sat-off, J., and WexJer, B. C.: Isoprote-r~nol-induced
myocardial infaretion in rats, Circulation Res. rt: 1101 ( J970).
lf'i9. Mueller, R. A., and Thronen, H.: Cardiac eatoohol·
ami~ .synthesis. turnover. and metabolism with isoproterenoi-
mduced myncytoly.sis, Cardiovas.c. Res, -S: 3M (July) 1971.
170> Wexler, R C.: Acute enzyme and m~tabolic changes
in artcri<-*'demtl(:: vs. nonarteriHsdetotic t"ati! following isopro·
tenmo!·mdu-cecl mvoeardtat infarction, Angj{,togy 22: 251
tMay) 197~, · ~
171. Batne-t, H. B., ,JeUinek. M .. and Kaiset. G. C.: Ef.
fe-et~ of isoprot.enmoi infu~ion on myocardial l)tructure and
cr)mpo\';Jtion. Am. H-ear'! ,J.. 79: 237 ( i970),
17:!. Haft, ,1, L et nl ; Intuvascular platelet aggregati-on
un l he heart induced In vivo b~ cate-ch(>iamine infusion. Ann.
Int. Mt-d. 76! 864 fMa)-·} 1972.
Fle<:kenRte-in. A., Janke, J., and Doering, H. J.: Myo-
!7:1.
cardn~l fibre necrooi..-., du-e to intracellula-r Ca • · over!rwd-a
new print·iple in cardiac pathophysiology, ahhtracted, 5th An·
nual M~e-tmg._ Inc Study Group for R-esearc-h in Cardiac Me·
tabuli::.m, ~- S. Dha:Ua. Chairman. The WJtmirwK Inn, Winni-
peg, Manltoh1;1. 1972, p, ;):-!,
ti·L SUtrzetki. B.. and Spink. W. W.: Hemodynamic ef.
fez'!~ of isoprotcron(;j in canl:ne- ~ndotmon shock .•}. CHn. In-
v(''\t. .fj': 2l93 (19M).
r7s. Rerej!ovlch, -!.. i:'t ai: Hemodynamic effects of
i;;opwh·rennl in cardiac .;urg~:~ry, .J. 1'hotac. Card:irwasc. Surg
l7t'.. Mueller, H., O't a.i: Effect of L•.nproterennl t>n vcntric·
u}ar worK and mym:atdi.ul metabolism in the vostoperati-ve
h!!<trt, ('!t{:Ul<ltin-n \supp 'l.l :~8: I 46 { I9AA:J
i~·;. Mutl'lh:r, H._ 8.., et a(.; SyBtemk hemorlyna_mi(' and
my•Kardtal metabohc efi't>tts of boprmc-renoi and ang1ot-ens.wn
afH:tl)}tt'n·ht,art surgery, ibuL 42:491 097{},!
liB. PurL P.P., and Bing, R ,J: Effe·et of d:rug'"' on myo-
rarol!ai ;·<~nlmt:tililV tn the intact dog und in experimental
lli'-'f•nml!al inf.arcwm. Am ,J. Can1w!. 21: .r$86\ 196(-\l
i79 (!ondnlL ~L and Alton. H.· Me-tab..>lism u{ J.hydl:'fn;.
:vty..rumim.• {dop&mint•l Hi: human ~uhjeCl$. Biochem. Ph.arma-
t nl l7: 90,:_"1 ( l~!,
ll".H Mc~ay ..J. L .. and Gnldhen:;. L, L: Hem<-.dynamH.'
t"fff)tts ni rlupam1ne m the clog he!M£> and Bt'tet n!pha adtencr·
gw hlo\'kad~. C\t(•<.ddttnn H.es. {5upp_ i l 18: 1 i 19€6L
i"l. Nforan. :\.. C: gvaluatlon of the ptt~rmu.::otogi-c ha~as
tm !he iherttp:- of ('ln;:ulator)' ;.hu.dc Am .J, CardioL 26: 5'10
i nr-:nj
New York State Journal of Med1eine 1977
 182. McNay, J, L., and Goldberg, L. I.: Comp,1u·tson of
effects of dopamine, isoprote:reuoi, norepinephrine, and
bradykinin Qt) caniM renal and femoral blood flow, J. Phar-
macol. & E>:por. Therap. l~h 23 !!965).
183. McNay, J. L.• McDonald, R H., Jr., and GoldberJ.
L. [.: D~t renal vlUOdilatation produced by dopamitre m
the dog, Cireulation Roll. 16: 510 (!96/H.
184. Giff.ord, R. R. et aL ~ Increased clearances of pheno-
barbital and salicylate produced by dopamine Jn the dog, Am.
J. M. Sc. 258: 3&1 (1969)
185. Meyer, M. B.• MeN~. ,J, L., &nd Goldberg, L. I.•
Effects of dopamine vn renal function and hemodynamics in
the dog, J. Pharmawl. & E>:por. Therap. 156: 186 ( !9671
186. ~is. R. P ~ and Alooso, N.: Diuretic e-ffect of dop·
amine in the rat, J. ~ndocrin<». 47: 1290970}.
187. GQWMrg, L. L, and McNJzy, J_ L.: The tardk•vascu.
Jar and renal actions of dopamine: the question of a speciru::
dopamine receptor; 1n Dattus, A. A,, Roes, G., and lhll, V.
E .• Eds.: CardWvascular Beta Adrenergic Resp:mses, Los An·
geles, Univ. of Calif. Pl$& 1970, p. lt9.
!88. Eble, J. N.: Propooed mechanism li>r the dep,...or
effect ot' dopamine in tlw anesthetized dog, J. Pbarmacot &
Exper. Ther&p. 145: 64 ( 196-tl
IB9. Yeh, B. K., McNay, J. L., and Goldberg, L. !.: At·
tenuA'ttion of do~amine renal and mesenteric vasod.Uation by
haloperidol: evtdenct> fw a s~ific dopamine receptor, 1bid.
163: 3030969).
100. Goldberg, L. L. and Yeh, B. K, • S!""'ific bloc!; of
dopamine rece-ptors ln the .renal' va&::u1Ar bed by chJnrproma-
zine, BMi~-1. Swltzerland, Proc. IV inL Cong, PharmacoL 1900,
p.359.
191. Mark, A. L.: Resporu~es of saphtnous and mesenteric
vein:s to administration of d<>pamine. J. C-Hn, invest. 49: 2W
(1970).
192. Harrison, D. C., d al.: The pulmonary and ~>ystemic
circulatory response to dopamine infusi®, BriL J. PharmacuL
3S:618 !1969).
193. McDonald, R. H., Jr., and Goldberg. L. L: Analysis
of the ca.rdiovaM:ular effe~ of ~opamine in the dog, J. Phar"
matuL & Ex per. Tberap. !40: 60 t t96il).
194. Black, N. L .. and Rolett, E. L.: D<mamitU!!·induee:d
atteratiOM in left ventricular performance, CirrWation Res.
!9: 7! (1966).
195. Ross, G .• and Brcwn. A" W,~ Cardiovascular effect!;!
o( dopamine in the .anestb«ized cat, Am. J. Physiot 212:: 82.~
(1967).
196. Goldberg, L. i.:. Cardiovascl.tlaT and renal actions of
dopamine: potential chnicf:l;l applications, PluirmscoL Re\',
24: l (Mar.) 1972.
197, Bejrablaya, D.. Bum. J. H .• and Walker, J. M.: The
action of sympathomimetic amines on heart rate In relation to
the ~ffect of reserpine, Brit. J. PharmacoL 13: 461 ( 1958).
198. Tsoi, T. H., Langer, S. Z., and Trendelenburg, U.:
Effects of dopamin~ and L·methyt~dopamine on smooth mu.s·
de and the cardiac pacemaker. J. Pharma«l"L & Exper. Thee·
up. !56: 310 09671.
l99. Tuttle, R, R.~ CbangU in the cardiovru>cutar eff~Wt of
dopamine (DA) c~ by desrnethylimipiramtne {DMlJ and
reserpine, Pharma<:f.'Uogist 1.2:213 { 1970}.
2()). Schuelke, 0. M .. I!!! al.: CQrotuuy vasodilation pro.
duced by dopamine after adrenergic blockade, J. Pharmaool.
& E>:per. Thenp. 176: am tFeb.l1971.
201. Brooks. H. L., et ai.: Dopamine-induced alterations
in cotml:aty hemodynamla. ln dogs, Circulation Rea, 34~ 699
(1969). . nephrine in Ul3.n, J. Clin. Invest. 41; 1 {1968).
20-2. Nay\er, W. G .• ;rt al,; E!fect of ~annne ~:m coronary
voocular resist-an« and myocatdtai funct1<.m, Card1ovasc. &s.
S: !Sl tAprJ 1911.
203. Goldberg, L. L, Talley, R. C., and McNey. J. L
The ~entiai rote of dopamine in tht! treatment of shock,
Progr. C.atdioVRS(\ Di1l.. 12:; 40 ( 1969).
204. Upp, H", et, al.; The eff.ocu of dopamine ?0 ~e·
p:reued myocardial functi-on following coronary embohxatton
in the clooedebestdog, Am. Heart J. &4:208 (Aug.) 1972.
2(}5. McCannell, K. Lc: Hemodynem;e fei.pon~ t? ~OP·
amine and to isoprotereMl foUowing acote myocardud InJUry,
Can. J. Physiol. PhiirmacoL 41; Z5 (1969).
206, Bagwell, K E., and Daniell, H. B.: Ct>mpar~ti\ffl .ef·
fects of dopamine and norepinephrine on m~ocar~tal hmctlott
and metabolism during ~~perimental cardl')gemc shock, J.
PharmacoL & Et--pe:r, Th¢rap. 173:357 (1970">.
207. Carvalho, M .. e-t .at.: Hemodynamic effect~ <if ;s:.
hydrol)'tytamine i.dop.amineJ in experimeur.atiy mduced
shock. Am. J. Catdio1. 23t 217 (1%9L
1978 New Vorl< State Journal of Medi~ine I August 1. 1973
20.8. . Wi~t:rauh, B. U .• et al.: H~mOO.ynamic response to
dop.amme m experimental myocardial infarction. Am. J.
Phy>icl. 217: 1716 (1969).
209. Navatt, G. W., et al.: DQpamint nwernal of the
abrupt bemodynQm.i<: ahnomuUities of myocardial inf.arctir.m.
CHn< !Ws. 18: 117 {!970)<
Z10. Goldberg, L. 1.. McDonald, R. H .. Jr., and Zimmer·
~.an, A. M.: Sodium. diuresis produced by _d<>r?Amjne in pa.~
ttents with congeative heart failure, New England J. Med.
281: 1060(1969).
211. McDonald. R H .• Jr., et aL Effects of dopa.nrina in
man: augment.atioo of sodium excretion, glomerular filtration
rate, and renal plasma flow, J. Clin.lnvest. 43: 1116 (!964).
212< H<>rw>tz, D .• Fox, S. M., lli, and Goldberg, L. 1.: Ef-
fects of dopamine ln man, Circulation Res. 10: 237 ( 1962}.
213< Bamardo, D. E .. Baldos, W. P .. and Makar, F. T.:
Effects of dopamin* on renal function in patients wlth cirrho....
sis, Gastroenterology 58: 524 {l970},
214, lWttenblum, R. Tai, A. R., and La.wso.n. D.: Cardiac
and renal hemodynamic effect.'il of dopamine in man, Cliu.
Res. lS: 326 !1910).
215. MeCanne!l, K. L., et <tt: Do.pamiM in the treatment
ofbypo<eMi<>n, New England J. Med. 275: 13811 0966).
2H.t . TaHey, R, C., et aL: A hemodynamic comparison of
dop.arnme and toop-wtereno! in patients in shock, Circulation
39: 361 (1969).
217 Loeb, H. S., et at: Acute
< hemodynamic effects of
dopamine tn patients with shock, i.bid. 44: 163 (Aug.) 1971.
218. Fev.rter. C.• Colin, L., and Hanquet. M.: La dop~
amirw dam: le traitement du shock, Rev. m·ed Liege 25~ 173
(1970L
219. Rotl:enblum. R. and Frieden. J.: Intravenou& dop-
aminh in the treatment Q{ myocardial dysfunction aft<l;t- open-
heart surgery, CHn. Re8. 19:337 {June) l97L
220, Winslow, E., et at.: 'l"rt'U'lSmyocardiai lactate metab-
olism durinJ treatment of shock with catooholamines, Circu}a.
tlon 40:207 0971)).
221. McCannell, K. L., and Moran. N. C,: Pharmacologi-
cal basts for the use of adrenergic sgon!ats and antagonists in
cardiogeme shock and hypotension, in F'tiedbetg, C. K., Ed ..
Acute Myocardial Infarction and Coronary Care Units, New
Yo:rk. G:rune & Stratton, 1969. p. 150.
222. Goldberg, L. L: The di"te<:t effects of .norepine-phrine.
epinephrine, and methoxamine- on myocardial cont.raetile force
in man, Cm:ulation 22: l 125 { 1960).
223. ('A)rday. E., and WiUittms, J. H., Jr.: Effeet of shock
and of vasopressor drugs on t.h~ regional circulation of the
brain, heart, kidney, and liver, Am. J. Med. 29: 2.28 0960).
2'l4. Corday, E., et aJ.; Reevaluation of the t1'1!'atment of
shock secondary to cardiae infarction, Dis. Cheat 56: 200
(1969).
225. Kones, R J.: Topks in biologi<:al transport. Ill. Ac-
tive and coupled transport, facilit.at~d diffuskm, bulk trans·
port (pinocytoo-is) and the Law of the Capmary, in prepara-
tjon.
2.26, Schmutze:r. K L., Rashke, E .• and Maluney~ J. V.,
Jr.: Intravenous 1-no:repiMphrine as a cause of reduced plas·
mn volume, Su:rgtzy 50: 452 (1961).
227. llottit:elli, J. T .. Tsagaris, T. J .. llrld LallJI", R. L.:
Mechanisms of pres.oor amine dependence. Am. J. CardieL
16: 847 0965!.
228. Abboud, F. M .. Schm1d, P. G., and E<:btein, J. W.;
Vascular respo~ after alpila adrenergic receptor blockad:c.
1. Rfiponses of capacitance and resistance vessels to norep-i-
229. Abboud. R M., and Eckst-ein, J. W.; V.scular re-
sponses after alpha adrenergic bl-ockade. II. ~ponses of ve-
nous and arterial segments to adrenergic: :st.imuJetion in the fore-
limb of dog, ibuL 47: !0 (i96il). .
230. Konest R. J., and Phillips, J. H,: Nevo•er inotroptc
agents for card1ogenic tthoek. South. M. J. $.5! 329 (May) 1972.
231. H<oufe-, D. B., et at.; Intluente of mpiratory acidosis
on ECG and pressor responses to E-pinephrine, norepinephrine,
and metaraminoL Proc. Soc. Exper. BioL & Med. 94: .561
(1967).
232. Cohn, J. N.: Blood pressure measurement in :Phock:
mechanism of inaccuracy ln auscultatory and palp.atory
moth<>ds< JAM.A. 199:972 (1967).
233, Jai.n, S:. R, and Lindahl, J.: Apex cazd!~am and
systo!Je time intervals in acute myocardial infaretton, Brit-.
Heart J. 33: 'tt7S (July) 197L
234. t:>owhng. ,J. T .. Sloman, G.~ and Urquhart. C.: S~s~
toile time interval fluctuations pruduced by acute. myocrudull
infarction, ibid, 34! 765 (SepL} 191 L
 2'JS. .H:am(!Sh, P., et al: SystoJi<- tkme intervals and left
vantricular function in acute myocardial lnfarcttOrL Circufa.
tion 45; 37tHFebJ 1972. •
236. Kones, R. J.: The infl-uence of glucagon infusivn Dn
the $Ystoli" time interval$. after myocardial infal"Ctu:m. ~ubmit.
tOO for publication
237. Diamond., C., et aL Acute myocardial infarction in
man. Comparauve hemodynamk efftxts. of norepinephrine
an<i glucagon, .;\m. J. Catdio.L 21~ 612 (June) t91 j.
238. Chidsey, C. A., Braunwald, K, and 1\.lorrow, A. (L:
Cateeholamine excretttm .and cardiac storru. of nor~pinepbrine
in congestive heart failure, Am. J. MOO. 39: 442 { 196.')).
239. M'mroe, R G., cet al.: N-orepincphrint' release and
left ventricular pret>lWrf m th~ isolated heart, Circulation Re;.,,
I~; '11411006).
240. Mathes, P .. and Gudbjarnasnn. S.: Stvrnge and re~
!ease of norepinephrine ln the unine heart following e:r;peri·
me:nu.l myocardial infarction, Cardi»vasc. Re!i\ {supp. 3) 4:
214 { 1970L
241. Mason, D. T., Spann, J. 1>""., Jr., and Zeli~. R.: Nt:'w
developments in tM understanding of the actions of the digi-
talis glycoofdes, Prog-r. Cardiovruoc. Dit:., t l: 443 (196~H.
242. Surawicz, IL Digitali:>. New York, Gnme & Strat·
ton, uno.
243. Stern, A.: The molecular medl$nism of ca.rd1a~; giy.
cosfdeaction, Am. HeartJ. 83! ?tZ{May) 1972.
24:4, Lee, K S., and Klaus, W.: T'he sulx:eHnhu biD;lJO for
the mechanism of inotropi-c actl\'Jn of (ardlae glyc(}Stde::>, Phar·
mac<>L Rev. 23: 193 (Sept.) 1971.
245. Langer, G. A.: Effects of digitalis on myocardial
ionic exchange, Circulation 46~ ISO (July} Hrn.
246:. Kones, R- J.. The equivalent elec.trkal circuit of the
sarcolemma, submitted for puOUcatl\in.
247. Luchi:, R. J., Park, C. D., and Waldbausen, J. A.:
Reiationshi.p between rnyocardiaJ ouabain content and inn·
tropic acttvlty, Am. J. Pb,ysioL 2~0~ 906 {A{)f ,) !971,
248. Deutscher, R. N., Haruson, D. C., and Goldman, R
H.: The relation between myocardial 3 H-rlig:o.xin cun«ntra-
t-ion and its hemodynamic effects, Am. J, GardioL 29; 47
\Jan.) 1972.
249. Wilson, W. S.: Metabohsrn of dl:gtudis, Progr. Car-
diovasc, Dis-. ll; 479 {May) 1971.
250. Doheny, J. E., et .aJ.: ~ew information regard.ing
digitalis met$bolism, Chest S9: 433 {Apr. I 197L
25L Bellet. S., Johnston, C. G., and Schecter, A.: fo.Jfect
of cardiac infarction on the toierunee of dQ~s to digltahs, Art'h.
Int. Me<!. 54: 50011934),
252. Trave-ll, J"' Gold, H., and MndeU, W_: Effect of ex·
peri:mental eardiac infarction on n'l>pon.w t<l dlgit.a.H,;, ibid. fH:
184 (l93llL
253. Morris, J. J., et aL Digitalis and experimental myo-
cardial infarction, Am. HeartJ. 17: 342' ( 1969}.
2.'Yt Hood. W. B., Jr., McCarthy, fL and Lown. 8,~
~yocardia} i:nfarrtton foUowing eoronary ligation m dogs:
hemodynamic effects of isoproterenol and acety!strophanthi-
d:in, Circulation Res. 21! 191 { 1967}.
255. Kumar, R., et al.: Expenm\1\ntal myocardial infarc-
tion. Vl Efficacy and toxicity of digitaHs in acute a:nd heal.
ing phase in lnute-t consciou;; dogs, J. CHn. Invest, 4'.t: :1.58
(1970\.
256. Askey. J. ~L Digitalis in acu~e myocardiat infan.>
tion, J.A.M.A. 145; 1008! 19511.
25i. Boyer. ;.,i, H.: Dig~tali£ in acute myo<:-ardutl infar<>
tion r.;ew England J. ~1ed. 252:536 t 1StJ5L
2s's. 8anazaro, P. J: Use of deslanosid~ in acutt myocar_"
dial infaKtion and c;udiac emetgendes, Am. Pract 8; l9:5~i:
09>i7). I . , 5::!5 (()cLJ 1972
259. Gor!in, R: .• and Robin, E. i:L Cardtac g yco;.tde::;, m
the treatment of cardmgenic :>hock, Brit. M~ J. l; 9:n! l955i ..
260. Gorlln, R: MOO~rn treatment of coronary tKdu~n·m
and insuffici-ency. M. Clin. :Xorth America 4-6: i243 ( 196~). . effeci of g'luca;ttm un arrhythmias due to digitalis toxicity,
261. Gunnar, R M., N al: The hemndynam1~ eife<:t~>'o.l
myocardlai infarctwn and N:sult::> of therapy, 1bui ;;4: ...,;.'-}
(197(}}.
262. Cohn, J. ~"' and. Tri~ta~i,. F. K:, CardiAc an-d
nphera! vascular effeet:; ot d1gnahs m card;ngemc ;.h1)<'k, ( n··
re·
cutati.fJn 36: S8 i l96i).
263. Cohn. J, !\' .• TristanL F. E .. and KhattL L M.: Car-
diac and pt-riphera! efft'!cts- of di.gna:lis in c!imcal ;,;ardmg-umc
:ohock. Am~ Heart J. 1S: :H8 ( i969} , .
264. L1pp, H., et al ~ Hemod:yrumw: etfects ol mtrav~mou~
dlgmdn m acute rnyocan.Hal inh:rNwn. Ann. Int Nl:\"d 76: 8b:,
(~ayi197:l.
August 1, 1973 / New Vorl< State Journal o! M&dicine
2&'1 . H~ge:\, M:, £'tat.~ Effects of intravenously adminib-
tt:re~ dtgo..:_mt?" mttd left w;ntricular failure in acute myocar-
dud mfarctton .1n man. Am. J. CardioL f9: 749-tJune} 1972,
266 Wolk, M. J., Sche-idt, S,. and KiUip, 1\: Heart fail~
ure <:ompticating acut~ mY1'JoC4t.rdial infarction, Circulation 4$:
1125 (May; 19/2.
267. Constant, J.: Digitalis in myocardlal infarction:
changing l'Ot'lcepts, !'e-w York State J Med. 10: 6$0 (1970).
268. CovelL J. W., et aL Studies on digitalis. XVL Efv
ffi:ts on myocardial oxygen consumption, ,J. CHn. Invest. 45·
l5:lS 09661 •
:269_ Bing, R .1., e-t af.; Eff-eet of strophanthus Qn coronary
b!(}(}d flow anrl cardiac oxygen cons.umpt)on of no:rm:at and
faihng human hearts, Circuiatkm 2:513 09501.
" 270. Hood, W. f3., Jr., et al.: Experimental myocardial
•nf&t<:tlon, Reductwn of left ventricular compliam:e in he-al·
ing phase, J. Clin.lnv.est. 49; 1316 (1970},
27!. Chai, C. Y., et al.: Mechani$mS of hrady-catdia in·
duced by dlg-itali,. substances, Am. J. PhysioL -2t2; 26 (1967:L
272. Cfumg, E. K: DigitaHs Int.-oxicatl-on 1 Baltimor-e 1'he
Withams & Wilkms Co., 1969. '
·.n:t Mason, D. T., et nL Current concepts and treat.
ment of digitalis to"&it::ity, Am. J, Cardioi. 27: 546 {May} 1971.
214, FiKh. C.: Dig:italki intoxication, J.A.M,A. 216: 1770
(.June} 197L
275. Butier, V. P., Jr.: Digoxin: tmm.unologi~ approaches
to measurement and rev.e-rsal o.f toxicity, New F.ngiand J,
Med. :!83: 1 !,50 (1!<70)
2:76. Smith, T. W.: Measurement uf serum digitalis gtyco~
sld~: elm kat implications, Circulation 43! 179 (Feb.) 1971.
Tl7. Idem: Contribution of quantit-.a.t.ive assay techni.;s to
the undttl'Standtng of the clinical pharmacology of digitalia,
<h«i 46: !88 \July) 1972.
278. Brennan, F. J_, et at.: Effects of ouabain on myocar-
dia! potassium and sodium balance in man, ibid. 4.5: 107
(Jan.l1912.
27ft. Goldsmith, C .• et aL: Co.rreJation of digitalis intoxi~
cation with myocardial conell1utration of tritiated digoxin. in
hypokalemic .and normokalemie dogs. ibid. {5>~PP- 3) 40: 92
11009i.
280. Prindle, K H., et at.: Influence of ~xtracellular po-
tast>ium concentration on myocardial uptake and inotropic ef·
feet of tritiated dt~xin, ibid. (supp. 3.} .tO: 165 {1969}.
28L AH:wrti, K. G-., et aL Rtversai of ouabain·itiduood
a-rrhy.thmi&~ in the dog by intravenous arginine hydrochloride,
Card:lovasc. Res. 5:226 (Apr.) 197L
282. Kones. R J., and Phillips., J. H.: Glucagon-present
status in cardinvascular disease, Clln. Pharmac-oL Therap. 12!
427 iJutw-} 1971.
283. Farah, A., and Tuttle, R.: Studies on the pharmaoot~
ogy of glu~agon, J. Pbarmaoo-t & Exp-er. Therap. t29; 49
0960)
284. GHdt, G., et al.: Giu<:agon·-it-S enhancement of car-
diac performance in the cat and dog and persistence -of its ino-
trop~c action despite beta reeeptor blockage with propranolol,
Ctr<:ulatkm ,RI:';:j, 22: 789( 1968).
285. Steiner, C., Wit, A. L, and Damato, A. N.: Effects
of glucagon on atrioventricular c:om:iuction and ventricular au-
tomaticity ln dogs, tbid. 24: 167 \1969L
:CBG" Whitsitt, L. S" and LU«hesi, B. R.: Effects of beta~
receptor blockade and glu.cagon on tM atrioventrl~\*lar tram-
mikStonsystem in the dog, ibid. 23:585 (1968),
287. Kents, R J., end PhiUips, J. H.: Newer inotropic
agents fnr cardJQgenic shock, Southern M. J. r"'. 329 (Mar.)
1912.
288. Idem: Glucagon in eardiQgenic &hock. Angiology 23:
289, ldem.· Glucagon in: congestive heart failure, Chest 59:
J92tApr.l i9?L
29{}, Cohn., K. E., Agmon, J., and Gamble, 0. W.: The
Am .•). CardtoL 2.'): 68~1. 097tH.
29! Luderit-z::, Bq and Bolte. H. D.: Cardiac actions of
ghJ("tlf(tm: electtnphysiologic effects on ventricular myocar·
dmrn, Ztschr. Kreu:olauffors.<:h $0: 13tH Feb.; l97L
ZS'2. Puri, P, S., and 8h'lg. R. J.: Effects of gtuc.agon on
mvno::atdiai ,;~mtraenlitv and hemodynamics in acute e-xpert·
mCnta~ mvocarrlial inf.&rction, Basis for its possible use in
>;ardiugeni:C ~hock, Am. Heart J. 18~ 66-0 {W69).
:..~;; Mancht'r..t.er. J. H .. ct ai.: Benefu:ial effects c.f gluca·
g'm >:> canme myot:atdiaf mfarction and shock, CEn. Res, 17:
2!'1:! i t009)
:194 Kum.u, tL ct a!.: Experimmltal myocardial infat:e.·
1979
 ~ion. ~tcacy of glucag:<m in acute and Mating phase m
X.
u~tact conscJOWi dogs; eff~ on hemodynamics and my()(;az.
dutl 01)'gen c<msumpt~on, Circuhttion 45: 5S (Jan.) 1972.
295, Nola, G. T., el aL Eff.eets of gtucagon on a multi~
strtss.ed cil'C:Ulation. Chest 6l~ 420 {May} 1972.
296. Gn:!gary, J .• eta{: Effects of ducagon on eardiovas·
cuiar dynamics and myQCardlal metsbo!iam in th~ low <:ardiac-
outputtttlte, Clin. Res. 17:243 0969-J.
297. GreenbetJ. B. H., Tsakiris. A. G., and Moffit, E. A.:
The bemodynartuc and metabolic eff~ of 2lucagon In pa.
tients with chronic valvular heart disease, M"ayo Chn. Proc.
45:132(1970).
298. Anl$terdam, E. A .• et uL Cfmiio<:irctdatory effll!t.-ts of
glucagon m patients with rongestive heart failure and ctudi-
ogonic shock, Am. J. Cardiol. 25: 32 ( 1970).
299. Parm~ey. W. W., and SonnenhHek. E. H.: Glucagon;
a new agent ln cardilu:: therapy, ibid. 21: 298 (Mar.) 1971:
300. Lvoff, R., and Wik:ken, D. E.: Glucagon m bean
faUure and in cardiopnic shock Experi-ence in 5() patients,
Circulation 4$; 534 {Mar.) 1972.
301. Eddy, J. D.. O'Bri•n. E. T., and Singh, S. P.: Gluca·
gon and huroodynamies of acute myoca.rdisJ infa.n:tion, Brit.
M. J. 4:003 (1969).
S01t Robert, M" and Hurnair, L.: Effe('t cardtownique du
gtucagon, Schweiz. med. Wcbnsthr.lOO: 1345 (1970).
303. ~urtagh, J. C., et ol.: Haemodynamk effects of glu"
cagon, Bnt. H ..ttJ. 32:307 0~70;.
304. Diamond, G., et al.: H6emodynamic effe<:ts of glue&·
gon during acute myocardial mfarction with !eft ventricular
failurt in man, ibUf 33: 290 {b.br.) 19'71.
305. Kontf.>, R, J.: Systolic time mtervals after acute
myocardial infarction; -effect of glucagon administration, in
prt;pmatltm.
300. Ghck, G.: Compari.s()ll of the peripheral v~ulat ef-
~U of gluca~. norepinephrine, isoprourenol and d-opamine,
Clin. Res. 18: 307 {1970).
307. Motsay, G. J., e:t at.; Effe<:t.s of corticosteroids on th~
drcul&tion in shock: exp(rrimental and clinical resulu., f'ed.
Proc. :It: Hl61 (l970l.
308. Dieu:nuw. R. H., and LiUehei, R C.: Cm:uiatory
collapse in shock, in Sehwaru:, S. l., Ed.: Principles of Sur·
pry, N•w York, McGraw Hill, 1969, p. !19.
300, Ullehei, R C., ut a[: Treatmertt of septlC shock,
Mod. Treatm. 4: 2!3 {1007).
:no. &achft.fd, N"; Maintenance of <:(IH viabitity, CiKula·
tion l•upp. 4) 40: 202 (1969).
31 L Buchanan, W, E., imd Schwartz, T. B.: Lysosomal
enzyme activity in heart and akelttal JnUS(.!lfl' of cortisone-
treat-00. rnts, Am,J. PhysioL !12: 732 (1967)_
312. Suarea~Roldan, P .• and Casas, C.: Effect of hydro-
cortisone on oorona.zy flow and cardiac: effl:cieru:-y, :preiimi.nary
report, Puerto Rko Heart Association Meeting, San Juan, P.
R .• (Sept. J 1967.
313. Hairaton, P., Dalton, D. H., and Lee. W. H.: Mas·
siw: corticwteroids: effect on myocardial in-otropism, Circula-
tion {supp. 4) 38:920968).
314. Starr, J. E .. Ahn, C., and Vasko. J. S.: The effects of
ad~~uroids on myocardial eontractility, ihfd. (11upp.
613!!: 189 (!969).
315. Teckl.enherg, P. L .• tt al.: The effe<:ts of miW>ive
doses of m.etbylp'f\t!dnisolmw on myocardial .c<mtractihty and
t*ri;>heral vascular resistance, Am. Heart J. 85; 216 tFebJ
1973.
316. Di•tzman. R. H., Block, J. H., and Ulleh<n. R. C.;
The role of steroids as vasodilators in card~ogenk s-hock. Am.
J. Cardiol, 21:96 (1968).
317. Ch<>u, C. C., Rudko, M., and Haddy, F. J.; Effect.s of
h:ydl'()(Ortisone on fo-mlimb resistance re:sp<.mse6 to vasoactive
ag-ent.'i- in intact and adrenalec:tomJxcd dogs, Chn. Res. J6: 43..1
11003).
:na, Joht\$0n. A. S., et af: Effect of cortiS<lne on the size
of e:tperimentaliy ptOOuced myocardial infarcts, Circulation 7:
224 (19.'\3).
319. Gerisch. R. A.• et aL: Acute my«ardud tnfarct.icm in
man treated with cl:lrtisone, Detroit Mich. Harper Hoop. Bull.
li: !97(1961).
320. Chapman, D. W.. !'l al.: The- effect of C<lrtisooo in
eJ.periment.al myocardial infart:tion, Am. J. M. Sc. 223: 41
(!962).
32L Opdyke. D. F'., el aL: Failure to reduce the slxe of
upm"hnente.lly produ<Ced myO<:a:rdlal iniar<:ts by cort.i.l'ione
treato:umt, Circulati:on 8: 544 {1953),
3.2'2:. Hepper, N. G.: The effect. of cortisone on ~aling of
experimentally producl!d myocardial lnfarction in. dogs, The>
1980 New York State Journal of Medicine I August 1. 1913
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sis. Mayo Graduate School of Medicine. Univ, of Minn.~ Roch~
e&tff. 19S4'
3~. , Libby, _P,. et aL. Redu,ction in .experimental myo.~
ca«hal nlfarct stze by cort;costernld. admuristrat:ion, J. Clin.
[n\'e$t. 52: 599lMar.) l913.
323. Raob, W.: MyocordW electrolyte derangement:
CTUC!al featUl"C. erf pluricauul. SO-£aUed COJ'OruUy heart disease
~f§OO}.lc cart:ilopathy), Ann. New York Acad. Sc. 141: 629
324 .. Haddy, .F. J., et ai.: LIJCal voscut.r ef!eetil of hypo.
kalemt~, alkaiosw, hypen;alcemut, and hypomagnesemia, Am.
J. Phy:uol. %04: 202(1963).
325. Hoddy, F. J., and &ott, J. B.: Effect.s of electrolytes
and water. upon. teststance to blood flow tbrough intact vaacu-
h~! beds, m BaJu.sz, E., Ed.: Electrolyte~j. and Catdiov.ascuiar
D~SeUll<!l, B~. S. Ka'!lot, 1965, p. 38.1_
32&., BaJus.z, E., Ed.: Experimental "metabolic" cardi·
opathle$ and their :relatiooship to human heart disease, Ann.
Ne-w York Acad. Sc, 15th 1 (1969}.
327. Klein, A. J.~ and Palmer, L. A.: Plasma c:ortisot in
myocardial lnfaretlon, Am .•1. Cordi¢111: 332(!963),
328, Logan, R W., .a:nd Mutdooh, W. R: BloodAew!s of
hydrocortis-one, tnnsamln~. and chol•terol after myocarw
diAl infarction, Lancf't 2:521 (1966)>
329. Bailey, R. R., Abomethy, M. H., and Beaven, D. W.:
Adrenocort.Jcal response to the stress of an acute myocardial
infarctmn, ibid. l: 9-70{1,967).
330, Hansen, B., et at.: Plasma~hydroeorti&one values in
heart disease~ Acta med. &:candinav. 186; 411 i1969t
~L Pra~b, a. et al.; ~rum. cortisot plasma free fatty
acid."> and unnary cateehoiamuws as indicators rtf oo:mplic:a·
tions in acute myocardial infarction, Cireulatkm 45: 736
(AI"·) 1972.
33'1. Lillehei, R C., et a.l. ~ The modern treatment Qf
shock ba~ on pbysiologicaJ pri:nciplea, CHn. PharmaooL
Thersp. 5: 63 {l963}.
33.'l .. pietzm.an, R. H.~ et at.: Low output syndromes:
reeogmtuw and treatment, J. Thorac. Cardiovasc. Surg. S1:
!38(1969).
334. Corday, E., and LiUehel. R. C.~ Pressot agents in
c•rdiogeni<; shock, Am. J, Cordi<>~.~: 900 (1969).
3.30. Schultz. L. S., et at.: Chnieal c:ardl.og-enie shock.
V li\$\)prf$S()J" versus corticoid therapy, Ann. Int. Med. 76; 867
(May) 1972,
336. DaU, J. L C., and PeeJ, A. A,: A tri$1 of bydrocorti~
sone in acute myocardial infarction, Lancet 2: 1097 {1963).
337. ScientH1c Subcommittee of the Scottish Society of
Physicians: Hydrocortif>one in severe .myooatdial infamion,
ibid. 2': 785 H964~.
338. Sambhi, M. P., et al.; Adn<nocmticoids in the man·
agcme.nt ofshock,lnt. A~b. Ciin. 2: 421 (1964}.
339. WiJoon, R. F., and Fis.her, R. R.: The hemodynamic
effects (),f massive steroids ln dlnical shock, Surg. Gynec. &'
Ooo<. t.:!'l: 7690968).
340. Shubin, H., and WeH, M, H.: Failure of corticoete-
roid to potentiate sympath~Jmimttic p~r response during
sbo<k,J.A.M.A. Ul1':808(1966).
341. Lefer. A, M.; Role of a myocardial dep.ressant facwr
in the pathogt.mffi,is of drculatoey s..hock, Fed. Proo. 2$: 1836
(!970!.
342. Tlmlinger, A. R., and Leier, A, M.: Cardiac actl.om
of a myocardial dep~nt facto:t isolated from shock plasma.
Pnx. $()(:. Exper. BKIL & Med. lU: 354 {Feb.} 1971.
343. Glenn, T. M., et al.: Production of a tnyocardiai d~h
presstmt factor in cardiogenic shock. AnL Heart .1. 82: 78
(July) 197!.
344. Crampton. R S., l!t aL Production of a. myocardial
d,epl"(::Sffant !actor in shock fuUnwjng myt>Cardial infa:retion;
preliminary evaluation of treatment with methylprednisol~
one. AttL J, Caffiiol. 2$; ZS7 (Feb.) 1972.
345. Prin:tmetal, M., and Kenna.tne:r, R.: Emergency
treatment Q{ ca.rdiac arrhythmias, J.A.M.A. 154: 1049 {1954).
346. Dahl, J. C.: The l,l..!),e of adrenal steroids in cs.rdiac
dis<-. Minn...,.,. Med. 4~: 451 (1963).
347. Baroody, N. B., and Baroody. W. G.: Adrenocotti-
coids in 3Cute myocardial infarttron, Am, J. M. Sc. !SO: 402
(1965).
348. Lusiani, G. B., et at.: Valore e Hmtti dell& teTapia
cortieooteroid-ea nella fase acute deU'infarto del miocardio, G,
Citn. Med. Sll: 2! (1969!.
:!49, Bardiai, D,. ct ol: Treatment of myocardial infare-
tion with hydrocortiso~. J. Isr. M.A. 74: 1£5 U96..~).
3f>C. Bartilai, D., et aL: U$e of hydi'OCOrtisone in the
t.reatmtmt of aet.ite myocardial inl&rction. Summary of a din·
ical tnal in 446 patients-, Chest 6.\" 488 !May} 1972.