The hazard of ventricular fibrillation in hypertrophied ventricles during cardiopulmonary bypass

The hazard of ventricular fibrillation in hypertrophied ventricles during cardiopulmonary bypass Christoj E. Hottenrott (by invitation), Bernard Towers (by invitation), Henry J. Kurkji (by invitation), James V. Maloney, and Gerald Buckberg (by invitation), Los Angeles, Calif.

Left ventricular subendocardial necrosis is the principal cause of fatal postoperative myocardial failure in patients whose intracardiac lesions have been satisfactorily repaired.':" This complication, occurring in the absence of coronary artery obstruction, is caused by ischemic injury to the myocardium.' It develops rarely in the normal left ventricle but more commonly in ventricles that are severely hypertrophic, such as found in aortic stenosis." We have previously reported preoperative factors which make the heart more vulnerable to this injury and postoperative factors that potentiate it." However, the adequacy of myocardial preservation during cardiopulmonary bypass is the principal determinant of the degree of ischemic damage sustained by the heart. In an effort to miniFrom the Division of Thoracic Surgery, Department of Surgery, and the Division of Pediatric Cardiology, Department of Pediatrics, UCLA Medical Center, Los Angeles, Calif. 90024. This work was supported in part by the Beaumont Foundation, the Frank W. Clark Charities, the Gilmore Foundation, the Wilbur May Foundation, and the Los Angeles County Heart Association Award No. 476. Read at the Fifty-third Annual Meeting of The American Association for Thoracic Surgery, Dallas, Texas, April 16, 17, and 18, 1973. Address for reprints: Gerald Buckberg, M.D., Division of Thoracic Surgery, UCLA Medical Center, Los Angeles, Calif. 90024.

742

mize this damage during extracorporeal circulation, many surgeons have employed ventricular fibrillation which they consider safe and effective since coronary perfusion is maintained while intracardiac repair is accomplished.r" Reis and associates" have shown that continuous application of the fibrillating stimulus may be deleterious to myocardial function and metabolism. Our!" studies suggest these adverse effects occur because electrically maintained fibrillation causes ischemia by diverting coronary blood flow away from the subendocardial muscle of a normal left ventricle. This ischemia does not occur, however, when the normal left ventricle fibrillates spontaneously after the stimulus is withdrawn. It is our hypothesis that conclusions based upon physiologic studies showing the safety of ventricular fibrillation in normal hearts cannot be applied to hypertrophied hearts. We here report experimental and clinical evidence that spontaneous ventricular fibrillation causes ischemic damage to the hypertrophied left ventricular myocardium. Methods Experimental preparation. Twenty-three dogs weighing 17 to 25 kilograms were

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anesthetized with chloralose, 100 mg. per kilogram. Cardiopulmonary bypass was instituted through a bilateral thoracotomy by diverting systemic and coronary venous blood into an extracorporeal circuit (bubble oxygenator) and returning it into the femoral artery. The extracorporeal circuit was primed with fresh heparinized whole blood. Blood temperature was maintained at 37° C. with a heat exchanger. Aortic root and left atrial pressures were monitored continuously. A catheter was placed into the coronary sinus through the right atrium for metabolic studies. Mean arterial blood pressure was maintained at 100 mm. Hg by regulating the perfusion rate between 70 and 100 c.c. per kilogram. The sinoatrial node was crushed, and heart rate was maintained at 100 beats per minute with a Grass physiologic stimulator. Hemodynamic observations were made before, during, and after ventricular fibrillation. Fibrillation was induced by increasing the voltage of a 60 cycle alternating current (AC) stimulus until fibrillation occured (1.5 to 4 volts). The stimulus was withdrawn from the heart, and the ventricles were allowed to fibrillate spontaneously for 60 minutes. Vents were placed in the left and right ventricles for decompression, and left atrial pressure was monitored continuously to assure the adequacy of decompression. At the conclusion of fibrillation, normal rhythm was restored with electrical countershock. Experimental groups. Nonhypertrophied left ventricle. Fifteen normal dogs were subjected to the above experimental procedure. Left ventricular hypertrophy. Eight dogs underwent constriction of the supravalvular aorta (gradients across the supravalvular stenosis varying from 75 to 150 mm. Hg; 92 ± 15 mm. Hg standard deviation) 3 to 5 months prior to the fibrillation study. Left ventricular hypertrophy was confirmed at autopsy by assessing the weight ratios of left ventricular free wall to total body weight. This ratio was (3.94 ± 0.25) x 10-3

compared to (3.28 ± 0.21) x 10- 3 In the control dogs (p < 0.025). Hemodynamic studies. Coronary. 1. Regional coronary flow was measured by injecting 8 to 10 jJ. radionuelide microspheres ('.nCe, "'Sr, and "SSc) into the arterial perfusion line. These spheres measure total coronary blood flow during cardiopulmonary bypass with 9 ± 3 per cent reproducibility and have the same intracardiac distribution as diffusible indicaters." A reference sample was collected from a peripheral artery during each microsphere injection. At the end of the procedure, the heart was removed and the ventricular free wall was divided into subendocardial, subepicardial, and midmyocardial layers of equal thickness. These layers were placed in separate vials for counting by gamma spectrometry. Flows were calculated by modification of the method of Rudolph and Heymann." 2. Phasic coronary flow was measured by placing an electromagnetic flowmeter transducer around the circumflex coronary artery and connecting it to a Statham Model 2200 flowmeter. 3. Left coronary flow through the coronary perfusion cannula was monitored in 6 patients during aortic valve replacement while coronary perfusion pressure was maintained at 100 mm. Hg. 4. Coronary vascular resistance was calculated by dividing coronary blood flow by mean aortic blood pressure. Systemic. Left ventricular function curves were inscribed in 10 control dogs and 4 dogs with left ventricular hypertrophy. This was accomplished by diverting systemic and coronary venous return through a calibrated occlusive roller pump and returning it through the pulmonary artery. Aortic blood pressure was maintained at 100 mm. Hg by the infusion or withdrawal of blood from the aorta through a cannula in the left subclavian artery. Heart rate was maintained at 100 beats per minute. Left ventricular function curves were determined by relating left ventricular stroke work (LVSW) to

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Thorocic ond Cordiovoscular Surgery

10

8 c

E

<,

_

Beating empty

_

Fibrillating

::::::

BeatIng empty _ Fibrillating _

100

6

c

E

0'

0 0

120

80

<,

0'

4

0

u u

Q

60

<,

u u

2

0-'-----

Normal LV LV H Fig. 1. Left ventricular (LV) oxygen consumption (cubic centimeter per 100 Gm. per minute) in the normal and hypertrophied heart (LVH) when they are beating and nonworking and after 60 minutes of spontaneous ventricular fibrillation. Note that oxygen consumption increased in normal hearts but did not change significantly in the hypertrophied heart during fibrillation.

mean left atrial pressure (mm. Hg) LVSW

SV x (AO - LA) x 1.36

= --------100

where AO is mean aortic blood pressure in mm. Hg, SV is stroke volume, and LA is left atrial pressure in mm. Hg. Metabolic observations. Left ventricular oxygen consumption was determined by measuring left ventricular coronary flow by the microsphere method and analyzing aliquots of aortic and coronary sinus blood for oxygen content. These samples were also analyzed for pH, lactate, and potassium. Procedure. Following inscription of a left ventricular function curve with right heart cardiopulmonary bypass, total cardiopulmonary bypass was instituted and metabolic and coronary hemodynamic studies were obtained after 15 minutes in the beating, empty heart under control conditions. These studies were repeated after 60 minutes of ventricular fibrillation and 5 to 10 minutes after defibrillation. The second ventricular function curve was inscribed 30 minutes after defibrillation. Histochemical studies. Following formalin fixation, full-thickness sections of left ventricular wall were cut at 6 p., embedded

40

20 0-'-------

Normal LV LV H Fig. 2. Left ventricular (LV) coronary blood flow (cubic centimeter per 100 Gm. per minute) in the normal and hypertrophied heart (LVH) when they are beating and nonworking and after 60 minutes of spontaneous ventricular fibrillation. Note the marked increase in left ventricular coronary flow in normal hearts after fibrillation. Conversely, left ventricular coronary flow does not increase during fibrillation in hypertrophied hearts.

in paraffin, and stained in three ways: (l) hematoxylin and eosin; (2) cresyl violet, acid fuchsin, orange G, and methyl green"; and (3) hematoxylin, basic fuchsin, and picric acid.>' Both fuchsin stains are known to demonstrate ischemic damage to myocardial fibers.>' 14 Control sections of normal and ischemic myocardium were used to check the accuracy of the staining solutions. Results Myocardial oxygen consumption (left ventricle). Fig. 1 shows that oxygen uptake of the beating, nonworking left ventricle was significantly greater in hypertrophied hearts (5.6 c.c. per 100 Gm. per minute) than in normal hearts (3.7 c.c. per 100 Gm. per minute; p < 0.05). Left ventricular oxygen consumption increased to 6.9 c.c. per 100 Gm. per minute in normal hearts (p < 0.01) after 60 minutes of ventricular fibrillation but did not change significantly in dogs with left ventricular hypertrophy (Table I). Total left ventricular flow. In the normal heart, spontaneous fibrillation was associ-

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Ventricular fibrillation during CPB

745

Table I Condition Beating, working Normal Oxygen consumed (c.c./Gm./min. ) Total heart 5.7 ± 0.7 8.7 ± 0.7 Left ventricle Coronary flow (c.c./100 Gm./ min.) Total heart 67 ± 11 Left ventricle 81 ± 9 Left ventricular subendocardium 89 ± 11 ENDO/EPI 1.1 ± 0.07 Art-cor. sinus changes pH 0.037 ± 0.028 Lactate extraction (per cent) -20.9 ± 5.6

(A-A-

CS)

Beating, empty

Spontaneous fibrillation

LVH

Normal

LVH

Normal

LVH

7.0 ± 0.8 9.66 ± 2.5

3.2 ± 0.6 3.7 ± 0.6

5.0 ± 0.67 5.63 ± 1

4.8 ± 0.7* 6.9 ± 1.1*

5.65 ± 0.8 5.67 ± 1.8

73 ± 12 83 ± 15

42 ± 12 43 ± 9

67± 9 82 ± 9

105± 15* 104 ± 18*

66± 9 73 ± 10

79 ± 14 0.96 ± 0.13

48 ± 11 1.1±0.1

87 ± 14 1.27 ± 0.26

139 ± 16* 1.5 ± 0.2*

70 ± 13 1.08 ± 0.17

0.003 ± 0.06

-0.029 ± 0.026 -14.3 ± 6

0.01 ± 0.04

-0.25 ± 0.14

-0.075 ± 0.08

-39.5 ± 3

-24 ± 10

-0.046 ± 0.029 -11.8 ± 3.5

0.07 ± 0.04*

-0.32 ± 0.49

0.2 ± 0.23

4.2 ± 10*

x 100

Potassium (mEq./L.)

-0.18 ± 0.46

o ± 0.08

Legend: LVH, Left ventricular hypertrophy. CS, Coronary sinus. Art., Arterial. Cor., Coronary. A, Aortic. Values are mean:': 1 SD. There were 15 hearts with normal left ventricles and 8 with left ventricular hypertrophy. *p

<

0.01.

ated with an increase in mean left ventricular flow from 43 to 104 c.c. per 100 Gm. per minute (Fig. 2); (p < 0.01). Flow remained increased for the duration of the 60 minute period of fibrillation. Conversely, in hypertrophied hearts, left ventricular flow increased an average of 28 per cent immediately after the onset of fibrillation (p < 0.05) but decreased progressively during the period of fibrillation (p < 0.05) because of a progressive increase in coronary vascular resistance. Left ventricular subendocardial flow* In the normal ventricle, left ventricular coronary flow increased 140 per cent following 60 minutes of ventricular fibrillation due to a decrease in coronary vascular resistance (p < 0.01). This flow increment was greatest in the subendocardial region, where flow increased from 48 to 139 c.c. per 100 Gm. per minute (194 per cent above control values, p < 0.01) (Fig. 3).

In hypertrophied hearts, the total blood flow delivered to the heart was similar when the heart was beating and empty and when it fibrillated spontaneously. In contrast to the normal heart, in which the proportion of total left ventricular flow delivered to subendocardial muscle increased during ventricular fibrillation, myocardial flow was redistributed away from the subendocardial region when the hypertrophied heart fibrillated. This was reflected by a fall in the subendocardial/subepicardial flow ratio from 1.27 ± 0.26 (beating, non-working heart) to 1.08 ± 0.17 (ventricular fibrillation) (Fig. 4). Reactive hyperemia. Experimental. In normal hearts, coronary flow fell to control levels within 1 to 2 minutes following defibrillation. Conversely, coronary flow increased 150 to 300 per cent following defibrillation of hypertrophied hearts. This hyperemic response was sus-

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Beating empty.

160

Flbnl/atlng _

140 120

c

100

E <, 0'

0

80

Q

<,

o o

60 40 20 0

Normal LV

LVH

Fig. 3. Blood flow through left ventricular (LV) subendocardial muscle in the normal and hypertrophied heart (LVH) when they are beating and nonworking and after 60 minutes of spontaneous ventricular fibrillation. Note the approximately 300 per cent increase in subendocardial flow during fibrillation in normal hearts. Conversely, coronary flow to the subendocardial muscle does not increase during fibrillation in hypertrophied hearts.

tained throughout the 30 minute interval that we allowed before repeating the ventricular function curves. Clinical. Coronary flow (left coronary perfusion cannula) decreased 25 to 60 per cent in each of 4 patients with left ventricular hypertrophy who developed spontaneous fibrillation during aortic valve replacement (p < 0.05). In each instance, defibrillation resulted in a hyperemic response similar to that observed in experimental studies on hypertrophied ventricles. Conversely, there was no reduction in coronary blood flow when spontaneous fibrillation developed in 2 patients with normal left ventricles who underwent aortic valve replacement for acute bacterial endocarditis. Myocardial metabolism. In dogs without ventricular hypertrophy, there was no significant difference in the aorta-coronary sinus

levels of pH, lactate, or potassium between the beating heart and the spontaneously fibrillating heart. These values remained constant in the post fibrillation period. In dogs with ventricular hypertrophy, the artery-coronary sinus pH difference increased from 0.01 ± 0.04 to 0.07 ± 0.04 units during ventricular fibrillation indicating myocardial hydrogen ion production (p < 0.01). Coronary sinus blood was even more acidic during the reactive hyperemic phase following defibrillation (aorta-coronary sinus pH 0.09 units, p < 0.01). The hypertrophied left ventricle extracted lactate normally when it beat and was empty, but it produced lactate (p < 0.01) during ventricular fibrillation. A large washout of lactate was noted after defibrillation (p < 0.01) (Fig. 5). Arterial and coronary sinus potassium concentrations were similar when the hypertrophied left ventricle beat and did no external work. During ventricular fibrillation, however, there was efflux of potassium ion from the myocardium (artery-coronary sinus difference 0.2 mEq. per liter), and this efflux was more pronounced (arterycoronary sinus difference 0.7 mEq. per liter) following defibrillation (p < 0.01). Myocardial performance. In each experiment in which left ventricular function curves were inscribed, control curves were compared to the curve recorded in the same animal following 60 minutes of ventricular fibrillation. Seven of 10 dogs with normal left ventricles showed minimal depression of left ventricular function (Fig. 6, A). Ventricular function curves were normal in the other 3 dogs. Conversely, severe depression of left ventricular function (Fig. 6, B) was seen when these curves were inscribed following defibrillation in 3 of 4 dogs with left ventricular hypertrophy. The dog that had normal ventricular function following defibrillation had the smallest degree of hypertrophy. Cardiac pathology. Macroscopic. Transverse sections of the hearts of normal dogs subjected to 60 minutes of spontaneous fibrillation were grossly

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Ventricular fibrillation during CPB

Number 5 November, 1973

Beating empty_

175

48

Flbnl/atlng _

150

46 44

1----- --- -1----- ----I

42

40 +10

OL----

0------

%

LACTATE

25

- 10 Normal

LV

-20

LV H

Fig. 4. Left ventricular (LV) myocardial flow distribution in the normal and hypertrophied heart (LVH) when they are beating and nonworking and after 60 minutes of spontaneous ventricular fibrillation. Note that the hypertrophied ventricle receives the greater proportion of left ventricular flow during the beating, nonworking condition than does the normal left ventricle. With fibrillation, the proportion of total left ventricular flow delivered to the suebndocardium increases in the normal heart and decreases in the hypertrophied heart.

normal. Similar sections from 8 dogs with hypertrophied left ventricles showed evidence of hyperemia and focal hemorrhage. These changes were usually more marked in the inner half of the wall of the hypertrophied left ventricle (Fig. 7), but there was no evidence of recent infarction. Microscopic. Full-thickness sections of left and right ventricular walls of 2 normal dogs subjected to 60 minutes of spontaneous fibrillation showed no histologic or histochemical evidence of myocardial ischemia (acid and basic fuchsin stains). Similar sections from 8 dogs with hypertrophied left ventricles showed focal hemorrhages in both ventricles. Myocardial fibers appeared normal on routine histologic stain (hematoxylin and eosin). When histochemical stains were employed, groups of ischemic muscle fiber were found at all levels in both ventricles. They were always more noticeable in the left ventricle as compared to the right and were particularly pronounced in the inner

1-----+--------j

-30 o norma/ LV eLVH

12

8

[K+] CS-A mEq/1

4

o

1,1--------1------ --'f Beating empty

Spent. f,b"l!.

Post fibrill

Fig. 5. Biochemical evidence of left ventricular myocardial ischemia. The effects of spontaneous fibrillation on coronary sinus-artery (CS-A) hydrogen ion differences (nanamoles), lactate metabolism, and potassium differences. Note that there is no significant change in any of these variables in the normal ventricle during spontaneous fibrillation or in the postfibrillation period. With left ventricular hypertrophy, there is hydrogen ion production, coronary sinus lactate production and loss of potassium from the myocardium. During the reactive hyperemic phase (defibrillation), an even greater rise in coronary sinus hydrogen ion, lactate, and potassium occurs.

half of the left ventricular wall (Fig. 8, A and B). There was some suggestion of myocardial edema as evidenced by increased distances between myocardial fibers and by enlargement of perivascular connective-tissue spaces. Discussion

Myocardial hypoxia is the most critical factor in the development of subendocardial

748

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45

NORMAL LV

e Q)

I

35 pre,',

cr>

~

f--

> -.J

o

: pre

,

I

o ., I

.

, ,, o, ,

20

I

,

.

p

I

o

I

15

, ,,

o ,,

,p

25

0

(f)

, ,,

I

, ,,

~

0:::

I

,0

0

w

I

I

.

30

0:::

~

o,

0 ,'

40 OJ E

LVH

I I

1 0

I

6

o

B I

5

I

10

Iii" 11/""11/"""IIIIII111//111/1 /III/II i 1111111111111111111111111111i11111

Fig. 7. Tr ansverse section of heart of dog with chronic aortic stenosis and left ventricular hyper trophy whose ventricular funct ion curve is shown in F ig. 6, B. Focal hemorrhages and venous congestion are present transmurally but are most prom inent in the inner half of the wall of the hypertrophied left ventricle.

necrosis after open-heart surgery . It has been assumed that this hypoxia can be avoided during card iopulmona ry bypass by employing ventricular fibrillation while perfusing the coronary arteries continually with

r

15

i

20

I

25

oxygenated blood. Conclusions regarding the safety of ventricular fibrillation have been based upon evidence marshalled from the following experimental and clinical studies: 1. The fibrillating heart consumes less oxygen than the beating, working heart,": 1 5 2. The beat ing, nonworking heart can increase its oxygen consumption during fibrillation by raising coronary flow by vasodilatation." 3. Normal ventricles show no metabolic or functional impairment or histologic changes after 30 to 60 minutes of spontaneou s flbrillation. >v 4. Postoperative mortality rates from centers using ventricular fibrillation are comparable to those from centers using other forms of card iac preservation." Despite these potential advantages of ventricular fibrillation, N ajafi" observed that left ventricular hemorrhagic necrosis was more common in patients whose hearts were fibrillated dur ing intramyocardial repair. Studies of ventricular fibrillation arc difficult to interpret because of differences in the duration, frequ ency, and types of fibrillation employed. There is evidence that ventricular fibrillation can cause myocardial

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Ventricular fibrillation during CPR

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November, 1973

damage if (l) it is used for prolonged time periods," (2) coronary perfusion is not adequately maintained,"- 19 or (3) an AC fibrillating stimulus is continually applied to the heart." Most studies in normal hearts show that ventricular fibrillation is safe if the electrical stimulus is detached from the heart (spontaneous fibrillation) and continuous coronary perfusion is maintained. Our experimental observations with the use of spontaneous fibrillation in nonhypertrophied hearts would support this contention," as do clinical reports of its safe use in patients undergoing aorto-coronary bypass grafting whose hearts are of normal size." During ventricular fibrillation, myocardial muscle fibers contract and develop tension asynchronously and at a rapid rate. Since tension and the rate of contraction are primary determinants of myocardial oxygen requirements," it is not surprising that the oxygen consumption of the fibrillating normal heart exceeds that of the beating, nonworking heartS - 1 0 , 15 and may approach that of the beating, working heart." Our studies suggest that these requirements may be highest in the subendocardial region of the left ventricle, since the greatest proportion of increased left ventricular flow is delivered to the subendocardium when the normal heart fibrillates spontaneously. This increased coronary flow probably provides sufficient oxygen to meet increased metabolic requirements, since neither metabolic, histochemical, nor functional impairment follows spontaneous fibrillation in normal hearts. Conversely, myocardial oxygen consumption did not rise in our experiments when hypertrophied hearts fibrillated spontaneously. In recent clinical studies, Isom and colleagues" observed a similar failure of hypertrophied hearts in increase their oxygen consumption during fibrillation. In their report, myocardial enzyme levels in coronary sinus blood were significantly higher when hypertrophied hearts fibrillated than when they beat and did no external work. Our studies show that coronary blood is

Fig. 8. Full-thickness 6/10 section of right ventricle (A) and left ventricle (B) of dog with chronic aortic stenosis after ventricular fibrillation (original magnification x18). Formalin fixation; stained with hematoxylin, basic fuchsin, and picric acid. Red blood cells and ischemic muscle fibers are stained black (red in original). Epicardial hemorrhages are seen at the top of both pictures. The left ventricle shows patches of hemorrhage and large areas of ischemic myocardium, mostly in the inner half of the wall. The right ventricle shows occasional groups of ischemic fibers.

diverted away from subendocardial muscle in fibrillating hypertrophied hearts, rather than toward this region as with normal fibrillating hearts. It is apparent from the metabolic evidence of anaerobic metabolism (myocardial lactate production and reduced coronary sinus pH) and loss of membrane

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Thoracic and Cardiovascular Surgery

integrity (potassium efflux into coronary sinus blood), that myocardial oxygen consumption fails to rise during fibrillation in hypertrophied hearts because coronary flow cannot increase sufficiently to meet metabolic demands. Further proof of the inadequacy of this flow is provided by the histochemical demonstration of left ventricular ischemia, which is most severe in the subendocardial region. These metabolic and histochemical changes caused the impaired myocardial performance which was detected when left ventricular function curves were inscribed following defibrillation. These observations emphasize how measurements of myocardial oxygen consumption may be misleading unless the adequacy of oxygen delivery is assessed simultaneously. Myocardial oxygen consumption is calculated from measurements of coronary flow and differences in artery-coronary sinus oxygen content; oxygen consumption is synonymous with oxygen requirement only if oxygen delivery is adequate. Since the heart normally extracts almost all the oxygen passing through the myocardium, coronary flow is the principal determinant of myocardial oxygen delivery. Myocardial ischemia can therefore occur with normal or even increased myocardial oxygen consumption if the coronary vessels cannot dilate sufficiently to provide enough increased oxygen supply to meet raised metabolic needs. This ischemia can also occur with reduced myocardial oxygen consumption if coronary flow becomes impeded and the requirements are raised simultaneously. We have shown this sequence in normal hearts that are caused to fibrillate continuously with an electrical stimulus." Several factors may contribute to the inability of subendocardial coronary blood flow to increase adequately in hypertrophied fibrillating hearts. It is well recognized that this region of the myocardium is the most vulnerable to ischemic damage, because it must receive most or all of its flow during diastole when the heart is beating; systolic compressive forces are highest in the subendocardial region and therefore prevent its

perfusion during ventricular contraction.v- 23 The vented, fibrillating ventricle attains a chamber size comparable to that in endsystole, so that the degree of extra-myocardial compression of the coronary arteries is determined by the amount of intrafascicular tension developed by the fibrillating muscle fibers. Theoretical analysis of intramyocardial stress gradients suggests that these compressive forces are highest in the subendocardial region, especially in hypertrophied hearts, in which the fibrillating fibers may impede flow through the coronary arteries as they course through the myocardium> The present study provides evidence for this impedance to flow, in that reactive coronary hyperemia followed defibrillation in experimental and clinical studies of hypertrophied hearts; simultaneous washout of acid metabolites indicates that this flow impediment caused ischemia. We did observe, in hypertrophied hearts, an initial increase in coronary flow during the early phase of ventricular fibrillation, but we noted that flow decreased progressively as the fibrillation was continued for 60 minutes. Similar changes in coronary flow during the course of fibrillation were observed in our clinical studies. It is conceivable that the progressive rise in myocardial vascular resistance was due to the development of intramyocardial edema, which may have compressed coronary veins or altered myocardial lymphatic flow. This contention is supported by our histologic studies. They showed increased distance between myocardial fibers suggesting that edema was present. Inadequate decompression of the left ventricular cavity during fibrillation may extend the ischemic injury caused by fibrillation. Malfunction of the ventricular vent would cause intracavitary pressure to rise, adding another counterforce which opposes subendocardial flow and impairs it further. Simultaneously, myocardial oxygen requirements increase as larger ventricular volumes raise wall tension." The extent of ischemic damage sustained

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by the hypertrophied may be worsened by pre- and postoperative factors. Recent studies have shown that the hypertrophied ventricle is more vulnerable to ischemic damage than is the normal ventricle." Since some patients with hypertrophied hearts show electrocardiographic evidence of ischemia prior to cardiopulmonary bypass, the degree of ischemic damage imposed by ventricular fibrillation may be even greater in these ventricles. We have previously produced subendocardial ischemia without bypass by lowering coronary diastolic blood pressure, raising left ventricular diastolic pressure, and shortening diastole.": 11 Consequently, any element of postoperative arterial hypotension (lowered aortic blood pressure), myocardial failure (elevated left ventricular diastolic pressure) or tachycardia (shortened diastole) would accentuate the ischemic injury which was present before operation and worsened during operation by fibrillation of hypertrophied ventricles. The deleterious effects of ventricular fibrillation on hypertrophied hearts did not occur when this intervention was imposed upon normal hearts. This observation emphasizes the importance of using experimental models that closely simulate the clinical problems after which they are patterned. We could find only one other study of the effects of ventricular fibrillation in hypertrophied hearts; Martino and colleagues" showed, in 1 dog, that up to 30 minutes of hypothermic (27° C). Ventricular fibrillation did not reduce maximum myocardial contractile force. While this observation suggests that hypothermia may reduce the vigor of fibrillation and protect the heart, further studies in this area are necessary. Clinical implications. On the basis of our studies, we have abandoned the use of ventricular fibrillation in hypertrophied hearts. We believe that the most physiologic method of cardiac preservation during cardiopulmonary bypass is to allow the heart to beat with the coronary arteries perfused while it does no external work. The beating,

nonworking left ventricle has a low oxygen requirement and receives most of its flow during diastole; all layers of the myocardium remain adequately perfused. Brief periods of anoxic arrest are preferred when a quiet operative field is essential. Myocardial oxygen requirements are lower with arrest than with ventricular fibrillation, and the duration and extent of anoxic injury is more easily estimated. Mild hypothermia has been useful in lowering oxygen needs still further; it also slows heart rate and provides a quieter operative field in the beating, empty heart when the cross-clamp is released. It is emphasized that ischemic arrest is used only when absolutely necessary; most operative procedures are conducted on the beating, nonworking heart. If fibrillation occurs during conduct of the procedure, electrical defibrillation is employed immediately. Since initiating this technique, the occurence of the low cardiac output syndrome and subendocardial necrosis has become rare.

Summary In normal ventricles, spontaneous fibrillation raises left ventricular oxygen consumption and subendocardial flow and lowers vascular resistance. It neither impairs myocardial function or metabolism nor causes histochemical damage. Conversely, when hypertrophied left ventricles fibrillate spontaneously, oxygen consumption fails to rise, vascular resistance increases progressively, and biochemical evidence of severe ischemia occurs (myocardial lactate production, decreased coronary sinus pH, and loss of intracellular potassium). Post-bypass ventricular function is depressed, and ischemia is demonstrable histochemically. Clinical studies during aortic valve replacement confirm these experimental findings. The most physiologic form of cardiac preservation appears to be to allow the heart to beat while empty. This study shows that spontaneous fibrillation may be safe in normal hearts but may cause ischemic damage to hypertrophied hearts.

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Thoracic and Cardiovascular Surgery

REFERENCES Taber, R. E., Morales, A. R., and Fine, G.: Myocardial Necrosis and the Postoperative Low Cardiac Output Syndrome, Ann. Thorac. Surg. 4: 12, 1967. 2 Najafi, H., Henson, D., Dye, W. S., Javid, H., Hunter, J. A., Callaghan, R., and Julian, O. c.: Left Ventricular Hemorrhagic Necrosis, Ann Thorac. Surg. 7: 550, 1969. 3 Buckberg, G. D., Towers, B., Paglia, D. E., Mulder, D. G., and Maloney, J. V.: Subendocardial Ischemia After Cardiopulmonary Bypass, J. THORAc. CARDIOVASC. SURG. 64: 669, 1972. 4 Morales, A. R., Fine, G., and Taber, R. E.: Cardiac Surgery and Myocardial Necrosis, Arch. Pathol. 83: 71, 1967. 5 Senning, A.: Ventricular Fibrillation During Extracorporeal Circulation, Acta Chir. Scand. Suppl. 171: 8, 1952. 6 Race, D., Stirling, G. R., and Morris, K. N.: Induced Ventricular Fibrillation in OpenHeart Surgery, J. THoRAc. CARDIOVASC. SURG. 47: 271, 1964. 7 Stoney, R. J., Zanger, L. C. c., and Roe, B. B.: Myocardial Metabolism and Ventricular Function Before and After Induced Ventricular Fibrillation, Surgery 52: 37, 1962. 8 Berglund, E., Monroe, R. G., and Schreiner, G. L.: Myocardial Oxygen Consumption and Coronary Blood Flow During Potassium-Induced Cardiac Arrest and During Ventricular Fibrillation, Acta Physiol. Scand. 41: 261, 1957. 9 Reis, R. L., Cohn, L. H., and Morrow, A. G.: Effects of Induced Ventricular Fibrillation on Ventricular Performance and Cardiac Metabolism, Circulation 36: 234, 1967 (Suppl. I). 10 Hottenrott, c., Buckberg, G. D., and Maloney, J. V., Jr.: The Effects of Ventricular Fibrillation on the Distribution and Adequacy of Coronary Blood Flow, Surg. Forum 23: 200, 1972. 11 Buckberg, G. D., Fixler, D. E., Archie, J. C., and Hoffman, J. I. E.: Experimental Subendocardial Ischemia in Dogs With Normal Coronary Arteries, Circ. Res. 30: 67, 1972. 12 Rudolph, A. M., and Heymann, M. A.: Circulation of the Fetus in Utero: Methods for Studying Distribution of Blood Flow, Cardiac Output and Organ Blood Flow, Circ. Res. 21: 163, 1967. 13 Poley, R. W., Fobes, C. D., and Hall, M. J.: Fuchsinophilia in Early Myocardial Infarction, Arch Pathol. 77: 325, 1964. 14 Lie, J. T., Holley, K. E., Kampa, W. R., and Titus, J. L.: New Histochemical Method for Morphologic Diagnosis of Early Stages of Myocardial Ischemia, Mayo Clin. Proc, 36: 319, 1971.

15 McKeever, W. P., Gregg, D. E., and Canney, P. C.: Oxygen Uptake of the Nonworking Left Ventricle, Circ. Res. 6: 612, 1958. 16 Read, R. C., Johnson, J. A., and Lillehei, C. W.: Coronary Flow and Resistance in the Dog During Total Body Perfusion, Surg. Forum 7: 286, 1956. 17 Wilson, H. E., Dalton, M. L., Kiphart, R. 1., and Allison, W. M.: Increased Safety of Aorto-Coronary Artery Bypass Surgery With Induced Ventricular Fibrillation to Avoid Anoxia, J. THORAc. CARDIOVASC. SURG. 64: 193, 1972. 18 Ghidoni, J. J., and Liotta, D.: Massive Subendocardial Damage Accompanying Prolonged Ventricular Fibrillation, Am. J. Pat hoI. 52: 21a, 1968. 19 Najafi, H., Lal, R., Khalili, M., Serry, c., Rogers, A., and Haklin, M.: Left Ventricular Hemorrhagic Necrosis, Ann. Thorac. Surg. 12: 400, 1971. 20 Braunwald, E.: Control of Myocardial Oxygen Consumption, Am. J. Cardiol. 27: 416, 1971. 21 Isom, O. W., Kulin, N. D., Falk, E. A., and Spencer, F. c.: Patterns of Myocardial Metabolism During Cardiopulmonary Bypass and Coronary Perfusion, 1. THoRAc. CARDIOVASC. SURG. 66: 705, 1973. 22 Brandi, G., and McGregor, M.: Intramural Pressure in the Left Ventricle of the Dog, Cardiovasc. Res. 3: 472, 1969. 23 Baird, R. J., Manktelow, R. T., Shah, P. A., and Ameli, F. M.: Intramyocardial Pressure: A Study of Its Regional Variations and Its Relationship to Intraventricular Pressure, J. THoRAc. CARDIOVASC. SURG. 59: 810, 1970. 24 Archie, J. P., Jr.: Determinants of Regional Intramyocardial Pressure, J. Surg. Res. In press. 25 Monroe, R. G., and French, G.: Ventricular Pressure-Volume Relationships and Oxygen Consumption in Fibrillation and Arrest, Circ. Res. 8: 260, 1960. 26 Iyengar, S. R. K., Ramchand, S., Charrette, E. 1. P., Iyengar, C. K. S., and Lynn, R. B.: Anoxic Cardiac Arrest: An Experimental and Clinical Study of Its Effects, J. THoRAc. CARD10VASC. SURG. 66: 722, 1973. 27 Martino, R. A., Kissack, A. S., Stuckey, J. H., Kavaler, F., and Fisher, V. J.: Myocardial Function After Electrically Induced Ventricular Fibrillation, Am. J. Cardiol. 24: 537, 1969.

Discussion DR. RONALD BAIRD Toronto, Ontario, Canada

I wish to comment on the paper by Dr. Buckberg and associates. The technique of measuring regional myocardial blood flow with radioactive microspheres

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Ventricular fibrillation during CPR

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November, 1973

is of great interest to the surgeon. We are all indebted to Dr. Buckberg and his associates for showing the usefulness of this method in plotting the changes in myocardial blood flow during cardiac bypass and ventricular fibrillation. Stimulated by their reports, we repeated their experiments dealing with the empty, beating heart and the heart which is fibrillating-spontaneously or in response to an alternating current or a square-wave direct current. We have tried to correlate the changes in myocardial blood flow with the changes in regional intramyocardial pressure. Our findings are different from but not incompatible with theirs. When the coronary perfusion pressure is kept constant, there is a marked increase in coronary flow on changing from the normal working ventricle to an empty, beating ventricle, and there is a further marked increase in flow on changing to ventricular fibrillation. The ratio of inner wall to outer wall flow is higher in both the empty, beating and the fibrillating heart than it is in the normal working heart. These changes are reasonable and are compatible with the changes in intramyocardial pressure. However, when the perfusion pressure is allowed to fall to a range between 50 and 60 mm. Hg, the distribution of coronary flow changes. With these low perfusion pressures, there is evidence of inadequate flow to the inner half of the myocardium, which is fibrillating in response to an alternating current fibrillator. In the normal dogs with which we were working, there was adequate subendocardial flow even at these low perfusion pressures when the heart was fibrillating either spontaneously or in response to squarewave direct current stimulation. I congratulate the authors on their paper and would ask Dr. Buckberg to comment on two points: First, the role of the perfusion pressure in his findings and, second, his present thoughts on the role of the alternating current fibrilla tor.

DR. BUCKBERG (Closing) I would like to thank Dr. Baird for his comments. I would certainly agree with the importance of maintaining adequate coronary perfusion pressure during bypass. As we know, the coronary arteries dilate when myocardial oxygen supply is reduced. When the coronary vessels become maximally dilated, then coronary blood flow and hence oxygen delivery is pressure dependent. Therefore, it is clear that, if the fibrillating muscle is inadequately perfused, a fall in perfusion pressure will produce a reduction in flow, especially to the subendocardium. It is not surprising that, by reducing perfusion pressure to 50 to 60 mm. Hg, Dr. Baird was able to produce subendocardial underperfusion in fibrillating hearts. It is also important to recognize that the heart usually gets its blood supply in diastole, so that even though an empty, beating heart may obstruct the flow during systole, it can be perfused adequately when it relaxes in diastole. One thing that our study indicated to us was that, even though it may be fine to derive conclusions from normal ventricles, we do not operate upon normal ventricles very often. Therefore, it is important to use an experimental model which most closely simulates the disease entity of interest. Our previous studies show that alternating current fibrillation produces ischemic damage in normal ventricles. The present studies lead us to believe that no form of ventricular fibrillation should be used in hypertrophied hearts. The most dramatic example of the obstruction of flow produced by fibrillation was recently seen in a massively hypertrophied heart. 'Upon opening the coronary perfusion cannulas, we had a flow of approximately 250 c.c. per minute into each coronary artery. The moment the heart fibrillated, the coronary flow fell 50 per cent without a change in perfusion pressure. This indicated a doubling of vascular resistance resulting from fibrillation.