Hemodynamic effects of glucagon and intraaortic balloon counterpulsation in canine myocardial infarction

Hemodynamic Effects of Glucagon and Intraaortic Balloon Counterpulsation in Canine Myocardial Infarction

JACK M . MATLOFF, MD WILLIAM W . PARMLEY, MD JOEL H . MANCHESTER, MD BAROUH BERKOVITS EDMUND H . SONNENBLICK, MD, FACC and DWIGHT E. HARKEN, MD, FACC Boston, Massachusetts

The hemodynamic effects of glucagon (50 µg/kg) and intraaortic balloon counterpulsation were investigated in open chest anesthetized dogs after production of myocardial infarction and cardiogenic shock . Glucagon produced striking increases in arterial pressure, cardiac output and maximal left ventricular dp/dt together with a reduction in left ventricular end-diastolic pressure and systemic vascular resistance. The condition of most animals was stabilized at a viable level with 1 or more doses of glucagon . The effects of counterpulsation during severe cardiogenic shock were slight, although good counterpulsation was always achieved during control studies with normal pressure. When counterpulsation was instituted in combination with glucagon therapy there was an increase in mean arterial pressure together with a reduction in maximal left ventricular dp/dt and peak systolic pressure . Thus, counterpulsation tended to reduce the increased oxygen cost of the inotropic effects of glucagon . We suggest that an appropriate combination of counterpulsation and isotropic support (as with glucagon) may be better than either method alone .

The occurrence of cardiogenic shock after acute myocardial infarction has been associated with a mortality rate of at least 80 percent despite vigorous medical therapy .1 ,2 The use in cardiogenic shock of mechanical assist devices, such as counterpulsation and left heart bypass, has not had uniformly beneficial results 3 .4 To be effective, temporary assistance of the circulation with mechanical devices still requires a certain minimal cardiac function- Thus, phannacologic assistance is often necessary . In cardiogenic shock, cardiotonic drugs such as digitalis and catecholamines may provide some temporary improvement in cardiac performance ; but arrhythmias, tachyphylaxis and changes in peripheral resistance limit the extended or increased use of these From the Thoracic Surgical Research Laboratory, Departments of Surgery and Medicine, Harvard Medical School and Peter Bent Brigham Hospital, Boston, Mass . This study was supported in part by National Institutes of Health Grants HE 08698-05, HE 11306-02 and American Heart Association Grant 67-782 . Manuscript received June 19, 1969, accepted September 8, 1969 . Address for reprints : William W . Parmley, MD, Department of Cardiology, CedarsSinai Medical Center, 4833 Fountain Ave ., Los Angeles, Calif. 90029 .

VOLUME 25, JUNE 1970

agents . Thus, there is a need for effective agents that increase the contractility of the failing heart in cardiogenic shock but have minimal detrimental side effects . Glucagon may be such an agent . The cardiovascular effects of glucagon, a polypeptide hormone, have been investigated in various animal preparations, 5,6 and in patients during cardiac catheterization7-10 and after prosthetic valve replacement ." Glucagon has been shown to produce a slight increase in heart rate, a moderate increase in cardiac contractility, an enhancement of A-V conduction 12 and a slight decrease in peripheral vascular resistance . No accompanying increases in ventricular automaticity have been noted ."'

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MATLOFF ET AL .

These effects have been shown to be independent of cardiac catecholamine stores and are not prevented by beta adrenergic blockade with propranolol5 •e

Moreover, the beneficial effects of glucagon may be additive to the effects of full digitalization without producing toxicity5 .7 . u The present study was undertaken to evaluate the effects of glucagon alone and in conjunction with intraaortic balloon counterpulsation in the treatment of experimental cardiogenic shock in dogs .

Methods and Materials Mongrel dogs weighing 18 to 25 kg were anesthetized with Nembutal® sodium, intubated and maintained on a Harvard respirator. Adjustments of respiratory volume and rate were made to maintain pO, in the range of 150 -!- 25 mm Hg, pCO 2 at 25 to 30 mm Hg and pH at 7 .42 to 7 .46 . During periods of induced cardiogenic shock, pH stability was maintained with intravenous administration of sodium bicarbonate as required . All infusions subsequent to induction of anesthesia were made through a cutdown procedure on the femoral vein . Electrocardiographic leads were inserted subcutaneously in the limbs . A bilateral transsternal incision in the fifth intercostal space afforded adequate exposure . An internal mammary or carotid artery was cannulated

Figure 1 . Radiograph of a representative canine heart at autopsy. Severe myocardial infarction and cardiogenic shock were produced by the injection of 0 .3 ml of elemental mercury into the left circumflex coronary arterial system (right) and 0 .1 to 0.2 ml into the left anterior descending arterial system (left) . The wide distribution of the mercury into smaller vessels is apparent .

676

with a Silon® catheter for measurement of peripheral arterial pressure . The pericardium was opened longitudinally, and marsupial sutures were placed to support the heart . A 16 or 18 mm flow probe was placed around the ascending aorta . A Do . 8F catheter was placed in the left ventricle through an apical purse-string suture for the measurement of left ventricular pressure . In no instance were collateral vessels at the apex of the ventricle compromised by this procedure . The left anterior descending and circumflex coronary arteries were dissected free near their bifurcation . Teflon®-coated pacing electrodes were placed in the right ventricular myocardium. Blood volume was maintained by the use of fresh heparinized blood or Ringer's lactate solution, or both, as indicated by changes in central venous pressure, peripheral arterial pressure and left ventricular end-diastolic pressure . Permanent heart block was induced by transatrial infiltration of the A-V node with a solution of 40 percent formaldehyde . 19 Thereafter, the heart was paced at a constant rate of 150 beats/min . The electrocardiogram, peripheral arterial pressure, left ventricular pressure, the rate of left ventricular pressure development (dp/dt) and central aortic flow were displayed on an 8 channel oscilliscope (Lexington) and recorded as indicated . Stroke volume was determined from the integral of central aortic flow . Measurements were made at appropriate intervals before and after intraaortic balloon counterpulsation of 10 minutes' duration and the infusion of 50 tg/kg of glucagon in 50 ml of 5 percent dextrose in water over 2 minutes . The intraaortic balloon was introduced through a femoral artery and positioned in the descending thoracic aorta with its distal tip at the origin of the left subclavian artery . Heparin, 1 mg/kg, was given prior to insertion of the balloon ; no clot or fibrin formation was seen . An 1S or 25 ml balloon was chosen according to the size of the animal . Subsequent measurements were made with the balloon collapsed by negative pressure . After control measurements were obtained, myocardial infarction and cardiogenic shock were produced by one of two techniques . Initially, the left circumflex coronary artery was ligated progressively over 15 minutes . This technique resulted in cardiogenie shock but was not totally reproducible . Thereafter, 0 .2 to 0 .4 ml of elemental mercury was injected directly into the left circumflex coronary artery through a no . 22 needle (Fig . 1) . This resulted in more reproducible cardiogenic shock ." Prior administration of 1 .0 mg of propranolol with either technique of infarction did not affect the incidence of arrhythmias . Repeat measurements were then obtained during relatively stable cardiogenic shock ; during 10 minutes of counterpulsation ; after an infusion of 50 µg/kg of glucagon ; and in association with the combination of counterpulsation and glucagon . In each instance the dog was allowed to return to the control state of cardiogenic shock for at least 10 minutes

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GLUCAGON AND COUNTERPULSATION IN MYOCARDIAL INFARCTION

before the next therapeutic phase was initiated . At the conclusion of the experiments the animals were killed .

TABLE I Effects of Glucagon (50 Ag/kg) After Acute Myocardial Infarction In Five Open Chest Dogs Without Pacing

Results Hemodynamic effects of glucagon after acute myocardial infarction in dogs without pacing : The hemodynamic changes produced by ligation of the left circumflex coronary artery in 5 dogs arc listed in Table I . Heart rate increased from an average of 147 to an average of 163 beats/min ; mean arterial pressure levels fell from 118 to 88 mm Hg . Although heart rate increased and left ventricular end-diastolic pressure rose from 9 to 18 mm Hg, maximal rate of

Heart rate (beats/min) Arterial pressure (mm Hg) S/D Mean LVEDP (mm Hg) Maximal dp/dt (mm Hg/sec) Peak aortic flow (%)

Control

Infarction*

Glucagont

147

163

206

144/101 (118) 9

114/78 (88) 18

137/81 (94) 18

3,190 100

2,760 70

5,720 98

rise of left ventricular pressure (dp/dt) fell from an average value of 3,190 to 2,760 mm Hg/sec and peak aortic flow declined 30 percent . Substantial myocardial infarction and cardiac depression were produced,

(P < 0 .05) .

but cardiogenic shock did not occur in any of these 5 dogs .

left ventricular end-diastolic pressure . LVEDP = left ventricular end-diastolic pressure ; S/D = systolic/diastolic .

All infarction values were statistically different from control !All glucagon values were statistically different from infarction (P < 0 .05) except for diastolic and mean arterial pressure and

After infarction, glucagon (50 ILg/kg) was infused in 50 ml of normal saline solution over a 3 to 4 minute period . The effect of glucagon, manifest at 1 to 2 minutes., was maximal in 5 to 7 minutes and was sustained for at least 15 to 20 minutes . Maximal hemodynamic effects of glucagon are listed in Table I . Average heart rate increased from 163 to 206 heats/ min . Although there was only a slight increase in

ure 2 . During counterpulsation, systolic unloading of

mean arterial pressure (from 88 to 94 mm Hg), pulse pressure increased from 36 to 56 mm Hg . Maximal dp/dt increased 108 percent, and aortic flow was re-

the ventricle reduced peak left ventricular pressure levels from 129 to 112 mm Hg, but mean arterial pressure levels were maintained at 88 mm Hg . Stroke volume and left ventricular end-diastolic pressure were essentially unchanged, but maximal dp/dt was reduced from 1,820 to 1,585 mm Hg/sea . After counterpulsation, hemodynamic measurements returned to control

stored to control levels . Left ventricular end-diastolic pressure levels were unchanged . In 4 of 5 animals, the hemodynamic improvement produced by glucagon was maintained by repeated

levels . Glucagon (50 pg/kg) was then administered over a 3 minute period . Maximal effects are illustrated in Figure 2 (right) . There was no change in mean arterial pressure, but pulse pressure increased

doses (1 to 5) for periods of more than 2 hours, at which time the experiment, was terminated since the condition of the animals was stable . The fifth animal, which had multiple ligations of the circumflex and

from 49 to 77 mm Hg . Stroke volume rose from 20 to 34 ml, and maximal dp/dt increased from 1,820 to 3,111 mm Hg/see. cumulative results in 7 dogs are recorded in The

anterior descending arteries, became increasingly bypotensive despite administration of glucagon, and it died . All 5 dogs had multiple ventricular premature beats, and in 2 dogs ventricular fibrillation developed

Table II . With counterpulsation there was a reduction in peak left ventricular systolic pressure from 109 to 90 mm Hg, with essentially no change in enddiastolic or mean arterial pressure . Average maximal dp/dt was reduced from 1,980 to 1,610 mm Hg/sec . There was little or no change in stroke volume, peak

which was unrelated to administration of glucagon . In 3 dogs ventricular fibrillation developed near the peak glucagon effect, coincident with a rapid supraventricular tachycardia . All these episodes of ventricular fibrillation were reverted with d-c countershock. Hemodynamic effects of counterpulsation and glucagon before myocardial infarction : To prevent the effects of alterations in heart rate, atrioventricular (A-V) block was produced before myocardial infarction, and 7 dogs were studied at a constant paced rate . A representative experiment is illustrated in Fig-

VOLUME 25, JUNE 1970

aortic flow or systemic vascular resistance . After counterpulsation and a return to control hemodynamic values the administration of glueagon (50 µg/kg) produced an increase in mean arterial pressure from 80 to 88 mm Hg and an increase in pulse pressure from 44 to 59 mm Hg . Although left ventricular enddiastolic pressure did not change, maximal dp/dt, peak aortic flow and stroke volume increased significantly, but systemic vascular resistance was substantially reduced .

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MATLOFF ET AL.

A-V BLOCK

ECG

AO FLOW

CF dl

CONTROL

ART PRESS lmm 1121

170/60

OnITFRFI1(SATION IIMFA-AORTIC BALLOON) .3/122

179

MEAN 9,m Hp)

69

U.

07

PEAK FLOW

1WTn

104%

215%

Ib

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20

II

AN% ~,MooE 1..c,

1970

1200

LEESlot,H9l

Hemodynamic effects of counterpulsation and glucagon after myocardial infarction : After all hemodynamic values returned to normal, myocardial infarction was produced by the intracoronary injection of elemental mercury, and the studies described were repeated when technically possible . A representative experiment is illustrated in Figure 3, as a continuation of Figure 2 . The dog had severe cardiogenic shock (mean arterial pressure 37 mm Hg) . With counterpulsation, there was no change in mean pressure or peak left ventricular pressure although peak aortic flow and stroke volume increased . Maximal left ventricular dp/dt was slightly reduced with little change in end-diastolic pressure . After counterpulsation was concluded, glucagon was administered . There was a substantial increase in mean arterial pressure (37 to 71 mm Hg) and in pulse pressure (17 to 55 mm Hg) . Left ventricular end-diastolic pressure, maximal dp/dt, peak aortic flow and stroke volume returned to control levels, The use of counterpulsation at the peak of the glucagon effect increased mean arterial pressure from 71 to 89 mm Hg . Stroke volume, peak flow, and left ventricular end-diastolic pressure remained constant- Peak left ventricular systolic pressure and maximal dp/dt were slightly reduced . The cumulative hemodynamic effects of glucagon in 9 dogs with infarction and a constant heart rate are shown in Table III, After myocardial infarction the

678

)40/63

PEAK LV SYSTOLIC rmm 1511

5

Figure 2. Representative experiment showing the effects of counterpulsation and glucagon (50 iAg/kg) on the electrocardiogram (ECG), aortic (Ao) blood flow, dp/dt, carotid arterial pressure (CA) and left ventricular (LV) pressure of an open chest anesthetized dog before myocardial infarction . Art = arterial ; LVED = left ventricular end-diastolic pressure ; RV = right ventricular ; S .V . = stroke volume .

average value of arterial pressure fell from 90 to 57 mm Hg ; that of left ventricular end-diastolic pressure increased from 7 to 13 mm Hg . Maximal dp/dt decreased from 1,980 to 1,140 mm Hg/sec, and peak aortic flow and stroke volume decreased 40 percent . At these levels of shock, glucagon (50 pg/kg) was administered intravenously . Maximal hemodynamic effects of glucagon occurred in 5 to 7 minutes . Mean TABLE II Effects of Counterpulsation (CP) or Glucagon (50 ,Mg/kg) in Seven Open Chest Dogs with Pacing

Heart rate (beats/min) Arterial pressure (mm Hg) S/D Mean Left ventricular pressure (mm Hg) Peak systolic End-diastolic Maximal dp/dt (mm Hg/sec) Peak aortic flow (%) Stroke volume (ml) Systemic vascular resistance (dyne sec cm-5)

Control (7 Dogs)

CP (6 Dog )

Glucagon (7 Dogs)

151

151

151

115/71 80

49/103* 78

132/69* 88*

109 9

90* 7

147* 7

1,980 100 20

1,610* 91 18

3,420* 204* 38*

2,120

2,300

1,230-

* Statistically different from control (P < 0 .05).

The American Journal of CARDIOLOGY



GLUCAGON AND COUNTERPULSATION IN MYOCARDIAL INFARCTION

MYOr.ARLXAI

COG na

INFARCTION

RV PACFMAKFR

16$mv,

AO FLOW

CA

LV

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Figure 3. Same dog as in Figure 2 after the production of severe myocardial infarction and shock . The successive hemodynamic effects of counterpulsation, glucagon, and glucagon plus counterpulsation are illustrated .

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TABLE III Effects of Glucagon (50 µg,/kg) After Acute Myocardial Infarction in Nine Open Chest Dogs with Pacing Control

Infarction

Glucagon

149

149

149

113/80 90 7

79/52 57 13

112/66 78 10

1,980 100 19

1,140 60 12

2,280 100 28

2,540

2,550

1,500

All infarction values were statistically different from control values (P < 0 .05) except for heart rate and systemic vascular resistance. All glucagon values were statistically different from infarction values (P < 0 .05) except for heart rate and left ventricular end-diastolic pressure.

VOLUME 25, JUNE 1970

SD

s

vascular resistance was substantially reduced .

Heart rate (beats/min) Arterial pressure (mm Hg) S/D Mean LVEDP(mm Hg) Maximal dp/dt (mm Hg/sec) Peak aortic flow (%) Stroke volume (ml) Systemic vascular resistance (dyne sec cm-5)

351103

70a

arterial pressure rose to an average value of 78 mm Hg, and pulse pressure increased from 27 to 46 mm Hg . Average left ventricular end-diastolic pressure fell from 13 to 10 mm Hg ; maximal left ventricular dp/dt and stroke volume doubled ; and systemic

27.7

r,IM.MNIN 6 CCINTFRBI $ATIl7N

Six of the 9 dogs continued to respond to additional doses (1 to 4) of glucagon as needed, and their condition was stable when each experiment was terminated 2 hours after the production of myocardial infarction . Two other dogs responded to an initial dose of glucagon but could not be maintained on further doses ; their condition deteriorated to death . The final animal responded to an initial dose of glucagon, but ventricular fibrillation developed much later, and resuscitation was not possible because of power failure of the defibrillator . The results of counterpulsation alone and of combined counterpulsation and glucagon after myocardial infarction are shown in Table IV . After myocardial infarction, mean arterial pressure fell from 93 to 57 mm Hg, but left ventricular end-diastolic pressure rose from 5 to 13 mm Hg . In addition, maximal dp/dt, peak aortic flow and stroke volume were reduced 50 percent. In the infarction state with counterpulsation, mean arterial pressure rose only slightly (from 57 to 63 mm Hg), and there was little change in peak left ventricular systolic pressure . Stroke volume rose from 10 to 14 ml without any change in left ventricular end-diastolic pressure . Counterpulsation was discontinued and the administration of glucagon (50 tg/kg) begun . Mean arterial pressure

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MATLOFF ET AL.

TABLE IV Effects of Counterpulsation (CP) or Glucagon (50 pq/kq), or Both, After Acute Myocardial Infarction In Three Open Chest Dogs with Pacing Control

Infarct

149

Heart rate (beats/min) Arterial pressure (mm Hg) S/D Mean Left ventricular pressure (mm Hg) Peak systolic LVEDP(mm Hg) Maximal dp/dt(mm Hg/sec) Peak aortic flow (%) Stroke volume (ml) Systemic vascular resistance (dyne sec cm -")

149

120/79 93

CONTf

1iisi

TIME

(MIN

0

121/65 83

58/123 90

70 13 820 50 10

68 14 770 52 14

121 7 2,120 121 30

119 7 1,974 111 31

2,800

3,440

2,720

1,670

1,560

produced a further increase in mean arterial pressure (from 83 to 90 mm Hg) ; there was little change in peak left ventricular systolic pressure, maximal dp/ dt or stroke volume . Prolonged counterpulsation in these dogs without further glucagon support failed to prevent rapid hemodynamic deterioration, and severe shock with pulsus alternans developed in all 3

rMRIAIIY

1N:clun

0

5

149

122 5 1,770 100 20

CONTC01.

+0wcA00x .IS

CP & Glucagon

149

33/84 63

SURGICAL A-V BUCK

DOG •7

Glucagon

149

75/47 57

rose from 57 to 83 mm Hg, and pulse pressure increased from 28 to 56 mm Hg. Left ventricular enddiastolic pressure fell to 7 mm Hg, but maximal left ventricular dp/dt, peak aortic flow and stroke volume more than doubled . Systemic vascular resistance was again substantially reduced . At the height of this glucagon effect, counterpulsation was instituted and

EVENT

CP

I

r s

x2

RV PPGFMAKFR-150/min.

uc*

Icr

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7

9

la e

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CAROTI D ART l00 PRESS. (-MEAN) !0 mull Hg 0-

LVEDP 15

Is

14

Is

13

mm Hg

4090

3000 V dPldt

I 0000

mm Hglsec. 1000

0

Figure 4 . Representative dog experiment showing the effects of glucagon before myocardial infarction, during d-c conversion of ventricular fibrillation (VF), and after myocardial infarction and shock. Arterial pressure, LVEDP and LV dp/dt are illustrated .

also

The American Joumel of CARDIOLOGY

GLUCAGON AND COUNTERPULSATION IN MYOCARDIAL INFARCTION

dogs . Infusion of glucagon during this period of progressive deterioration again improved the hemodynamic indexes and eliminated the pulsus alternans . Effects of glucagon in relation to ventricular fibrillation : Ventricular fibrillation was common in these dogs, occurring either as a single episode or as multiple episodes in 8 of 9 dogs with induced A-V block and myocardial infarction . The induction of myocardial infarction was closely followed by ventricular fibrillation in 6 of 9 dogs despite preinfarction therapy with 1 mg of propranolol . Four of the 9 dogs had an episode of ventricular fibrillation temporally associated with the administration of glucagon ; in each there was reversion to sinus rhythm after a single d-c countershock . In contrast to these 4 dogs, the episodes of ventricular fibrillation associated with myocardial infarction alone often required multiple attempts at defibrillation with Do countershock . In 3 dogs ventricular fibrillation was refractory to d-c countershock until glucagon was administered directly into the left ventricle . After 1 minute of manual systole, in each of these 3 dogs reversion to the regular paced rate occurred with d-c countershock . An example of this situation is depicted in Figure 4 . The left axes plot phasic and mean arterial pressure and left ventricular end-diastolic pressure and dp/dt . With the administration of glucagon under control conditions there was an increase in arterial pressure and maximal dp/dt with no change in end-diastolic pressure. After all indexes had returned to control levels, the left circumflex coronary artery was partially occluded . A precipitous fall in arterial pressure resulted, ensuing in ventricular fibrillation . Manual systole accompanied by infusion of sodium bicarbonate was instituted, but 4 d-c shocks over the next 4 minutes failed to restore the paced rhythm . Accordingly, glucagon, 2 mg, was injected into the left ventricle ; after an additional minute of manual systole, a fifth d-c shock was successful in restoring a regular paced rhythm . Fifteen minutes later, total occlusion of the left circumflex coronary artery produced hypotension to shock levels . The administration of glucagon over the next 3 minutes effected a . substantial rise in arterial pressure and maximal left ventricular dp/dt but no basic change in end-diastolic pressure .

Discussion The experimental models of myocardial infarction in the present study (Tables III and IV) result in profound cardiogenic shock and early mortality in 100 percent of untreated animals . The injection of elemental mercury directly into the coronary circulation to produce cardiogenic shock in the dog has already been described in great detail by Lluck et al .'s Given the presence of hypotension with diminished

VOLUME 25, JUNE 1970

perfusion of an already compromised coronary circulation, this inexorable downhill course is predictable and parallels clinical experience .' The mechanism of death in these animals relates to arrhythmias with ventricular fibrillation or to pump failure, or both . Therapeutic intervention in this setting must be predicated upon potential reversibility of the physiologic downward spiral that ensues after infarction . Glucagon : In the present study, the administration of glucagon produced a positive inotropic response manifested by an increase in cardiac output, a rise in peripheral arterial pressure despite a decrease in systemic vascular resistance, a decrease in left ventricular end-diastolic pressure and an increase in dp/dt (Table III) . With restoration of adequate arterial pressure, the condition of the animals tended to stabilize at a viable level despite the persistence of coronary occlusion . Ventricular arrhythmias accompanying the shock state generally subsided with the restoration of adequate cardiac, output and peripheral pressure . Dogs that required further doses of glucagon to maintain hemodynamic stability continued to respond without evident tachyphylaxis . In the initial group of dogs without pacing (Table I), glucagon produced a supraventricular tachycardia . This chronotropic response mitigated against the beneficial effects of glucagon and probably was deleterious by virtue of increased oxygen requirements . Fortunately in man, only a modest chronotropic effect has been observed . The cardiotonic effects of glucagon arc of some special note . Glucagon is a polypeptide hormone (molecular weight 3,500) produced by the alpha cells of the pancreas which acts physiologically to induce glycogenolysis and raise blood glucose levels . This action is mediated by stimulation of adenyl cyclase activity which converts adenosine triphosphatase (cyclic (ATP) to adenosine 3'5'-monophosphate AMP) . Cyclic AMP, in turn, activates phosphorylase activity which promotes glycogenolysis . 16 The positive inotropic and chronotropic effects •o f glucagon, which may also he mediated by cyclic AMP,ls , rr have been demonstrated in isolated cardiac muscle and dog preparations5 es and in man at the time of cardiac catheterization' -1 c and after cardiac surgery ." Furthermore, A-V conduction is enhanced 12 whereas atrial but nott ventricular automaticity is increased . 13 These inotropic actions of glucagon occur despite the depletion of cardiac norepinephrine stores and persist despite blockade of the beta adrenergic receptor mechanism with propranolol 5 .5 Although glucagon also causes a fall in serum potassium levels, it has not produced arrhythmias in digitalized patients . 7-11 However, since glucagon does produce a substantial increase in myocardial oxygen consump-

681

MATLOFF ET AL.

tion in cardiogenic shock by virtue of its effects on arterial pressure and contractility (Table III), areas of ventricular myocardium that receive a marginal blood supply may become more hypoxic and thus serve as a focus for potentially serious arrhythmias . Thus, occasional episodes of ventricular fibrillation were temporally associated with the peak glucagon effect .

Counterpulsation : In view of the dismal results with usual pharmacologic agents in the therapy of cardiogenic shock,' , ' considerable attention has been directed to the development of mechanical assist devices .3 In principle, these devices provide external energy to sustain cardiovascular function to permit recovery of the heart from the primary insult . Counterpulsation achieves these ends by reduction of systolic and augmentation of diastolic pressure . The former reduces resistance to ventricular ejection ; the latter augments coronary perfusion . One might anticipate an advantage to augmenting coronary perfusion pressure since the latter has been shown in dogs to enhance the formation of collaterals's This may help to preserve marginal and compromised areas of myocardium and limit the extent of infarction . However, these actions are predicated on a certain minimal ventricular function and cardiac output . Accordingly, augmentation of underlying cardiac

contractility becomes paramount to permit eounterpulsation to work . Indeed, in the present studies, intraaortic balloon counterpulsation alone was generally ineffective during the shock state when cardiac function was very seriously compromised (Table IV) Thus, at the level of cardiogenic shock produced in our study, counterpulsation alone did not improve hemodynamics enough to maintain viability, and there was continued cardiovascular deterioration . Clinical implications : Some degree of inotropic support may be needed in cardiogenic shock, and our study suggests that glucagon may be a useful agent . The increased oxygen cost of any isotropic agent may be deleterious, but maintenance of a viable cardiac output and coronary arterial perfusion pressure is mandatory . In these circumstances counterpulsation might reduce the oxygen cost of increased inotropy by unloading the ventricle during systole and substantially reducing the pressure-time per rninute . An appropriate combination of inotropic support (as with glucagon) and circulatory assistance with counterpulsation might provide adequate pressures and outputs at a minimum of oxygen cost, permitting survival of patients in marginal cases . The use of glucagon has been reported to be beneficial in 3 cases of cardiogenic shock, 1H but its potential value in this setting in man has yet to be evaluated .

References 1 . Friedberg CK: Cardiogenic shock in acute myocardial infarction . Circulation 23 :325-330, 1961 2 . Cronln RFP, Moore S, Marpole DG : Shock following myocardial infarction : a clinical survey of 140 cases . Caned Med Ass J 93 :57-64, 1965 3 . Soroff HS, Giron F, Ruiz U : Physiologic support of heart action . New Eng J Med 280:693-704, 1969 4 . Kantrowitz A, Krakauer JS, Rosenbaum A, et al : Phaseshift balloon pumping in medically refractory cardiogenic shock . Arch Surg (Chicago) 99 :739-745, 1969 5 . Glick G, Parmley WW, Wechsler AS, et al : Glucagon : its enhancement of cardiac performance in cat and dog and persistence of its inotropic action despite beta receptor blockade with propranolol . Circ Res 22 :789-799, 1968 6 . Lucchesi BR: Cardiac actions of glucagon . Circ Res 22 :777-787, 1968 7 . Parmley WW, Glick G, Sonnenblick EH : Cardiovascular effects of glucagon in man . New Eng J Med 279 :12-17, 1968 8 . Klein SW, Morch JE, Mahon WA : Cardiovascular effects of glucagon in man . Caned Med Ass J 98 :1161-1164, 1968 9 . Linhart JW, Barold SS, Cohen LS, et al: Cardiovascular effects of glucagon in man . Amer J Cardiol 22 :706-710, 1968 10. Williams JF Jr, Childress RH, Chip JN, et al : Hemodynamic effects of glucagon in patients with heart disease. Circulation 39 :38-47, 1968

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11 . Parmley WW, Matloff JM, Sonnenblick EH : Hemodynamic effects of glucagon in patients following prosthetic valve replacement . Circulation 39 : Suppl 1 :163-167, 1969 12. Whitsitt LS, Lucchesi BR: Effects of beta-receptor blockade and glucagon on the atrioventricular transmission system in the dog . Circ Res 23 :585-596, 1968 13 . Steiner C, Wit AL, Damato AN : Effects of glucagon on atrioventricular conduction and ventricular automaticity in dogs . Circ Res 24 :167-168, 1969 14 . Steiner C, Kovalik ATW : A simple technique for production of chronic complete heart block in dogs . J Appi Physic] 25 :631-632, 1968 15 . Lluck S, Moguilevsky HC, Pietra G, at al : A reproducible model of cardiogenic shock in the dog . Circulation 39:205-218, 1969 16 . Sutherland EW, Robinson GA, Butcher RW : Some aspects of biological role of adenosine 3', 5'-monophosphate (cyclic AMP) . Circulation 35 :279-306, 1968 17 . Levey GS, Epstein SE : Activation of adenyl cyclase by glucagon in cat and human heart . Circ Res 24:151-156, 1969 18 . Jacobey JA, Taylor WJ, Smith GT, at al : New therapeutic approach to acute coronary occlusion . II . Opening dormant coronary collateral channels by counterpulsation . Surg Forum 12:225-227, 1961 19 . Mahon WA, Morch JE, Klein SW : Cardiovascular effects of intravenous glucagon in man . Circulation 28 : Suppl 6 :12, 1968

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