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Surgical cardioplegia with butyl alcohol
Surgical Cardioplegia with Butyl Alcohol An Exverimental Study H U N T E R H. McGUIRE, JR., M.D., LEWIS H. BOSHER, JR., M.D., AND ROBERT W. RAMSEY, PH.D., Medical College of Virginia
The cardioplegic property of monovalent alcohols in isolated frog hearts perfused with Ringer's solution was demonstrated by Dold in 1906.2 In 1913 Kuno 5 demonstrated the prompt reversibility of alcohol cardioplegia induced in guinea pig hearts perfused with Locke's solution. Ramsey1~ utilized butyl alcohol for studying the mechanism of narcosis of striated muscle. He found that exposure of a muscle fiber to a solution of butyl alcohol caused a sudden rise of the muscle's rheobase at a time interval inversely proportional to the alcohol concentration, indicating that the narcotic and paralytic effect occurred in the cell membrane either by depolarization or by blocking the membrane potential in a polarized state. Although immunity of the contractile mechanism to butyl alcohol was not proven, this was suggested by the prompt recovery of contractility upon washout of the alcohol. Of the monovalent alcohols, Ramsey chose butyl alcohol because it is the most powerful narcotic of the homologous series of alcohols which is sufficiently soluble for physiologic application. On the basis of his experience and from the theoretical analysis of physical membranes in narcosis by Mullins) Ramsey suggested butyl alcohol as an agent for induced surgical cardioplegia. The cardioplegic property of other narcotics, i.e., barbiturates and morphine derivatives, is frequently observed in the research laboratory and perhaps occasionally overlooked clinically. Therefore preliminary studies for determining alcohol
dosages also included evaluation of a potent and transient barbiturate, methitural, and a rapidacting synthetic narcotic, alpha-prodine hydrochloride (Nisentil). Preliminary studies were conducted with the isolated, metabolically supported canine heart (Fig. 1). In this preparation cardiac arrest was demonstrated by lack of electrical activity on electrocardiogram and myocardial recovery was evaluated by means of a Walton-Brodie arch gauge. Here it was found that the minimal effective concentrations of alcohols in Ringer's solution were 10% ethanol, 1.7% butanol and 1.0% n-pentanol (amyl alcohol). Moreover, it was found that 50 cc. of the alcoholic Ringer's solution must be perfused through the coronary arteries in order to achieve arrest. When concentration was increased and volume decreased, recovery was delayed. In the same experimental preparation, methitural sodium in sufficient dose to produce cardioplegia yielded very poor recovery even after one minute Cordlopleg*c EKG
Arch Gouge Controchhty
From the Division of Thoracic and Cardiovascular Surgery, Department of Surgery, and from the Department of Physiology, Medical College of Virginia, Richmond, Va.
SigrnomotOrpump
Dr. McGuire is a Virginia Heart Association Research Fellow. This work was supported by U. S. Public Health Grant N I H H-3065 (C2), and in part by a grant from the Tidewater Heart Association (Virginia). Paper submitted for publication February 20, 1961; accepted April 8. 1961. ] S R - Vol. I , N o . 3 - S e p t e m b e r , 1961
IOOcc/min.
/ F.V.
Iv
Supporhng Dog
Fig. 1. Preparation for the study of arrest and recovery in the isolated canine heart.
179
180
McGuIRE, BosH~R, a n d RAMSEY
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ISOLATED
-
Vol. I, N o . 3 - S e p t e m b e r , 1961
CARDIOPLEGIA-NISENTIL
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~ . . - - ~ " ~ '
Control
9 '.7
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Fig. 2. Electrocardiogram and arch gauge tracings from a heart arrested for 15 minutes with 30 cc. of 0,3 per cent Nisentil in Ringer's solution. Even with a neutralizing dose of Lorfan, the heart does not recover within 20 minutes following washout of Nisentil.
arrest. Nisentil, 90 mg. in 50 cc. Ringer's solution, produced prompt arrest and prompt recovery when washed out within three minutes of injection, but when arrest was prolonged to ten minutes or more, recovery was unsatisfactory (Fig. 2). Ethyl alcohol was eliminated because of the high concentration necessary for cardioplegia. However, we have seen a heart recover 60 per cent of its control function after one-hour ethanol arrest. In the isolated heart, butyl alcohol (butanol) and amyl alcohol (pentanol) appeared equally promising (Fig. 3). Amyl alcohol, however, was eliminated because it is twice as toxic and less than one-third as soluble as butyl alcohol. T h e following functional studies in intact animals are therefore limited to the effects of butyl alcohol cardioplegia.
chloralose and urethane, and anticoagulated with heparin, 5 mg./kg. Cardiopulmonary bypass was established for 15 minutes with rotary p u m p and homologous lung oxygenatorY T h e perfusion circuit was then modified for controlled venous inflow, and at increasing flow rates from 400 to 3000 cc./min, the mean right atrial, pulmonary artery, left atrial and aortic pressures were recorded. With pressures converted to centimeters of water the following formulas yield ventricular stroke work. RV Stroke Work (gm.-meters) - Flow (cc./min.) X (PA - - RA pressure) Pulse rate X 100 LV Stroke W o r k (gm.-meters) ~__
METHOD
Flow (cc./min.) X (Ao - - LA pressure) Pulse rate X i00
Twenty-one mongrel dogs, averaging 11.9 kg., were anesthetized with morphine sulfate, alpha
All studies were made at 35 ~ C. with normal arterial p H and hematocrit. Pulse rates were not
] S R - VoI. I, N o . 3 - S e p t e m b e r , 1961
SURGICAL CARDIOPLEGIA WITH BUTYL ALCOHOL
181
controlled. T h e average m a x i m u m control stroke work for all left ventricles was 31.7 gm.-meters, and for all right ventricles was 4.5 gm.-meters. By plotting each filling pressure (mean atrial pressure) against the stroke work which it produced, a control ventricular function curve was constructed for each n o r m a l ventricle (Curves I of Figures 4 through 7). T o t a l perfusion was then reinstituted and, with both sides of the heart drained, the aorta was occluded. Control animals suffered simple hypoxic arrest. In four experiments the aorta was released after 15 minutes of occlusion, and in six, arrest was continued for 30 minutes of occlusion. I n nine dogs 50 cc. of 1.7% butyl alcohol in Ringer's lactate* was injected rapidly into the p r o x i m a l clamped aorta. T h e alcohol was allowed to return to the extracorporeal circuit. I n four of the chemically arrested dogs the aorta was released after 15 minutes, and in five, arrest was continued for 30 minutes. U p o n release of the aorta, both atria were decompressed until cardiac
action was adequate to prevent distention of the heart. Post-arrest ventricular function (Curve II) was studied after 15 minutes of recovery perfusion and again (Curve III) after an additional 15 minutes (approximately one h o u r after arrest). T h e function curves thus obtained were then plotted together to form a family of curves produced by a single heart (Figs. 4-7). T h e relationship between the curves of a single heart is expressed as the average ratio between their stroke works over a selected range of atrial pressures. T h i s ratio is determined by assigning a value of 100 per cent to the area under the control curve and relating the areas u n d e r the postarrest curves to their controls in terms of per cent. T h i s technique, reported previously in greater detail, has given valid expression to the results of over eighty families of curves and allows statistical integration of the results of m a n y experiments. 6, *
* 10.5 cc. reagent grade 1-butanol dissolved in 489.5 cc. Ringer's lactate.
F i f t e e n m i n u t e h y p o x i c arrest resulted in con-
RESULTS siderable depression in all instances, with only
ISOLATED CARDIOPLEGIA EKG
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2'
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7'
9'
IZ*
m ringers
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at t'
Fig. 3. A comparison of electrocardiogram and arch gauge tracings from a left ventricle before, during and after 15 minute arrest with I per cent amyl alcohol (above) and 1.7 per cent butyl alcohol (below). The rate of recovery of the isolated heart is approximately the same with these two agents.
182
McGuie.E, BOSIJER, and RAMSEY
]SR
CARDIAC ARREST- Aorhc Occlusion - i5 rnin LEFT HEART
6 -12- 59
RIGHTHEART
Control ]I ~ Post Arrest - 15 mm pert ~ l ~ Post Arrest- 3Om#n pert I ~
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6
8
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Fig. 4. Simultaneous right and left ventricular function curves of a heart following 15 minutes of aortic occlusion. Curve I: ,Control. Curve II: After i5 m i n u t e recovery on bypass. Curve III: After 30 m i n u t e bypass.
CARDIAC
_ LEFT HEART
/ ~
ARREST
T (100%)
Vol. I, No. 3 - September, 1961
-
partial recovery one hour post-arrest. Figure 4 is an example of this finding and Table I summarizes the four experiments of this type. T h e average left ventricular function is 49 per cent of control 15 minutes post-release, and is only 55 per cent after one hour recovery. Thirty minute hypoxic arrest resulted in profound depression and delayed recovery. Figure 5 is an example of this arrest, and Table 2 summarizes the six experiments of this type. One of these hearts was unable to sustain circulation 15 minutes post-arrest, and the average left ventricular function at 15 minutes is only 21 per cent of control, with recovery to 41 per cent after an additional 15 minute perfusion. Fifteen minute butanol arrest. Arrest occurred during or shortly after the rapid injection of 1.7% alcohol Ringer's solution into the proximal clamped aorta, on an average of 30 seconds after occlusion of the aorta. All hearts were well relaxed and grossly quiet, although in half of the cases there appeared to be gentle ventricular fibrillation throughout the arrest period. Three of four
- Aortic
Occlusion - 30mAn.
I - 4-60
RIGHT HEART
40
/
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36 34 32
~ 30 ~ 28
I ~ Control IT ~ Post A r r e s t - 15 m/n p e r t llT i - - , - I POSt A t r e s t - J O m m p e r t
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Ventricular function curves following 30 minutes of aortic occlusion.
30
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Vol. I, No. 3 - September,
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183
SURGICAL CARDIOPLEGIA WITH BUTYL ALCOHOL
T a b l e 1. F i f t e e n M i n u t e Aortic Occlusion MAXIMUMSTROKEWORK(GM.-MF,TERS) Right Left II III I II
I
~ FUNCTION III
I
Right II
III
I
Left II
III
Exp. No. X-15'-1
3,6
0,9
0.9
38.0
10,7
6,7
100
29
25
100
28
20
X-15'-2
5.0
2.4
3.0
24.2
19.0
17.5
100
52
60
100
67
68
X-15'-3
5.6
3.1
3.4
29,1
24.4
32.1
100
50
54
100
69
104
X-15'--4
8,6
3.8
5.6
26.9
10.3
17.2
100
48
66
100
32
34
5.7
2.6
3.2
29.6
16.1
18.6
I00
45
51
I00
49
55
Average X-15'
CARDIAC 40
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ARREST -
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Alcohol-
15 min. RIGHT HEART
I - 20 - 60
HEART
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4
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a
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AP cm. H e 0
Fig. 6. Ventricular function curves following 15 minutes of butyl alcohol arrest.
T a b l e 2. T h i r t y M i n u t e Aortic Occlusion
I
MAXIMUMSTROKE WORK (GM.-METER$) Right Left II III I II
Exp. No. X-30'-I
5.6
1.2
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5.2
0.9
X-30'-3
4.1
1.9
X-30'-4
5.5
1.3
X-30'-5
1,3
X-30'-6
1,9
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3.9
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2.1
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I
Right II
III
I
22
100
Left II 0
II[
38.2
11.1
22.3
100
0
12
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9.8
15.5
100
20
42
100
13
35
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27.9
6.8
14.3
100
76
113
100
23
54
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28
48
100
21
41
184
McGumE,
J S R - V o l . I , N o . 3 - September, 1961
BOSHER, a n d RAMSEY
T a b l e 3. F i f t e e n M i n u t e B u t a n o l A r r e s t M A X I M U M STROKE WORK (G1VI.-I~ETERS)
I
Right If
]II
~ FUNCTION
I
Left II
III
]
Right II
III
I
Left II
III
Exp. No. BU-15'-I
1.7
1.7
2,4
23.5
29.3
30.7
100
96
134
100
77
116
BU-15'-2
2.7
4.9
5.2
28.4
37.5
37.8
I00
107
175
100
91
121
BU-15'-3
3.2
3.2
3.9
31.5
30.0
34.7
100
100
133
100
96
103
BU-15'4
7.6
6.8
6.7
51.4
48.7
48.8
100
36
51
100
112
110
3.8
4.2
4,6
33.6
36.4
38.0
100
85
123
100
94
113
Average BU-15'
123% for right ventricles, and 94% and 113% for left ventricles. This constitutes a considerable advantage over the control experiments (Fig. 8). Thirty minute butanol arrest. In these instances the quality of arrest was the same as with 15 minute alcohol arrest. Three of five hearts required electrical defibrillation and in all cases EKG returned to normal within the 15 minute recovery perfusion. In no case, however, was recovery as satisfactory as following 15 minute arrest, and in one case recovery was grossly delayed and the heart unable to sustain circulation at 15 minute post-arrest (Fig. 7). T h e average post-arrest function, however, was 50% and 92%
hearts developed ventricular fibrillation upon release of the aorta, but return of normal color and coronary resistance was prompt, and electrical defibrillation was easily accomplished. Post-arrest function curves revealed significant depression of only one right ventricle and even in this case the left ventricle did not suffer appreciably, and its gross recovery was prompt and excellent (Fig. 6). T h e maximum depression of the left ventricle caused by 15 minute butyl alcohol arrest was 77 per cent of control (Table 3), and in every case left ventricular function exceeded its control function after 30 minutes of recovery perfusion. T h e average post-arrest function was 85% and
GARDIAG ARREST-
5O 48 46
--
LEFT
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44 42
40 38
Butyl
A l c o h o l - 3 0 min.
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RIGHT HEART
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56 34
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AP cm. F/tO
0
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I
I
I
I
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6
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I
1
I
I
14 Is m2o
AP cm. HzO
Fig. 7. Ventricular function curves following 30 minutes of butyl alcohol arrest.
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Vol. I, N o . 3 - S e p t e m b e r , 1961 CONTROL
--
BUTYL ALCHOL
~DOST ARREST -
ISmm perf
AORTIC OCCLUSIONol 25" -
POST ARREST - 3 0 m m per|
z O p-o
SURGICAL
I
Z
Z o p. o :100
LEFTBH EART
z iO0
g Bo Z 0
WITH
CONTROL POST ARREST - 15 mln perf POST ARREST-SOmm petf
-
AORTIC OCCLUSION Of 35" - -
RIGH'( H E A R /
CARDIOPLEGIA
BUTYL
185
ALCOHOL
BUTYL ALCOHOL AORTIC OCCLUSIONo~ 35"
RIGHT HEART
LEFT HEART
8O
6O
o 60
40
~ 4o
~ 2o
~ i I
i I1
VENTRICULAR
t "wr
i I
FUNCTION
i ]I
FOLLOWING
2O
i
;
yrr
~
VENTRICULAR
15' C A R D I O P L E G I A
Fig. 8. Comparison of average ventricular function following 15 minutes of aortic occlusion at 35~ C. and at 25* C., and following 15 minutes of butyl alcohol arrest.
I I
T;'r FUNCTION
i ]I FOLLOWING
i Trr
30' CARDIOPLEGIA
Fig. 9. Comparison of average ventricular function following 30 minutes of aortic occlusion and 30 minutes of butyl alcohol arrest.
Table 4. Thirty Minute Butanol Arrest M A X I M U M STROKE WORK ( G M . - M E T E R S )
I
Right II
III
Exp. No. BU-30'-I BU-30'-2 BU-30'-3 BU-30'-4 BU-31Y-5
3.9 5.8 4.7 1.7 4.2
3.1 0 3.0 2.3 3.0
Average BU-30'
4.1
2.3
070 F U N C T I O N
I
Left II
III
3.3 5.2 3.1 3.8 3.1
25.6 45.9 44.6 19.1 33.3
30.0 0 21.4 22.4 20.2
3.7
33.7
18.8
for right ventricles, and 48% and 78% for left ventricles (Table 4), showing a marked improvement over the control hypoxic arrest (Fig. 9). VARIATIONS ON CARDIOPLEGIC TECHNIQUE In an attempt to add regional myocardial hypothermia to alcohol cardioplegia, arrest was attempted by perfusion of the coronaries with 1.7% butyl alcohol in Ringer's at 0 ~ C. These hearts behaved as if only cold Ringer's had been injected. Other hearts were arrested with butyl alcohol by the standard technique, followed immediately by coronary perfusion with Ringer's solution at 0 ~ C. These hearts promptly resumed a slow beat, indicating that the alcohol had been washed out by the Ringer's. In two animals, 30 minute arrest at 24 to 27 ~ C. was achieved by infusing 50 cc. of 1.7% butyl alcohol at room temperature, followed immediately by 50 cc. of 0.17% butanol at 0 ~ C. I n these cases arrest and recovery were grossly satisfactory, but post-arrest ventricular function in each case was below the
I
Right II
III
I
Left II
III
23.0 42.5 23.7 28.3 22.8
100 I00 I00 100 100
19 0 75 99 57
96 53 78 146 89
100 100 100 100 100
48 0 42 101 47
87 79 49 119 56
28.1
I00
50
92
100
48
78
average for 30 minute alcohol arrest at 35 ~ C. T h e fine muscular activity observed in half of the hearts during arrest suggested that the concentration of butyl alcohol might be inadequate. Therefore, two bypassed canine hearts were arrested for 30 minutes with 2% butyl alcohol in Ringer's. In both cases intractable ventricular rigor developed upon release of the aorta. I n another experiment the heart was arrested with 50 cc. of 1.7% butyl alcohol in Ringer's and during the subsequent 30 minute arrest period, another 50 cc. of the same solution was slowly perfused through the coronary arteries. This heart failed to beat upon release of the aorta. TOXICITY Butyl alcohol is commonly thought to be an extremely toxic substance, properly f o u n d in lacquer solvents and properly avoided in bad whiskey. Acute parenteral administration produces generalized cell narcosis. Its lethal effect is by depression of the central nervous system. T h e lowest reported LDs0 is 0.76 ml./kg., or approxi-
186
McGuIRE,BOSHER,a n d RAMSEY
mately six times the toxicity of ethyl alcohol.7 T h e probable lethal dose for man is reported to be between 500 rag. and 5 gm./kg. 4 Butyl alcohol is presumably metabolized in the liver and no toxic effects of chronic parenteral administration are reported. Because no data were available on the acute intravenous toxicity of butyl alcohol in dogs, we administered the drug intravenously at a rate of 20 mg./kg./min, to eight dogs, four of whom were moderately narcotized with morphine sulfate. Vital signs, sensorium and EKG were observed continuously. The stages of toxicity observed were as follows: (1) somnolence, (2) anesthesia and bradycardia, (3) respiratory depression and hypotension with tachycardia, (4) irreversible hypotension with apnea and bradycardia, and (5) asystole. T h e first three stages appeared to be reversible. T h e m i n i m u m toxic dose was 150 mg./kg, and the minimum lethal dose was 310 mg./kg. Animals which were not narcotized with morphine tolerated 30 per cent greater doses of butyl alcohol. Our LDs0 of 0.8 gm./kg, corresponds roughly to the lowest dose previously reportedY We have thus shown that our pharmacologic (cardioplegic) dose of 850 rag. for 10 kg. dogs is 57 per cent of the minimal toxic dose, and 27 per cent of the m i n i m u m lethal dose. Since the dog's heart-body weight ratio is greater than man's, it is expected that a greater margin of safety might be found clinically. T h e narrow margin of safety demonstrated in these experiments, however, suggests that after cardioplegia the first 100 cc. of coronary sinus blood should be discarded. In the cardioplegic experiments reported here, coronary sinus blood was returned to the extracorporeal circuit without apparent complication. A survivor of 30 minute butyl alcohol arrest autopsied two weeks postoperatively revealed no evidence of renal or hepatic damage, and myocardial histology on all alcohol-arrested hearts (acute experiments) revealed normal myocardium. DISCUSSION
Previous studies in our laboratory 6 support the popular clinical impression that cardioplegia by either acetylcholine or potassium offers little protcction against myocardial ischemia. Twenty-five degree hypothermia gives only partial protection (Fig. 8), results in a tonic heart requiring a larger ventriculotomy, and is technically more cumbersome than chemical arrest. Thcrcfore, we have continued the search for a safe chemical cardioplegic agent. Narcotics whose paralytic effects on muscle cells
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Vol. I, No. 3 - September,
1961
may be reversed by washing the cells are presumed to exert their effect on the cell membranes rather than on the internal contractile mechanism. Therefore, the narcotic whose molecule is most perfectly adapted to the structure of the cell membrane might be expected to be the most effective as well as the most reversible narcotic. Many narcotics, such as the straight-chain alcohols, behave as if an equilibrium were established between cell and media at the narcotic concentration, and hence are susceptible to thermodynamic analysis. Moreover, one is justified in assuming that the narcosis in such cases is a physical process. Ferguson, 3 and Brink and Posternak 1 have analyzed a wide variety of published data and have shown that in a homologous series there is often equal narcotic action at equal thermodynamic activities. The problem of calculating the activity coefficients of narcotics in solution is a complex one and all authors must use simplifying assumptions. A later analysis by Mullins 9 approached the problem from a more sophisticated basis than Ferguson or Brink and Posternak, in the course of which it was necessary to assume an arbitrary but constant membrane solubility parameter (or cohesive energy density) for a particular membrane. For some membranes, Mullins found that the assumed value of the membrane's solubility parameter which best fitted the data was the same as the solubility parameter for 1-butanol. T h e inference from this is that the "holes" or "spaces" in the membrane lattice structure are of a size or volume which can be matched by four ethylenic groups and one polar group. Hence butyl alcohol would be an "ideal" narcotic. These theoretical observations were borne out in our preliminary studies in which other narcotics and alcohols of the homologous series were evaluated for cardioplegia and recovery rate in the isolated dog heart. Butyl alcohol was the most promising agent tested. Furthermore, in the doses required for cardioplegia it appeared that toxicity would not be a limiting factor. Functional studies of intact canine hearts after 15 minutes of butyl alcohol cardioplegia were very encouraging, revealing protection against myocardial ischemia and almost complete recovery of ventricular function when tested 15 minutes after restoring coronary circulation. When cardioplegia was prolonged to 30 minutes, however, results were disappointing. Although recovery was significantly more rapid than following anoxic arrest, depressed ventricular function revealed limitations of butanol arrest by the technique employed. Furthermore, slight in-
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Vol. I, N o . 3 - S e p t e m b e r , 1961
SURGICAL CARDIOPLEGIA WITH BUTYL ALCOHOL
crease in c o n c e n t r a t i o n or v o l u m e of the arresting solution a p p e a r e d to be dangerous. T h e a d d i t i o n of 25 ~ regional h y p o t h e r m i a to 30 m i n u t e s of b u t a n o l arrest failed to i m p r o v e post-arrest ventricular function. T h e s e findings preclude the clinical use of butyl alcohol by the present t e c h n i q u e b u t do n o t exclude the possibility that by some variation in technique or by the use of o t h e r dosages, cardioplegic or metabolic adjuvants, or a m o r e effective c o m b i n a t i o n with h y p o t h e r m i a , b u t a n o l m a y be developed as a safe agent for chemical cardioplegia.
sible i m p r o v e m e n t to be achieved by variations in technique r e m a i n to be explored. REFERENCES 1. Brink, F., and Posternak, J. M,: Thermodynamic
2. 3. 4. 5.
SUMMARY
T h e o r e t i c a l analysis of cell m e m b r a n e s in narcosis a n d experimental observations of the effect of narcotics on the isolated canine heart gave rise to the prediction that b u t y l alcohol w o u l d be an ideal narcotic for i n d u c t i o n of chemical cardioplegia for o p e n heart surgery. I n a series of acute canine experiments ventricular f u n c t i o n was tested after 15 minutes a n d after 30 m i n u t e s of arrest. Results indicated that butyl alcohol offers excellent p r o t e c t i o n of the n o r m o t h e r m i c heart arrested for 15 minutes, b u t gives o n l y partial protection d u r i n g 30 m i n u t e s of arrest. T h e reason for this failure a n d the pos-
187
6.
7.
8.
9. 10.
analysis of the relative effectiveness of narcotics, j. Cell. 8: Comp. Physiol., 32:211, 1948. Dold, H.: Ueber die Wirkung des Athylalkohols und verwandter Alkohole auf das Froschherz. Pfliiger's Arch. ges. Physiol., 112:600, 1906. Ferguson, J.: The use of chemical potentials as indices of toxicity. Proc. Roy. Soc., Series B, 127:387, 1939. Gleason, M. N., Gosselin, R. E., and Hodge, H. C.: Clinical Toxicology of Commercial Products. Williams & Wilkins Co., Baltimore, 1957, p. 33. Kuno, Y.: Ueber die Wirkung der einwertigen Alkohole auf das ueberlebende saugetierherz. Arch. exper. Path. u. Pharmakol., 74:399, 1913. Kusunoki, T., Cheng, H., McGuire, H. H., Jr., and Bosher, L. H., Jr.: Myocardial dysfunction after cardioplegia. J. Thorac. & Cardiovas. Surg., 40:813, 1960. Lendle, L.: Untersuchungen ueber die Narkosegeschwindigkeit homologer and isomerer einwertiger Alkohole. Arch. exper. Path. u. Pharmakol., 129:85, 1928. McGuire, H. H., Jr., Bosher, L. H., Jr., and Ramsey, R. W.: Exploration into narcosis for surgical cardioplegia. Tr. Am. Soc. for Artificial Internal Organs, 6:323, 1960. Mullins, L. J.: Some physical mechanisms in narcosis. Chem. Rev., 54:289, 1954. Ramsey, R. W.: The narcosis of frog muscle by n-hutyt alcohol. J. Cell. & Comp. Physiol., 11:65, 1938.
The cardioplegic property of monovalent alcohols in isolated frog hearts perfused with Ringer's solution was demonstrated by Dold in 1906.2 In 1913 Kuno 5 demonstrated the prompt reversibility of alcohol cardioplegia induced in guinea pig hearts perfused with Locke's solution. Ramsey1~ utilized butyl alcohol for studying the mechanism of narcosis of striated muscle. He found that exposure of a muscle fiber to a solution of butyl alcohol caused a sudden rise of the muscle's rheobase at a time interval inversely proportional to the alcohol concentration, indicating that the narcotic and paralytic effect occurred in the cell membrane either by depolarization or by blocking the membrane potential in a polarized state. Although immunity of the contractile mechanism to butyl alcohol was not proven, this was suggested by the prompt recovery of contractility upon washout of the alcohol. Of the monovalent alcohols, Ramsey chose butyl alcohol because it is the most powerful narcotic of the homologous series of alcohols which is sufficiently soluble for physiologic application. On the basis of his experience and from the theoretical analysis of physical membranes in narcosis by Mullins) Ramsey suggested butyl alcohol as an agent for induced surgical cardioplegia. The cardioplegic property of other narcotics, i.e., barbiturates and morphine derivatives, is frequently observed in the research laboratory and perhaps occasionally overlooked clinically. Therefore preliminary studies for determining alcohol
dosages also included evaluation of a potent and transient barbiturate, methitural, and a rapidacting synthetic narcotic, alpha-prodine hydrochloride (Nisentil). Preliminary studies were conducted with the isolated, metabolically supported canine heart (Fig. 1). In this preparation cardiac arrest was demonstrated by lack of electrical activity on electrocardiogram and myocardial recovery was evaluated by means of a Walton-Brodie arch gauge. Here it was found that the minimal effective concentrations of alcohols in Ringer's solution were 10% ethanol, 1.7% butanol and 1.0% n-pentanol (amyl alcohol). Moreover, it was found that 50 cc. of the alcoholic Ringer's solution must be perfused through the coronary arteries in order to achieve arrest. When concentration was increased and volume decreased, recovery was delayed. In the same experimental preparation, methitural sodium in sufficient dose to produce cardioplegia yielded very poor recovery even after one minute Cordlopleg*c EKG
Arch Gouge Controchhty
From the Division of Thoracic and Cardiovascular Surgery, Department of Surgery, and from the Department of Physiology, Medical College of Virginia, Richmond, Va.
SigrnomotOrpump
Dr. McGuire is a Virginia Heart Association Research Fellow. This work was supported by U. S. Public Health Grant N I H H-3065 (C2), and in part by a grant from the Tidewater Heart Association (Virginia). Paper submitted for publication February 20, 1961; accepted April 8. 1961. ] S R - Vol. I , N o . 3 - S e p t e m b e r , 1961
IOOcc/min.
/ F.V.
Iv
Supporhng Dog
Fig. 1. Preparation for the study of arrest and recovery in the isolated canine heart.
179
180
McGuIRE, BosH~R, a n d RAMSEY
]SR
ISOLATED
-
Vol. I, N o . 3 - S e p t e m b e r , 1961
CARDIOPLEGIA-NISENTIL
!i
gouge o ' r
~ . . - - ~ " ~ '
Control
9 '.7
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6'
p o l l - re ltll~f~
Fig. 2. Electrocardiogram and arch gauge tracings from a heart arrested for 15 minutes with 30 cc. of 0,3 per cent Nisentil in Ringer's solution. Even with a neutralizing dose of Lorfan, the heart does not recover within 20 minutes following washout of Nisentil.
arrest. Nisentil, 90 mg. in 50 cc. Ringer's solution, produced prompt arrest and prompt recovery when washed out within three minutes of injection, but when arrest was prolonged to ten minutes or more, recovery was unsatisfactory (Fig. 2). Ethyl alcohol was eliminated because of the high concentration necessary for cardioplegia. However, we have seen a heart recover 60 per cent of its control function after one-hour ethanol arrest. In the isolated heart, butyl alcohol (butanol) and amyl alcohol (pentanol) appeared equally promising (Fig. 3). Amyl alcohol, however, was eliminated because it is twice as toxic and less than one-third as soluble as butyl alcohol. T h e following functional studies in intact animals are therefore limited to the effects of butyl alcohol cardioplegia.
chloralose and urethane, and anticoagulated with heparin, 5 mg./kg. Cardiopulmonary bypass was established for 15 minutes with rotary p u m p and homologous lung oxygenatorY T h e perfusion circuit was then modified for controlled venous inflow, and at increasing flow rates from 400 to 3000 cc./min, the mean right atrial, pulmonary artery, left atrial and aortic pressures were recorded. With pressures converted to centimeters of water the following formulas yield ventricular stroke work. RV Stroke Work (gm.-meters) - Flow (cc./min.) X (PA - - RA pressure) Pulse rate X 100 LV Stroke W o r k (gm.-meters) ~__
METHOD
Flow (cc./min.) X (Ao - - LA pressure) Pulse rate X i00
Twenty-one mongrel dogs, averaging 11.9 kg., were anesthetized with morphine sulfate, alpha
All studies were made at 35 ~ C. with normal arterial p H and hematocrit. Pulse rates were not
] S R - VoI. I, N o . 3 - S e p t e m b e r , 1961
SURGICAL CARDIOPLEGIA WITH BUTYL ALCOHOL
181
controlled. T h e average m a x i m u m control stroke work for all left ventricles was 31.7 gm.-meters, and for all right ventricles was 4.5 gm.-meters. By plotting each filling pressure (mean atrial pressure) against the stroke work which it produced, a control ventricular function curve was constructed for each n o r m a l ventricle (Curves I of Figures 4 through 7). T o t a l perfusion was then reinstituted and, with both sides of the heart drained, the aorta was occluded. Control animals suffered simple hypoxic arrest. In four experiments the aorta was released after 15 minutes of occlusion, and in six, arrest was continued for 30 minutes of occlusion. I n nine dogs 50 cc. of 1.7% butyl alcohol in Ringer's lactate* was injected rapidly into the p r o x i m a l clamped aorta. T h e alcohol was allowed to return to the extracorporeal circuit. I n four of the chemically arrested dogs the aorta was released after 15 minutes, and in five, arrest was continued for 30 minutes. U p o n release of the aorta, both atria were decompressed until cardiac
action was adequate to prevent distention of the heart. Post-arrest ventricular function (Curve II) was studied after 15 minutes of recovery perfusion and again (Curve III) after an additional 15 minutes (approximately one h o u r after arrest). T h e function curves thus obtained were then plotted together to form a family of curves produced by a single heart (Figs. 4-7). T h e relationship between the curves of a single heart is expressed as the average ratio between their stroke works over a selected range of atrial pressures. T h i s ratio is determined by assigning a value of 100 per cent to the area under the control curve and relating the areas u n d e r the postarrest curves to their controls in terms of per cent. T h i s technique, reported previously in greater detail, has given valid expression to the results of over eighty families of curves and allows statistical integration of the results of m a n y experiments. 6, *
* 10.5 cc. reagent grade 1-butanol dissolved in 489.5 cc. Ringer's lactate.
F i f t e e n m i n u t e h y p o x i c arrest resulted in con-
RESULTS siderable depression in all instances, with only
ISOLATED CARDIOPLEGIA EKG
Ccrmo~
SOcc
t.0 % ~
rr~ ringers
Aoret~ullff Ist ~ti~it po~ Currant
r
iii
1"30" 2'
4'
Bt 30"
7"
8'
p~st-releose
$ BUTANOL
i"~
C0tttrol
50r
L7% butonot
t4'
Ao released t~
~'30"
2'
4'
7'
9'
IZ*
m ringers
0o=t arrest
at t'
Fig. 3. A comparison of electrocardiogram and arch gauge tracings from a left ventricle before, during and after 15 minute arrest with I per cent amyl alcohol (above) and 1.7 per cent butyl alcohol (below). The rate of recovery of the isolated heart is approximately the same with these two agents.
182
McGuie.E, BOSIJER, and RAMSEY
]SR
CARDIAC ARREST- Aorhc Occlusion - i5 rnin LEFT HEART
6 -12- 59
RIGHTHEART
Control ]I ~ Post Arrest - 15 mm pert ~ l ~ Post Arrest- 3Om#n pert I ~
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8
i I I I I I I J IO 12 14 16 18 20 22 2q
I 2
4
A P - cm ##20
6
8
[0 12 14
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Fig. 4. Simultaneous right and left ventricular function curves of a heart following 15 minutes of aortic occlusion. Curve I: ,Control. Curve II: After i5 m i n u t e recovery on bypass. Curve III: After 30 m i n u t e bypass.
CARDIAC
_ LEFT HEART
/ ~
ARREST
T (100%)
Vol. I, No. 3 - September, 1961
-
partial recovery one hour post-arrest. Figure 4 is an example of this finding and Table I summarizes the four experiments of this type. T h e average left ventricular function is 49 per cent of control 15 minutes post-release, and is only 55 per cent after one hour recovery. Thirty minute hypoxic arrest resulted in profound depression and delayed recovery. Figure 5 is an example of this arrest, and Table 2 summarizes the six experiments of this type. One of these hearts was unable to sustain circulation 15 minutes post-arrest, and the average left ventricular function at 15 minutes is only 21 per cent of control, with recovery to 41 per cent after an additional 15 minute perfusion. Fifteen minute butanol arrest. Arrest occurred during or shortly after the rapid injection of 1.7% alcohol Ringer's solution into the proximal clamped aorta, on an average of 30 seconds after occlusion of the aorta. All hearts were well relaxed and grossly quiet, although in half of the cases there appeared to be gentle ventricular fibrillation throughout the arrest period. Three of four
- Aortic
Occlusion - 30mAn.
I - 4-60
RIGHT HEART
40
/
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36 34 32
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Ventricular function curves following 30 minutes of aortic occlusion.
30
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Vol. I, No. 3 - September,
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183
SURGICAL CARDIOPLEGIA WITH BUTYL ALCOHOL
T a b l e 1. F i f t e e n M i n u t e Aortic Occlusion MAXIMUMSTROKEWORK(GM.-MF,TERS) Right Left II III I II
I
~ FUNCTION III
I
Right II
III
I
Left II
III
Exp. No. X-15'-1
3,6
0,9
0.9
38.0
10,7
6,7
100
29
25
100
28
20
X-15'-2
5.0
2.4
3.0
24.2
19.0
17.5
100
52
60
100
67
68
X-15'-3
5.6
3.1
3.4
29,1
24.4
32.1
100
50
54
100
69
104
X-15'--4
8,6
3.8
5.6
26.9
10.3
17.2
100
48
66
100
32
34
5.7
2.6
3.2
29.6
16.1
18.6
I00
45
51
I00
49
55
Average X-15'
CARDIAC 40
LEFT
ARREST -
Butyl
Alcohol-
15 min. RIGHT HEART
I - 20 - 60
HEART
38 36 ( t o 3 %)
•I=)
34 32 30 28
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I
I
I
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14 16 18 20 22 2q 26 2 8 30 32 34 36 38
4
6
A P cm. H e 0
a
i I I i I I 12 14 t6 la zozz 24 z6
io
AP cm. H e 0
Fig. 6. Ventricular function curves following 15 minutes of butyl alcohol arrest.
T a b l e 2. T h i r t y M i n u t e Aortic Occlusion
I
MAXIMUMSTROKE WORK (GM.-METER$) Right Left II III I II
Exp. No. X-30'-I
5.6
1.2
X-30'-2
5.2
0.9
X-30'-3
4.1
1.9
X-30'-4
5.5
1.3
X-30'-5
1,3
X-30'-6
1,9
X-30'
3.9
Average
2.1
~O FUNCTION III
I
Right II
III
I
22
100
Left II 0
II[
38.2
11.1
22.3
100
0
12
1.4
36.6
9.8
15.5
100
20
42
100
13
35
2.5
27.9
6.8
14.3
100
76
113
100
23
54
1.1
40.8
14.0
19.8
100
0
0
100
32
56
0
0.5
17.1
0
10.8
100
0
48
100
0
35
1.4
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10,6
12.2
100
56
66
100
53
55
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1.4
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8.7
15.8
100
28
48
100
21
41
184
McGumE,
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BOSHER, a n d RAMSEY
T a b l e 3. F i f t e e n M i n u t e B u t a n o l A r r e s t M A X I M U M STROKE WORK (G1VI.-I~ETERS)
I
Right If
]II
~ FUNCTION
I
Left II
III
]
Right II
III
I
Left II
III
Exp. No. BU-15'-I
1.7
1.7
2,4
23.5
29.3
30.7
100
96
134
100
77
116
BU-15'-2
2.7
4.9
5.2
28.4
37.5
37.8
I00
107
175
100
91
121
BU-15'-3
3.2
3.2
3.9
31.5
30.0
34.7
100
100
133
100
96
103
BU-15'4
7.6
6.8
6.7
51.4
48.7
48.8
100
36
51
100
112
110
3.8
4.2
4,6
33.6
36.4
38.0
100
85
123
100
94
113
Average BU-15'
123% for right ventricles, and 94% and 113% for left ventricles. This constitutes a considerable advantage over the control experiments (Fig. 8). Thirty minute butanol arrest. In these instances the quality of arrest was the same as with 15 minute alcohol arrest. Three of five hearts required electrical defibrillation and in all cases EKG returned to normal within the 15 minute recovery perfusion. In no case, however, was recovery as satisfactory as following 15 minute arrest, and in one case recovery was grossly delayed and the heart unable to sustain circulation at 15 minute post-arrest (Fig. 7). T h e average post-arrest function, however, was 50% and 92%
hearts developed ventricular fibrillation upon release of the aorta, but return of normal color and coronary resistance was prompt, and electrical defibrillation was easily accomplished. Post-arrest function curves revealed significant depression of only one right ventricle and even in this case the left ventricle did not suffer appreciably, and its gross recovery was prompt and excellent (Fig. 6). T h e maximum depression of the left ventricle caused by 15 minute butyl alcohol arrest was 77 per cent of control (Table 3), and in every case left ventricular function exceeded its control function after 30 minutes of recovery perfusion. T h e average post-arrest function was 85% and
GARDIAG ARREST-
5O 48 46
--
LEFT
~./
HEART
44 42
40 38
Butyl
A l c o h o l - 3 0 min.
I - 27 - 60
RIGHT HEART
T 000%1 (79%)
56 34
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I
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I
!
I
I
I
e io Iz 14 16 l e a o 2 2 2 4 z 6 ze 30
AP cm. F/tO
0
--
I
I
I
I
I
z
4
6
e
io iz
I
I
1
I
I
14 Is m2o
AP cm. HzO
Fig. 7. Ventricular function curves following 30 minutes of butyl alcohol arrest.
JSR
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Vol. I, N o . 3 - S e p t e m b e r , 1961 CONTROL
--
BUTYL ALCHOL
~DOST ARREST -
ISmm perf
AORTIC OCCLUSIONol 25" -
POST ARREST - 3 0 m m per|
z O p-o
SURGICAL
I
Z
Z o p. o :100
LEFTBH EART
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WITH
CONTROL POST ARREST - 15 mln perf POST ARREST-SOmm petf
-
AORTIC OCCLUSION Of 35" - -
RIGH'( H E A R /
CARDIOPLEGIA
BUTYL
185
ALCOHOL
BUTYL ALCOHOL AORTIC OCCLUSIONo~ 35"
RIGHT HEART
LEFT HEART
8O
6O
o 60
40
~ 4o
~ 2o
~ i I
i I1
VENTRICULAR
t "wr
i I
FUNCTION
i ]I
FOLLOWING
2O
i
;
yrr
~
VENTRICULAR
15' C A R D I O P L E G I A
Fig. 8. Comparison of average ventricular function following 15 minutes of aortic occlusion at 35~ C. and at 25* C., and following 15 minutes of butyl alcohol arrest.
I I
T;'r FUNCTION
i ]I FOLLOWING
i Trr
30' CARDIOPLEGIA
Fig. 9. Comparison of average ventricular function following 30 minutes of aortic occlusion and 30 minutes of butyl alcohol arrest.
Table 4. Thirty Minute Butanol Arrest M A X I M U M STROKE WORK ( G M . - M E T E R S )
I
Right II
III
Exp. No. BU-30'-I BU-30'-2 BU-30'-3 BU-30'-4 BU-31Y-5
3.9 5.8 4.7 1.7 4.2
3.1 0 3.0 2.3 3.0
Average BU-30'
4.1
2.3
070 F U N C T I O N
I
Left II
III
3.3 5.2 3.1 3.8 3.1
25.6 45.9 44.6 19.1 33.3
30.0 0 21.4 22.4 20.2
3.7
33.7
18.8
for right ventricles, and 48% and 78% for left ventricles (Table 4), showing a marked improvement over the control hypoxic arrest (Fig. 9). VARIATIONS ON CARDIOPLEGIC TECHNIQUE In an attempt to add regional myocardial hypothermia to alcohol cardioplegia, arrest was attempted by perfusion of the coronaries with 1.7% butyl alcohol in Ringer's at 0 ~ C. These hearts behaved as if only cold Ringer's had been injected. Other hearts were arrested with butyl alcohol by the standard technique, followed immediately by coronary perfusion with Ringer's solution at 0 ~ C. These hearts promptly resumed a slow beat, indicating that the alcohol had been washed out by the Ringer's. In two animals, 30 minute arrest at 24 to 27 ~ C. was achieved by infusing 50 cc. of 1.7% butyl alcohol at room temperature, followed immediately by 50 cc. of 0.17% butanol at 0 ~ C. I n these cases arrest and recovery were grossly satisfactory, but post-arrest ventricular function in each case was below the
I
Right II
III
I
Left II
III
23.0 42.5 23.7 28.3 22.8
100 I00 I00 100 100
19 0 75 99 57
96 53 78 146 89
100 100 100 100 100
48 0 42 101 47
87 79 49 119 56
28.1
I00
50
92
100
48
78
average for 30 minute alcohol arrest at 35 ~ C. T h e fine muscular activity observed in half of the hearts during arrest suggested that the concentration of butyl alcohol might be inadequate. Therefore, two bypassed canine hearts were arrested for 30 minutes with 2% butyl alcohol in Ringer's. In both cases intractable ventricular rigor developed upon release of the aorta. I n another experiment the heart was arrested with 50 cc. of 1.7% butyl alcohol in Ringer's and during the subsequent 30 minute arrest period, another 50 cc. of the same solution was slowly perfused through the coronary arteries. This heart failed to beat upon release of the aorta. TOXICITY Butyl alcohol is commonly thought to be an extremely toxic substance, properly f o u n d in lacquer solvents and properly avoided in bad whiskey. Acute parenteral administration produces generalized cell narcosis. Its lethal effect is by depression of the central nervous system. T h e lowest reported LDs0 is 0.76 ml./kg., or approxi-
186
McGuIRE,BOSHER,a n d RAMSEY
mately six times the toxicity of ethyl alcohol.7 T h e probable lethal dose for man is reported to be between 500 rag. and 5 gm./kg. 4 Butyl alcohol is presumably metabolized in the liver and no toxic effects of chronic parenteral administration are reported. Because no data were available on the acute intravenous toxicity of butyl alcohol in dogs, we administered the drug intravenously at a rate of 20 mg./kg./min, to eight dogs, four of whom were moderately narcotized with morphine sulfate. Vital signs, sensorium and EKG were observed continuously. The stages of toxicity observed were as follows: (1) somnolence, (2) anesthesia and bradycardia, (3) respiratory depression and hypotension with tachycardia, (4) irreversible hypotension with apnea and bradycardia, and (5) asystole. T h e first three stages appeared to be reversible. T h e m i n i m u m toxic dose was 150 mg./kg, and the minimum lethal dose was 310 mg./kg. Animals which were not narcotized with morphine tolerated 30 per cent greater doses of butyl alcohol. Our LDs0 of 0.8 gm./kg, corresponds roughly to the lowest dose previously reportedY We have thus shown that our pharmacologic (cardioplegic) dose of 850 rag. for 10 kg. dogs is 57 per cent of the minimal toxic dose, and 27 per cent of the m i n i m u m lethal dose. Since the dog's heart-body weight ratio is greater than man's, it is expected that a greater margin of safety might be found clinically. T h e narrow margin of safety demonstrated in these experiments, however, suggests that after cardioplegia the first 100 cc. of coronary sinus blood should be discarded. In the cardioplegic experiments reported here, coronary sinus blood was returned to the extracorporeal circuit without apparent complication. A survivor of 30 minute butyl alcohol arrest autopsied two weeks postoperatively revealed no evidence of renal or hepatic damage, and myocardial histology on all alcohol-arrested hearts (acute experiments) revealed normal myocardium. DISCUSSION
Previous studies in our laboratory 6 support the popular clinical impression that cardioplegia by either acetylcholine or potassium offers little protcction against myocardial ischemia. Twenty-five degree hypothermia gives only partial protection (Fig. 8), results in a tonic heart requiring a larger ventriculotomy, and is technically more cumbersome than chemical arrest. Thcrcfore, we have continued the search for a safe chemical cardioplegic agent. Narcotics whose paralytic effects on muscle cells
JSR
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Vol. I, No. 3 - September,
1961
may be reversed by washing the cells are presumed to exert their effect on the cell membranes rather than on the internal contractile mechanism. Therefore, the narcotic whose molecule is most perfectly adapted to the structure of the cell membrane might be expected to be the most effective as well as the most reversible narcotic. Many narcotics, such as the straight-chain alcohols, behave as if an equilibrium were established between cell and media at the narcotic concentration, and hence are susceptible to thermodynamic analysis. Moreover, one is justified in assuming that the narcosis in such cases is a physical process. Ferguson, 3 and Brink and Posternak 1 have analyzed a wide variety of published data and have shown that in a homologous series there is often equal narcotic action at equal thermodynamic activities. The problem of calculating the activity coefficients of narcotics in solution is a complex one and all authors must use simplifying assumptions. A later analysis by Mullins 9 approached the problem from a more sophisticated basis than Ferguson or Brink and Posternak, in the course of which it was necessary to assume an arbitrary but constant membrane solubility parameter (or cohesive energy density) for a particular membrane. For some membranes, Mullins found that the assumed value of the membrane's solubility parameter which best fitted the data was the same as the solubility parameter for 1-butanol. T h e inference from this is that the "holes" or "spaces" in the membrane lattice structure are of a size or volume which can be matched by four ethylenic groups and one polar group. Hence butyl alcohol would be an "ideal" narcotic. These theoretical observations were borne out in our preliminary studies in which other narcotics and alcohols of the homologous series were evaluated for cardioplegia and recovery rate in the isolated dog heart. Butyl alcohol was the most promising agent tested. Furthermore, in the doses required for cardioplegia it appeared that toxicity would not be a limiting factor. Functional studies of intact canine hearts after 15 minutes of butyl alcohol cardioplegia were very encouraging, revealing protection against myocardial ischemia and almost complete recovery of ventricular function when tested 15 minutes after restoring coronary circulation. When cardioplegia was prolonged to 30 minutes, however, results were disappointing. Although recovery was significantly more rapid than following anoxic arrest, depressed ventricular function revealed limitations of butanol arrest by the technique employed. Furthermore, slight in-
JSR -
Vol. I, N o . 3 - S e p t e m b e r , 1961
SURGICAL CARDIOPLEGIA WITH BUTYL ALCOHOL
crease in c o n c e n t r a t i o n or v o l u m e of the arresting solution a p p e a r e d to be dangerous. T h e a d d i t i o n of 25 ~ regional h y p o t h e r m i a to 30 m i n u t e s of b u t a n o l arrest failed to i m p r o v e post-arrest ventricular function. T h e s e findings preclude the clinical use of butyl alcohol by the present t e c h n i q u e b u t do n o t exclude the possibility that by some variation in technique or by the use of o t h e r dosages, cardioplegic or metabolic adjuvants, or a m o r e effective c o m b i n a t i o n with h y p o t h e r m i a , b u t a n o l m a y be developed as a safe agent for chemical cardioplegia.
sible i m p r o v e m e n t to be achieved by variations in technique r e m a i n to be explored. REFERENCES 1. Brink, F., and Posternak, J. M,: Thermodynamic
2. 3. 4. 5.
SUMMARY
T h e o r e t i c a l analysis of cell m e m b r a n e s in narcosis a n d experimental observations of the effect of narcotics on the isolated canine heart gave rise to the prediction that b u t y l alcohol w o u l d be an ideal narcotic for i n d u c t i o n of chemical cardioplegia for o p e n heart surgery. I n a series of acute canine experiments ventricular f u n c t i o n was tested after 15 minutes a n d after 30 m i n u t e s of arrest. Results indicated that butyl alcohol offers excellent p r o t e c t i o n of the n o r m o t h e r m i c heart arrested for 15 minutes, b u t gives o n l y partial protection d u r i n g 30 m i n u t e s of arrest. T h e reason for this failure a n d the pos-
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9. 10.
analysis of the relative effectiveness of narcotics, j. Cell. 8: Comp. Physiol., 32:211, 1948. Dold, H.: Ueber die Wirkung des Athylalkohols und verwandter Alkohole auf das Froschherz. Pfliiger's Arch. ges. Physiol., 112:600, 1906. Ferguson, J.: The use of chemical potentials as indices of toxicity. Proc. Roy. Soc., Series B, 127:387, 1939. Gleason, M. N., Gosselin, R. E., and Hodge, H. C.: Clinical Toxicology of Commercial Products. Williams & Wilkins Co., Baltimore, 1957, p. 33. Kuno, Y.: Ueber die Wirkung der einwertigen Alkohole auf das ueberlebende saugetierherz. Arch. exper. Path. u. Pharmakol., 74:399, 1913. Kusunoki, T., Cheng, H., McGuire, H. H., Jr., and Bosher, L. H., Jr.: Myocardial dysfunction after cardioplegia. J. Thorac. & Cardiovas. Surg., 40:813, 1960. Lendle, L.: Untersuchungen ueber die Narkosegeschwindigkeit homologer and isomerer einwertiger Alkohole. Arch. exper. Path. u. Pharmakol., 129:85, 1928. McGuire, H. H., Jr., Bosher, L. H., Jr., and Ramsey, R. W.: Exploration into narcosis for surgical cardioplegia. Tr. Am. Soc. for Artificial Internal Organs, 6:323, 1960. Mullins, L. J.: Some physical mechanisms in narcosis. Chem. Rev., 54:289, 1954. Ramsey, R. W.: The narcosis of frog muscle by n-hutyt alcohol. J. Cell. & Comp. Physiol., 11:65, 1938.