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Effect of small-amplitude electrical activity on myocardial preservation in the cold potassium-arrested heart
J THoRAc CARDIOVASC SURG 91:684-689, 1986
Effect of small-amplitude electrical activity on myocardial preservation in the cold potassium-arrested heart Recent reports indicate that small-amplitude electrical activity may be present in the cold potassiumarrested heart. Twenty-four mongreldogs were placed on cardiopulmonary bypass and cooledto a rectal temperature of 26° C. Myocardial preservation was provided with a combinationof systemichypothermia 26° C. potassium (20 mEqjL) crystalloid cardioplegic solution(10 m1jkg) infused initially and every 30 minutes during 90 minutes of ischemic arrest, and topical hypothermia. Myocardial temperature was maintained between 8° and 10° C. Electrical activity and transmural myocardial temperature were monitored with specially designed plunge electrodes. Left ventricular stroke work index, cardiac index, and maximum rate of rise of left ventricular pressure were measured before bypass and 45 minutesafter ischemic arrest. Biopsy specimens were taken before bypass and at 15 and 45 minutes after ischemic arrest. The specimenswere used to measure adenosinetriphosphate and to analyze electron microscopic ultrastructure. Small-amplitude electrical activity was present in 16 of 24 animals during cardioplegic arrest. Cardiac index decreased 18 m1jminjkg (not significant), left ventricularstroke work index fell by 0.28 ± 0.1 gm-mjbeatjkg (p < 0.007), and maximum rate of rise of left ventricular pressure decreased 409 mm Hgjsec (p < 0.01) in the eight animals without small-amplitude electrical activity. Adenosine triphosphate concentration was unchanged and electron microscopic ultrastructure was well preserved. In contrast, small-amplitude electrical activity (16 animals) resulted in a decrease in cardiac index of 67 m1jminjkg (p < 0.001), a decrease in left ventricular stroke work index of 0.79 ± 0.8 gm-mjbeatjkg (p < 0.001),and a fall in maximumrate of rise of left ventricularpressure of 775 mm Hgjsec (p < 0.001). Adenosine triphosphate concentration decreased from 25 to 21 ILmoljgm (p < 0.04) and electron microscopic ultrastructure was poorly preserved (p < 0.001). This study demonstrates that smallamplitude electrical activity in the cardioplegia-arrested heart at 10° C impairs myocardial preservation.
R. W. Landymore, M.D., F.R.C.S.C., A. E. Marble, Ph.D.(Eng.), A. Trillo, M.D., M. MacAulay, M.D., G. Faulkner, M.D., and C. Cameron, B.N., Halifax. Nova Scotia. Canada
Recent reports have suggested that electrical activity may be present after the infusion of potassium cardioplegic solutions." 2 Electrical activity was recorded from the canine myocardium with specially designed plunge
From Dalhousie University, Department of Surgery, Division of Thoracic and Cardiovascular Surgery, Halifax, Nova Scotia, Canada. Supported by a New Brunswick Heart Foundation Grant. Read at the Eleventh Annual Meeting of The Western Thoracic Surgical Association, Incline Village, Nev., June 16-20, 1985. Address for reprints: R. W. Landymore, M.D., F.R,C.S.C., Room 3065, R.C. Dickson Centre, Victoria General Hospital, Halifax, Nova Scotaia, Canada B3H 2Y9.
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electrodes in the potassium-arrested heart at 10° C when mechanical activity had ceased and the electrocardiogram was isoelectric. We3 have recently repeated these earlier experiments and have confirmed that small-amplitude electrical potentials frequently persist after the infusion of potassium cardioplegic solution. These observations prompted the present study, which was designed to determine the effects of small-amplitude electrical activity on myocardial preservation.
Materials and methods Twenty-four mongrel dogs, weighing between 20 and 30 kg, received 1 ml of fentanyl citrate and droperidol (Innovar) for preoperative sedation. Anesthesia was
Volume 91 Number 5 May, 1986
induced and maintained with sodium pentobarbital and ventilation was provided with a Bird Mark 7 pressureregulated ventilator.* Pancuronium bromide (0.1 tug] kg) was administered intravenously after intubation. Surgical preparation. The femoral arteries were exposed bilaterally and the chest was opened through a median sternotomy. Systemic heparin was administered in a dose of 2 rug/kg. An 8F USCI catheter] was placed in the right femoral artery for blood pressure monitoring and a 7F Swan-Ganz thermodilution catheterf was positioned in the pulmonary artery. A No. 14 USCI arterial catheter was inserted into the left femoral artery in preparation for cardiopulmonary bypass, and two No. 34 USCI cannulas provided venous return and were positionedin the superior and inferior venae cavae. A 5F Millar catheter-tipped transducer§ (frequency response oto 24 kHz) was introduced through the apex of the left ventricle and was used to measure left ventricular end-diastolic pressure and left ventricular contractility, as denoted by the maximum rate of rise of left ventricular pressure (dp/dt max) ' Cardiopulmonary bypass was established with a Harvey bubble oxygenator] and a Medtronic impellar pum~1 (Model 1835OOU) driven by a Medtronic circulatory assist console (Model 1810) that would deliver nonpulsatile flow at a rate of 2.5 L/min/m2• The azygos vein and cavae were snared and both ventricles were vented during the arrest. The aorta was cross-clamped after a rectal temperature of 26 0 C was reached, and crystalloid cardioplegic solution, 10 ml/kg (20 rnEq of potassium per liter), at 4 C was administered with a Gish1[ cardioplegia administration set initially and at 30 and 60 minutes during the 90 minute arrest. Epicardial, myocardial, and endocardial temperatures were continuously monitored over the left anterior descending coronary distribution with specially designed plunge electrodes. The triple thermistor was calibrated against a mercury thermometer and temperatures were recorded on a Gould-Brush Model 260 six-channel recorder.# Myocardial temperature' was maintained within a range of 8 0 to 100 C with saline slush placed in the pericardial well and over the anterior surface of the heart. Myocardial electrograrns were recorded with 0
*Bird Corp., Palm Springs, Calif. tC.R. Bard Inc., Billerica, Mass. tAmerican Edwards Laboratories, Irvine, Calif. §Millar Instruments, lnc., Houston, Texas.
Small-amplitude electrical activity
685
specially designed plunge electrodes positioned over the left anterior descending coronary distribution.' The electrical signal from the plunge electrode was conditioned with a Krohn-Hite (Model 3342) filter* and amplified with a Gould-Brush 13-421 level shifter and Gould-Brush 260 preamplifier and recorder. The Krohn-Hite filter (a sixth order filter) was used in the low pass mode with a comer frequency of 50 Hz, which substantially reduced 60 Hz interference. Electrical activity detected by the plunge electrode was recorded on chart paper during the 90 minute arrest. Analysis of high-energy phosphates and myocardial ultrastructure. Two transmural left ventricular biopsy specimens were obtained with a Travenol biopsy needle after sternotomy and at 15 and 45 minutes after ischemic arrest. The specimens were used to determine high-energy phosphates and to analyze electron microscopic ultrastructure. The specimens for high-energy phosphates were immediately plunged into liquid nitrogen and later analyzed by the method described by Ellis and Gardner. s The specimens for electron microscopic study were fixed in a 3% glutaraldehyde solution and prepared by the method described by Hayat," Myocardial ultrastructure preservation was scored according to a system reported by Breyer and associates.' Mitochondrial ultrastructure preservation was scored by the third author (A.T.), a certified pathologist, in a blind fashion. The pathologist was not aware of the outcome of each experiment and had no prior knowledge of when the biopsy sample was taken during the experiment. Hemodynamic measurements. Cardiac index, left ventricular stroke work index, and myocardial contractility, denoted by dp/dt max , were measured after sternotomy and 45 minutes after ischemic arrest. Measurements were taken at a heart rate of 150 beats/min and at a left ventricular end-diastolic pressure of 10 mm Hg. Animals with a heart rate of less than 150 beats/min were temporarily atrially paced with a Cordis Chronocor (Model 156B) pacemaker.j Left ventricular enddiastolic pressure was adjusted to 10 mm Hg by withdrawing circulating volume or infusing volume from the oxygenator through the arterial cannula. Standard formulas were used to calculate hemodynamic measurements and have been outlined in a previous manuscript." The results are reported as the arithmetic mean with standard error. The chi square test, Student's t test, and linear regression were used for statistical analysis,
IIMedtronic Circulatory Systems Division, 1475 County Road B, Roseville, Minn. 'lIGish Biomedical Inc., Santa Ana, Calif.
*Krohn-Hite corporation, Avon, Mass.
#Gould Inc., Oxnard, Calif.
tCordis Corp., Miami, Fla..
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6 8 6 Landymore et al.
Table I. Mean decrease and percent change in ventricular function after 90 minutes of ischemia Percent change Cardiac index
-46%
(rnl/rnin/kg) 0.28 ± 0.1
LVSWI
-39%
0.79 ± 0.8
-20%
775
-68%
(gm-rn/beat/kg) dp/dt...,. (mm Hg/sec)
409
± 181
± 136
-38%
Legend: LVSWI. Left ventricular stroke work index. dpjdt mu • Maximum rate of rise of left ventricular pressure. Values are mean ± standard error of the mean.
Table II. Measurements of adenosine triphosphate iumolfgm dry weight of cardiac muscle) ATP iumollgm) Norfibrillators Before ischemia After ischemia 15 minutes 45 minutes
Fibrillators
24.6 ± 2
25.3 ± 1.5
25.5 ± 1.6 25.1 ± 1.7
23.9 ± 1.7 21.6 ± 1.5
Legend: There was no significant change in adenosine triphosphate (ATP) after 90 minutes of ischemia in the nonfibrillators. However. ATP decreased significantly (p < 0.04) in the fibrillators after 90 minutes of ischemia and 45 minutes of reperfusion.
Table
m. Scoring system for mitochondrial injury? o
Normal I Enlargement and clumping of mitochondria II Focal disruption of cristae III Edema. disappearance of granules, increased disruption of cristae IV Swelling, condensation. and loss of cristae
Results Twenty-four adult mongrel dogs underwent 90 minutes of ischemic arrest. Myocardial protection was provided with a combination of systemic hypothermia (26 0 C), topical hypothermia, and crystalloid cardioplegic solution containing potassium, 20 mEqjL. Transmural myocardial temperature was continuously monitored with plunge electrodes and maintained between 8 0 and 10 0 C. Blood gases were maintained within the monnal physiologic range. The infusion of potassium cardioplegic solution into the ascending aorta resulted in a complete visual mechanical arrest and an isoelectric electrocardiogram in each animal; this condition was maintained throughout the 90 minutes of ischemia. Electrical activity was completely eliminated in eight of 24 animals (nonfibril-
lators) but in 16 animals (fibrillators) the plunge electrode detected electrical activity during the arrest. Intermittent small-amplitude electrical activity was present in nine of the 16 fibrillators. Although plunge electrode activity ceased after the infusion of potassium cardioplegic solution, small-amplitude electrical activity became apparent within 10 to 15 minutes before the reinfusion of the potassium cardioplegic solution and persisted until the solution was reinfused at 30 minutes. Plunge electrode activity again became apparent before the scheduled reinfusion of cardioplegic solution at 60 minutes but ceased with the reinfusion of the solution at 1 hour. The remaining seven animals had continuous small-amplitude electrical activity throughout the 90 minutes of ischemia. The mean body weight for the nonfibrillators was 25.6 ± 1.0 kg and for the fibrillators, 25.8 ± 1.1 kg. The hematocrit value during cardiopulmonary bypass was 25.8% ± 2.7% for the nonfibrillators and 25.9% ± 1.5% for the fibrillators. The total volume of potassium cardioplegic solution administered to the nonfibrillators was 4.6 ± 0.3 mljgm of cardiac muscle and for the fibrillators, 4.7 ± 0.3 mljgm of cardiac muscle. The hemodynamic measurements are illustrated in Table I. Although both animal groups experienced impairment of left ventricular function after 90 minutes of ischemia, the decrease in left ventricular was more pronounced in those animals with electrical activity. Cardiac index decreased by 18 mljminjkg (p < 0.3), left ventricular stroke work index by 0.28 ± 0.1 gmmjbeatjkg (p <0.007), and dpjdtmax decreased by 409 mm Hgjsec (p < 0.01) in the eight animals without small-amplitude electrical activity. In contrast, cardiac index decreased by 67 mljminjkg (p < 0.001), left ventricular stroke work index by 0.79 ± 0.8 gm-rn/ beat/kg (p < 0.001) and dp/dtmax fell by 775 mm Hg/sec (p < 0.001) in the 16 animals that had smallamplitude electrical activity during ischemic arrest. Myocardial adenosine triphosphate (ATP) concentrations are illustrated in Table II. ATP was 26.4 ± 2 J.Lmolj gm before cardiopulmonary bypass and decreased to 25.1 ± 1.7 J.Lmol/gm 45 minutes after ischemic arrest (p < 0.6) in those animals without small-amplitude electrical activity. ATP concentration was 25.3 ± 1.5 J.Lmolj gm in the fibrillators with plunge electrode activity and decreased to 21.6 ± 1.5 J.Lmoljgm 45 minutes after ischemia (p < 0.04). The scoring system for mitochondrial ischemic injury as described by Breyer and associates? is illustrated in Table III. Eight animals without small-amplitude electrical activity had no demonstrable change in the mitochondrial ultrastructure after 90 minutes of isch-
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emic arrest and 45 minutes of reperfusion. In contrast, animals that demonstrated small-amplitude electrical activity during ischemic arrest had varying degrees of mitochondrial injury (p < 0.001). The animals with persistent fibrillation during the arrest demonstrated disruption of cristae (score 2), mitochondrial edema, decrease in mitochondrial granules, and increased disruption of cristae (score 3); animals with partial fibrillation had lesser degrees of mitochondrial injury. Linear regression analysis of the data indicated a high correlation between the duration of microfibrillation and the degree of mitochondrial injury (r = 0.89). Discussion Cardioplegia is now routinely used by most cardiac centers to protect the myocardium during elective ischemic arrest." The infusion of cold potassium cardioplegic solution into the ascending aorta produces a rapid diastolic arrest and lowers myocardial temperature, which reduces metabolic demands and preserves highenergy phosphates. to Myocardial preservation is dependent upon the cessation of electromechanical activity and reduction of myocardial temperature, to whereas persistent electrical activity is associated with use of high-energy phosphates, decrease in left ventricular function, and poor preservation of electron microscopic ultrastructure after prolonged aortic crossclamping.":" Recently, Ferguson and colleagues! recorded electrical activity in the myocardium at 10° C after the infusionof cardioplegic solution, when mechanical activity had ceased and the electrocardiogram was isoelectric. These observations are alarming, because they indicate that monitoring myocardial temperature and the use of multidose cardioplegia may not assure optimal myocardial preservation during elective cardiac arrest. Persistent electrical activity from the myocardium is barely conceivable after the infusion of potassium cardioplegic solution when the heart is flaccid and the electrocardiogram is isoelectric, However, we' repeated these earlier experiments': 2 and found that small-amplitude electrical activity frequently persists after infusion of the potassium cardioplegic solution. In our previous experiments, we' demonstrated that continuous or intermittent smallamplitude electrical activity may be recorded from the myocardium when the heart is arrested with a crystalloid cardioplegic solution (20 mEq of potassium per liter). We submitted the electrical potentials recorded from the myocardium during cardioplegic arrest to spectral analysis. This method of data analysis differentiates the frequency content of the recorded waveforms into component parts and separates electrical and
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687
mechanical artifact from underlying myocardial activity. Spectral analysis of the plunge electrode signal confirmed that electrical potentials may persist after infusion of the potassium cardioplegic solution. Subsequent experiments have indicated that high-dose potassium cardioplegia (30 mliq/L) abolishes these electrical potentials. These results prove the presence of persistent electrical activity after cardioplegic arrest by demonstrating a cause and effect relationship between the presence of small-amplitude electrical activity and the concentration of potassium in the cardioplegic solution. These earlier observations prompted the present study to determine the effects of persistent small-amplitude electrical activity on myocardial preservation. Our data indicate that persistent small-amplitude electrical activity after cardioplegic arrest results in impairment of left ventricular function, continued use of high-energy phosphates, and injury to intracellular organelles. In contrast, in animals without small-amplitude electrical activity high-energy phosphates are spared, mitochondrial injury does not develop, and left ventricular function is good after ischemic arrest. Why an electrical arrest is maintained in some animals while small-amplitude electrical activity persists in others, despite the use of similar volumes and concentrations of potassium cardioplegic solutions, is unclear, although the presence or absence of electrical activity is probably related to the concentration of intracellular potassium. This hypothesis is supported by the fact that electrical activity ceased in those animals with intermittent fibrillation after infusion of the cardioplegic solution but returned before reinfusion of the solution, which suggests that the concentration of intracellular potassium had gradually decreased after cardioplegic arrest and permitted the resumption of electrical activity. Earlier studies have shown that multiple-dose cardioplegia provides superior preservation than single-dose cardioplegia, although single-dose cardioplegia frequently produced a complete electromechanical arrest that was maintained throughout long periods of aortic cross-clamping.'>'? Multiple-dose cardioplegia was thought to be superior to single-dose cardioplegia because reinfusion of the solution at regular intervals washed out toxic anaerobic metabolites and replenished the ischemic myocardium with substrate. Our data suggest, however, that multiple-dose cardioplegia may provide increased myocardial protection by a different mechanism and that regular infusions of cardioplegic solution may prevent, or reduce the amount of, smallamplitude electrical activity during prolonged aortic cross-clamping by maintaining higher intracellular concentrations of potassium.
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6 8 8 Landymore et al.
Our data have shown that electrical activity is present after the infusion of cold potassium cardioplegic solution and that small-amplitude electrical activity is associated with impaired myocardial preservation. Our observations indicate the need for more sophisticated techniques to monitor the administration of cardioplegia during ischemic arrest and suggest the need for further studies to develop improved cardioplegia that would prevent small-amplitude electrical activity.
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REFERENCES Ferguson TB, Smith PK, Buhrman WC, Lofland GK, Cox JL: Monitoring of the electrical status of the ventricle during cardioplegic arrest (abstr). Circulation 66:Suppl 2:152, 1982 Smith PK, Buhrman WC, Ferguson TB, Levett JM, Cox JL: Differential transmural myocardial arrest using hyperkalemic and normokalemic cardioplegic solutions (abstr). J Am Coli Cardiol 1:698, 1983 Landymore RW, Marble AE, Cameron C: Spectral analysis of small amplitude electrical activity in the cold potassium-arrested heart. Ann Thorac Surg 41:372-377, 1986 Kasell J, Gallagher JJ: Construction of a multipolar needle electrode for activation study of the heart. Am J Physiol 233:H312-H317,1977 Ellis RJ, Gardner C: Determination of myocardial highenergy phosphates using bioluminescence. Anal Biochem 105:354-360, 1980 Hayat MA: Principles and Techniques of Electron Microscopy, vol I, New York, 1970, Van Nostrand Reinhold Co., pp 111-150 Breyer RH, Meredith JW, Mills SA, Trillo A, Barringer ML, Shihabi ZK, Schey HM, Cordell AR: Is a left ventricular vent necessary for coronary artery bypass operations performed with cardioplegic arrest? J THoRAc CARDIOVASC SURG 86:338-349, 1983 Landymore R, Marble A, MacKinnon G, Leadon R, Gardner M: Effects of oral amiodarone on left ventricular function in dogs. Clinical implications for patients with life-threatening ventricular tachycardia. Ann Thorac Surg 37:141-146, 1984 Miller OW Jr, Ivey TO, Bailey WW, Johnson DO, Hessel EA: The practice of coronary artery bypass surgery in 1980. J THoRAc CARDIOVASC SURG 81:423-427, 1981 Buckberg GO: A proposed "solution" to the cardioplegic controversy. J THoRAc CARDIOVASC SURG 77:803-815, 1979 Engelman RM, Rousou JH, Longo F, Auvil J, Vertrees RA: The time course of myocardial high-energy phosphate degradation during potassium cardioplegic arrest. Surgery 81:138-147,1979 Danforth W, Naegle S, Bing RJ: Effect of ischemia and reoxygenation on glycolytic reactions and adenosinetriphosphate in heart muscle. Circ Res 8:965-971, 1960 Reibel 0, Rovetto M: Myocardial ATP synthesis and
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mechanical function following oxygen deficiency. Am J PhysioI234:H620-H624, 1978 Lucas SK, Elmer EB, Flaherty JT, Prodromos CC, Bulkley BH, Gott VL, Gardner TJ: Effect of multipledose potassium cardioplegia on myocardial ischemia, return of ventricular function, and ultrastructural preservation. J THoRAc CARDIOVASC SURG 80:102-110, 1980 Engelman RM, Auvil J, O'Donoghue MJ, Levitsky S: The significance of multidose cardioplegia and hypothermia in myocardial preservation during ischemic arrest. J THoRAe CARDIOVASC SURG 75:555-563, 1978 Takamoto S, Levinle FH, LaRaia PJ, Adzick NS, Fallon JT, Austen WG, Buckley MJ: Comparison of single-dose and multiple-dose crystalloid and blood potassium cardioplegia during prolonged hypothermic aortic occlusion. J THoRAe CARDIOVASC SURG 79:19-28, 1980 Buckberg GO, Brazier JR, Nelson RL, Goldstein SM, McConnell DH, Cooper N: Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. J THoRAc CARDIOVASC SURG 73:87-94, 1977
Discussion DR. WILLIAM A. GA Y, JR. Sait Lake City, Utah
The continuing discussion about various aspects of myocardial protection signifies that all of the problems have not yet been answered and that there is no universally agreed upon recipe or technique that guarantees success. What is it that we are trying to protect the heart from? It is not really hypoxia or the effects of hypoxia, but rather the effects of ischemia. That is, we are trying to protect the heart from the detrimental effects of a deficit of both oxygen and nutrients brought about by a reduction of the delivery rate of a perfusate that is basically normal in oxygen content and in nutrient content. How does hyperkalemic cardioplegia work? According to the Nernst equation, which we all learned in our elementary medical school physiology,as it applies to excitable membranes, the potential difference across that membrane, or the excitability of that cell, is proportional to the natural logarithm of the ratio between the intracellular and extracellular potassium concentrations. Increasing the extracellular potassium concentration by infusing a hyperkalemic solution disturbs that ratio and results in a change in membrane excitability. Over time the concentrations may tend to return toward their original values and the membranes may then return to their normally excitable or near normally excitable state. That small-amplitude electrical activity is noticed more frequently or, perhaps, sooner in the deeper layers as measured by these plunge electrodes than on the surface as detected by the surface electrocardiogram, as a rule, is entirely logical. First, the inherent pacemaker rate or rate of diastolic depolarization in the deeper layer.tissues or the subendocardial layer is more rapid and greater than that in ventricular myocardium itself. Second, the endocardial or deeper layers of the ventricle are much more likely to be warmer and to warm more quickly
Volume 91 Number 5 May, 1986
than the ventricular muscle itself. These facts still do not answer the question of why some animals or some heart exhibit this type of activity and others do not. In the absence of knowing the exact intracellular and extracellular potassium concentratons of these cells, I doubt that we are about to find out. I have one suggestion for the authors and one question of them. First, I suggest that another study be done, comparing antegrade cardioplegic administration, the way it was carried out in this study, with retrograde cardioplegic perfusion of the coronary sinus, to see if this alternative technique, at least in the canine model, will influence this small amplitude electrical activity. My question is this: You have significantly frightened us today by telling us that something that we cannot normally detect is likely to produce harm to the patients that we are operating on. How can we in the normal operating room situation detect this small-amplitude electrical activity, and what are your suggestions as to how to prevent it? DR. HILLEL LAKS Los Angeles, Calif
I would like to suggest that one of the reasons for the return of the small-amplitude electrical activity is the noncoronary collateral flow, and that the reason for the variability in some animals, may be an individual difference in the amount of noncoronary collateral flow. I also wonder whether the perfusion pressure of cardiopulmonary bypass, which also influences the amount of noncoronary collateral flow, could have varied in the different animals. Was such a difference noted in those who did and those who did not get return of activity? DR. LANDYMORE (Closing) Dr. Gay has suggested that retrograde coronary perfusion might be an effective method of preventing small-amplitude electrical activity. Retrograde perfusion is an effective method of delivering cardioplegia in the presence of coronary artery stenosis, but I doubt whether retrograde coronary perfusion
Small-amplitude electrical activity
689
would affect the presence of small-amplitude electrical activity in our model, because the animals all have a normal coronary circulation. The second and more important question was, "How do we prevent small-amplitude electrical activity during cardioplegic arrest?" Small-amplitude electrical activity cannot be observed visually and the electrocardiogram is isoelectric; therefore there are at present no monitoring techniques that may be used to determine the presence or absence of continuous electrical activity after the infusion of cardioplegic solution. Recording electrical activity in our laboratory has required a very complex measurement system to prevent mechanical and electrical artifact from interfering with. the small-amplitude electrical signal. I therefore doubt whether this type of measurement would be applicable to the operating room. However, I believe with the further investigations that although we may not be able to measure the electrical activity in the operating room, we may be able to develop improved cardioplegic solutions that will prevent continued electrical activity. Preliminary experiments in our laboratory indicate that the activity may be abolished by the addition of a calcium-channel blocker to potassium cardioplegia or by increasing the concentration of potassium in the cardioplegic solution to 30 mliq/L. Dr. Laks has questioned whether or not noncoronary collateral flow may have resulted in cardioplegic washout with the spontaneous return of electrical activity. The model that we are using for this experiment is essentially an isolated heart preparation; both ventricles are vented during the 90 minutes of arrest, the cavae and azygos vein are snared, and the aorta and pulmonary artery are cross-clamped. There is very little return from the left and right ventricular vents during the arrest. Thus there is a negligible amount of noncoronary collateral circulation. I have also been asked whether or not the perfusion pressure during bypass was significantly different between the two animal groups. Perfusion pressure was not statistically different between the two groups and was in the range of 80 to 100 mm Hg during the entire perfusion.
Effect of small-amplitude electrical activity on myocardial preservation in the cold potassium-arrested heart Recent reports indicate that small-amplitude electrical activity may be present in the cold potassiumarrested heart. Twenty-four mongreldogs were placed on cardiopulmonary bypass and cooledto a rectal temperature of 26° C. Myocardial preservation was provided with a combinationof systemichypothermia 26° C. potassium (20 mEqjL) crystalloid cardioplegic solution(10 m1jkg) infused initially and every 30 minutes during 90 minutes of ischemic arrest, and topical hypothermia. Myocardial temperature was maintained between 8° and 10° C. Electrical activity and transmural myocardial temperature were monitored with specially designed plunge electrodes. Left ventricular stroke work index, cardiac index, and maximum rate of rise of left ventricular pressure were measured before bypass and 45 minutesafter ischemic arrest. Biopsy specimens were taken before bypass and at 15 and 45 minutes after ischemic arrest. The specimenswere used to measure adenosinetriphosphate and to analyze electron microscopic ultrastructure. Small-amplitude electrical activity was present in 16 of 24 animals during cardioplegic arrest. Cardiac index decreased 18 m1jminjkg (not significant), left ventricularstroke work index fell by 0.28 ± 0.1 gm-mjbeatjkg (p < 0.007), and maximum rate of rise of left ventricular pressure decreased 409 mm Hgjsec (p < 0.01) in the eight animals without small-amplitude electrical activity. Adenosine triphosphate concentration was unchanged and electron microscopic ultrastructure was well preserved. In contrast, small-amplitude electrical activity (16 animals) resulted in a decrease in cardiac index of 67 m1jminjkg (p < 0.001), a decrease in left ventricular stroke work index of 0.79 ± 0.8 gm-mjbeatjkg (p < 0.001),and a fall in maximumrate of rise of left ventricularpressure of 775 mm Hgjsec (p < 0.001). Adenosine triphosphate concentration decreased from 25 to 21 ILmoljgm (p < 0.04) and electron microscopic ultrastructure was poorly preserved (p < 0.001). This study demonstrates that smallamplitude electrical activity in the cardioplegia-arrested heart at 10° C impairs myocardial preservation.
R. W. Landymore, M.D., F.R.C.S.C., A. E. Marble, Ph.D.(Eng.), A. Trillo, M.D., M. MacAulay, M.D., G. Faulkner, M.D., and C. Cameron, B.N., Halifax. Nova Scotia. Canada
Recent reports have suggested that electrical activity may be present after the infusion of potassium cardioplegic solutions." 2 Electrical activity was recorded from the canine myocardium with specially designed plunge
From Dalhousie University, Department of Surgery, Division of Thoracic and Cardiovascular Surgery, Halifax, Nova Scotia, Canada. Supported by a New Brunswick Heart Foundation Grant. Read at the Eleventh Annual Meeting of The Western Thoracic Surgical Association, Incline Village, Nev., June 16-20, 1985. Address for reprints: R. W. Landymore, M.D., F.R,C.S.C., Room 3065, R.C. Dickson Centre, Victoria General Hospital, Halifax, Nova Scotaia, Canada B3H 2Y9.
684
electrodes in the potassium-arrested heart at 10° C when mechanical activity had ceased and the electrocardiogram was isoelectric. We3 have recently repeated these earlier experiments and have confirmed that small-amplitude electrical potentials frequently persist after the infusion of potassium cardioplegic solution. These observations prompted the present study, which was designed to determine the effects of small-amplitude electrical activity on myocardial preservation.
Materials and methods Twenty-four mongrel dogs, weighing between 20 and 30 kg, received 1 ml of fentanyl citrate and droperidol (Innovar) for preoperative sedation. Anesthesia was
Volume 91 Number 5 May, 1986
induced and maintained with sodium pentobarbital and ventilation was provided with a Bird Mark 7 pressureregulated ventilator.* Pancuronium bromide (0.1 tug] kg) was administered intravenously after intubation. Surgical preparation. The femoral arteries were exposed bilaterally and the chest was opened through a median sternotomy. Systemic heparin was administered in a dose of 2 rug/kg. An 8F USCI catheter] was placed in the right femoral artery for blood pressure monitoring and a 7F Swan-Ganz thermodilution catheterf was positioned in the pulmonary artery. A No. 14 USCI arterial catheter was inserted into the left femoral artery in preparation for cardiopulmonary bypass, and two No. 34 USCI cannulas provided venous return and were positionedin the superior and inferior venae cavae. A 5F Millar catheter-tipped transducer§ (frequency response oto 24 kHz) was introduced through the apex of the left ventricle and was used to measure left ventricular end-diastolic pressure and left ventricular contractility, as denoted by the maximum rate of rise of left ventricular pressure (dp/dt max) ' Cardiopulmonary bypass was established with a Harvey bubble oxygenator] and a Medtronic impellar pum~1 (Model 1835OOU) driven by a Medtronic circulatory assist console (Model 1810) that would deliver nonpulsatile flow at a rate of 2.5 L/min/m2• The azygos vein and cavae were snared and both ventricles were vented during the arrest. The aorta was cross-clamped after a rectal temperature of 26 0 C was reached, and crystalloid cardioplegic solution, 10 ml/kg (20 rnEq of potassium per liter), at 4 C was administered with a Gish1[ cardioplegia administration set initially and at 30 and 60 minutes during the 90 minute arrest. Epicardial, myocardial, and endocardial temperatures were continuously monitored over the left anterior descending coronary distribution with specially designed plunge electrodes. The triple thermistor was calibrated against a mercury thermometer and temperatures were recorded on a Gould-Brush Model 260 six-channel recorder.# Myocardial temperature' was maintained within a range of 8 0 to 100 C with saline slush placed in the pericardial well and over the anterior surface of the heart. Myocardial electrograrns were recorded with 0
*Bird Corp., Palm Springs, Calif. tC.R. Bard Inc., Billerica, Mass. tAmerican Edwards Laboratories, Irvine, Calif. §Millar Instruments, lnc., Houston, Texas.
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685
specially designed plunge electrodes positioned over the left anterior descending coronary distribution.' The electrical signal from the plunge electrode was conditioned with a Krohn-Hite (Model 3342) filter* and amplified with a Gould-Brush 13-421 level shifter and Gould-Brush 260 preamplifier and recorder. The Krohn-Hite filter (a sixth order filter) was used in the low pass mode with a comer frequency of 50 Hz, which substantially reduced 60 Hz interference. Electrical activity detected by the plunge electrode was recorded on chart paper during the 90 minute arrest. Analysis of high-energy phosphates and myocardial ultrastructure. Two transmural left ventricular biopsy specimens were obtained with a Travenol biopsy needle after sternotomy and at 15 and 45 minutes after ischemic arrest. The specimens were used to determine high-energy phosphates and to analyze electron microscopic ultrastructure. The specimens for high-energy phosphates were immediately plunged into liquid nitrogen and later analyzed by the method described by Ellis and Gardner. s The specimens for electron microscopic study were fixed in a 3% glutaraldehyde solution and prepared by the method described by Hayat," Myocardial ultrastructure preservation was scored according to a system reported by Breyer and associates.' Mitochondrial ultrastructure preservation was scored by the third author (A.T.), a certified pathologist, in a blind fashion. The pathologist was not aware of the outcome of each experiment and had no prior knowledge of when the biopsy sample was taken during the experiment. Hemodynamic measurements. Cardiac index, left ventricular stroke work index, and myocardial contractility, denoted by dp/dt max , were measured after sternotomy and 45 minutes after ischemic arrest. Measurements were taken at a heart rate of 150 beats/min and at a left ventricular end-diastolic pressure of 10 mm Hg. Animals with a heart rate of less than 150 beats/min were temporarily atrially paced with a Cordis Chronocor (Model 156B) pacemaker.j Left ventricular enddiastolic pressure was adjusted to 10 mm Hg by withdrawing circulating volume or infusing volume from the oxygenator through the arterial cannula. Standard formulas were used to calculate hemodynamic measurements and have been outlined in a previous manuscript." The results are reported as the arithmetic mean with standard error. The chi square test, Student's t test, and linear regression were used for statistical analysis,
IIMedtronic Circulatory Systems Division, 1475 County Road B, Roseville, Minn. 'lIGish Biomedical Inc., Santa Ana, Calif.
*Krohn-Hite corporation, Avon, Mass.
#Gould Inc., Oxnard, Calif.
tCordis Corp., Miami, Fla..
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Table I. Mean decrease and percent change in ventricular function after 90 minutes of ischemia Percent change Cardiac index
-46%
(rnl/rnin/kg) 0.28 ± 0.1
LVSWI
-39%
0.79 ± 0.8
-20%
775
-68%
(gm-rn/beat/kg) dp/dt...,. (mm Hg/sec)
409
± 181
± 136
-38%
Legend: LVSWI. Left ventricular stroke work index. dpjdt mu • Maximum rate of rise of left ventricular pressure. Values are mean ± standard error of the mean.
Table II. Measurements of adenosine triphosphate iumolfgm dry weight of cardiac muscle) ATP iumollgm) Norfibrillators Before ischemia After ischemia 15 minutes 45 minutes
Fibrillators
24.6 ± 2
25.3 ± 1.5
25.5 ± 1.6 25.1 ± 1.7
23.9 ± 1.7 21.6 ± 1.5
Legend: There was no significant change in adenosine triphosphate (ATP) after 90 minutes of ischemia in the nonfibrillators. However. ATP decreased significantly (p < 0.04) in the fibrillators after 90 minutes of ischemia and 45 minutes of reperfusion.
Table
m. Scoring system for mitochondrial injury? o
Normal I Enlargement and clumping of mitochondria II Focal disruption of cristae III Edema. disappearance of granules, increased disruption of cristae IV Swelling, condensation. and loss of cristae
Results Twenty-four adult mongrel dogs underwent 90 minutes of ischemic arrest. Myocardial protection was provided with a combination of systemic hypothermia (26 0 C), topical hypothermia, and crystalloid cardioplegic solution containing potassium, 20 mEqjL. Transmural myocardial temperature was continuously monitored with plunge electrodes and maintained between 8 0 and 10 0 C. Blood gases were maintained within the monnal physiologic range. The infusion of potassium cardioplegic solution into the ascending aorta resulted in a complete visual mechanical arrest and an isoelectric electrocardiogram in each animal; this condition was maintained throughout the 90 minutes of ischemia. Electrical activity was completely eliminated in eight of 24 animals (nonfibril-
lators) but in 16 animals (fibrillators) the plunge electrode detected electrical activity during the arrest. Intermittent small-amplitude electrical activity was present in nine of the 16 fibrillators. Although plunge electrode activity ceased after the infusion of potassium cardioplegic solution, small-amplitude electrical activity became apparent within 10 to 15 minutes before the reinfusion of the potassium cardioplegic solution and persisted until the solution was reinfused at 30 minutes. Plunge electrode activity again became apparent before the scheduled reinfusion of cardioplegic solution at 60 minutes but ceased with the reinfusion of the solution at 1 hour. The remaining seven animals had continuous small-amplitude electrical activity throughout the 90 minutes of ischemia. The mean body weight for the nonfibrillators was 25.6 ± 1.0 kg and for the fibrillators, 25.8 ± 1.1 kg. The hematocrit value during cardiopulmonary bypass was 25.8% ± 2.7% for the nonfibrillators and 25.9% ± 1.5% for the fibrillators. The total volume of potassium cardioplegic solution administered to the nonfibrillators was 4.6 ± 0.3 mljgm of cardiac muscle and for the fibrillators, 4.7 ± 0.3 mljgm of cardiac muscle. The hemodynamic measurements are illustrated in Table I. Although both animal groups experienced impairment of left ventricular function after 90 minutes of ischemia, the decrease in left ventricular was more pronounced in those animals with electrical activity. Cardiac index decreased by 18 mljminjkg (p < 0.3), left ventricular stroke work index by 0.28 ± 0.1 gmmjbeatjkg (p <0.007), and dpjdtmax decreased by 409 mm Hgjsec (p < 0.01) in the eight animals without small-amplitude electrical activity. In contrast, cardiac index decreased by 67 mljminjkg (p < 0.001), left ventricular stroke work index by 0.79 ± 0.8 gm-rn/ beat/kg (p < 0.001) and dp/dtmax fell by 775 mm Hg/sec (p < 0.001) in the 16 animals that had smallamplitude electrical activity during ischemic arrest. Myocardial adenosine triphosphate (ATP) concentrations are illustrated in Table II. ATP was 26.4 ± 2 J.Lmolj gm before cardiopulmonary bypass and decreased to 25.1 ± 1.7 J.Lmol/gm 45 minutes after ischemic arrest (p < 0.6) in those animals without small-amplitude electrical activity. ATP concentration was 25.3 ± 1.5 J.Lmolj gm in the fibrillators with plunge electrode activity and decreased to 21.6 ± 1.5 J.Lmoljgm 45 minutes after ischemia (p < 0.04). The scoring system for mitochondrial ischemic injury as described by Breyer and associates? is illustrated in Table III. Eight animals without small-amplitude electrical activity had no demonstrable change in the mitochondrial ultrastructure after 90 minutes of isch-
Volume 91 Number 5 May, 1986
emic arrest and 45 minutes of reperfusion. In contrast, animals that demonstrated small-amplitude electrical activity during ischemic arrest had varying degrees of mitochondrial injury (p < 0.001). The animals with persistent fibrillation during the arrest demonstrated disruption of cristae (score 2), mitochondrial edema, decrease in mitochondrial granules, and increased disruption of cristae (score 3); animals with partial fibrillation had lesser degrees of mitochondrial injury. Linear regression analysis of the data indicated a high correlation between the duration of microfibrillation and the degree of mitochondrial injury (r = 0.89). Discussion Cardioplegia is now routinely used by most cardiac centers to protect the myocardium during elective ischemic arrest." The infusion of cold potassium cardioplegic solution into the ascending aorta produces a rapid diastolic arrest and lowers myocardial temperature, which reduces metabolic demands and preserves highenergy phosphates. to Myocardial preservation is dependent upon the cessation of electromechanical activity and reduction of myocardial temperature, to whereas persistent electrical activity is associated with use of high-energy phosphates, decrease in left ventricular function, and poor preservation of electron microscopic ultrastructure after prolonged aortic crossclamping.":" Recently, Ferguson and colleagues! recorded electrical activity in the myocardium at 10° C after the infusionof cardioplegic solution, when mechanical activity had ceased and the electrocardiogram was isoelectric. These observations are alarming, because they indicate that monitoring myocardial temperature and the use of multidose cardioplegia may not assure optimal myocardial preservation during elective cardiac arrest. Persistent electrical activity from the myocardium is barely conceivable after the infusion of potassium cardioplegic solution when the heart is flaccid and the electrocardiogram is isoelectric, However, we' repeated these earlier experiments': 2 and found that small-amplitude electrical activity frequently persists after infusion of the potassium cardioplegic solution. In our previous experiments, we' demonstrated that continuous or intermittent smallamplitude electrical activity may be recorded from the myocardium when the heart is arrested with a crystalloid cardioplegic solution (20 mEq of potassium per liter). We submitted the electrical potentials recorded from the myocardium during cardioplegic arrest to spectral analysis. This method of data analysis differentiates the frequency content of the recorded waveforms into component parts and separates electrical and
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mechanical artifact from underlying myocardial activity. Spectral analysis of the plunge electrode signal confirmed that electrical potentials may persist after infusion of the potassium cardioplegic solution. Subsequent experiments have indicated that high-dose potassium cardioplegia (30 mliq/L) abolishes these electrical potentials. These results prove the presence of persistent electrical activity after cardioplegic arrest by demonstrating a cause and effect relationship between the presence of small-amplitude electrical activity and the concentration of potassium in the cardioplegic solution. These earlier observations prompted the present study to determine the effects of persistent small-amplitude electrical activity on myocardial preservation. Our data indicate that persistent small-amplitude electrical activity after cardioplegic arrest results in impairment of left ventricular function, continued use of high-energy phosphates, and injury to intracellular organelles. In contrast, in animals without small-amplitude electrical activity high-energy phosphates are spared, mitochondrial injury does not develop, and left ventricular function is good after ischemic arrest. Why an electrical arrest is maintained in some animals while small-amplitude electrical activity persists in others, despite the use of similar volumes and concentrations of potassium cardioplegic solutions, is unclear, although the presence or absence of electrical activity is probably related to the concentration of intracellular potassium. This hypothesis is supported by the fact that electrical activity ceased in those animals with intermittent fibrillation after infusion of the cardioplegic solution but returned before reinfusion of the solution, which suggests that the concentration of intracellular potassium had gradually decreased after cardioplegic arrest and permitted the resumption of electrical activity. Earlier studies have shown that multiple-dose cardioplegia provides superior preservation than single-dose cardioplegia, although single-dose cardioplegia frequently produced a complete electromechanical arrest that was maintained throughout long periods of aortic cross-clamping.'>'? Multiple-dose cardioplegia was thought to be superior to single-dose cardioplegia because reinfusion of the solution at regular intervals washed out toxic anaerobic metabolites and replenished the ischemic myocardium with substrate. Our data suggest, however, that multiple-dose cardioplegia may provide increased myocardial protection by a different mechanism and that regular infusions of cardioplegic solution may prevent, or reduce the amount of, smallamplitude electrical activity during prolonged aortic cross-clamping by maintaining higher intracellular concentrations of potassium.
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Our data have shown that electrical activity is present after the infusion of cold potassium cardioplegic solution and that small-amplitude electrical activity is associated with impaired myocardial preservation. Our observations indicate the need for more sophisticated techniques to monitor the administration of cardioplegia during ischemic arrest and suggest the need for further studies to develop improved cardioplegia that would prevent small-amplitude electrical activity.
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REFERENCES Ferguson TB, Smith PK, Buhrman WC, Lofland GK, Cox JL: Monitoring of the electrical status of the ventricle during cardioplegic arrest (abstr). Circulation 66:Suppl 2:152, 1982 Smith PK, Buhrman WC, Ferguson TB, Levett JM, Cox JL: Differential transmural myocardial arrest using hyperkalemic and normokalemic cardioplegic solutions (abstr). J Am Coli Cardiol 1:698, 1983 Landymore RW, Marble AE, Cameron C: Spectral analysis of small amplitude electrical activity in the cold potassium-arrested heart. Ann Thorac Surg 41:372-377, 1986 Kasell J, Gallagher JJ: Construction of a multipolar needle electrode for activation study of the heart. Am J Physiol 233:H312-H317,1977 Ellis RJ, Gardner C: Determination of myocardial highenergy phosphates using bioluminescence. Anal Biochem 105:354-360, 1980 Hayat MA: Principles and Techniques of Electron Microscopy, vol I, New York, 1970, Van Nostrand Reinhold Co., pp 111-150 Breyer RH, Meredith JW, Mills SA, Trillo A, Barringer ML, Shihabi ZK, Schey HM, Cordell AR: Is a left ventricular vent necessary for coronary artery bypass operations performed with cardioplegic arrest? J THoRAc CARDIOVASC SURG 86:338-349, 1983 Landymore R, Marble A, MacKinnon G, Leadon R, Gardner M: Effects of oral amiodarone on left ventricular function in dogs. Clinical implications for patients with life-threatening ventricular tachycardia. Ann Thorac Surg 37:141-146, 1984 Miller OW Jr, Ivey TO, Bailey WW, Johnson DO, Hessel EA: The practice of coronary artery bypass surgery in 1980. J THoRAc CARDIOVASC SURG 81:423-427, 1981 Buckberg GO: A proposed "solution" to the cardioplegic controversy. J THoRAc CARDIOVASC SURG 77:803-815, 1979 Engelman RM, Rousou JH, Longo F, Auvil J, Vertrees RA: The time course of myocardial high-energy phosphate degradation during potassium cardioplegic arrest. Surgery 81:138-147,1979 Danforth W, Naegle S, Bing RJ: Effect of ischemia and reoxygenation on glycolytic reactions and adenosinetriphosphate in heart muscle. Circ Res 8:965-971, 1960 Reibel 0, Rovetto M: Myocardial ATP synthesis and
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mechanical function following oxygen deficiency. Am J PhysioI234:H620-H624, 1978 Lucas SK, Elmer EB, Flaherty JT, Prodromos CC, Bulkley BH, Gott VL, Gardner TJ: Effect of multipledose potassium cardioplegia on myocardial ischemia, return of ventricular function, and ultrastructural preservation. J THoRAc CARDIOVASC SURG 80:102-110, 1980 Engelman RM, Auvil J, O'Donoghue MJ, Levitsky S: The significance of multidose cardioplegia and hypothermia in myocardial preservation during ischemic arrest. J THoRAe CARDIOVASC SURG 75:555-563, 1978 Takamoto S, Levinle FH, LaRaia PJ, Adzick NS, Fallon JT, Austen WG, Buckley MJ: Comparison of single-dose and multiple-dose crystalloid and blood potassium cardioplegia during prolonged hypothermic aortic occlusion. J THoRAe CARDIOVASC SURG 79:19-28, 1980 Buckberg GO, Brazier JR, Nelson RL, Goldstein SM, McConnell DH, Cooper N: Studies of the effects of hypothermia on regional myocardial blood flow and metabolism during cardiopulmonary bypass. J THoRAc CARDIOVASC SURG 73:87-94, 1977
Discussion DR. WILLIAM A. GA Y, JR. Sait Lake City, Utah
The continuing discussion about various aspects of myocardial protection signifies that all of the problems have not yet been answered and that there is no universally agreed upon recipe or technique that guarantees success. What is it that we are trying to protect the heart from? It is not really hypoxia or the effects of hypoxia, but rather the effects of ischemia. That is, we are trying to protect the heart from the detrimental effects of a deficit of both oxygen and nutrients brought about by a reduction of the delivery rate of a perfusate that is basically normal in oxygen content and in nutrient content. How does hyperkalemic cardioplegia work? According to the Nernst equation, which we all learned in our elementary medical school physiology,as it applies to excitable membranes, the potential difference across that membrane, or the excitability of that cell, is proportional to the natural logarithm of the ratio between the intracellular and extracellular potassium concentrations. Increasing the extracellular potassium concentration by infusing a hyperkalemic solution disturbs that ratio and results in a change in membrane excitability. Over time the concentrations may tend to return toward their original values and the membranes may then return to their normally excitable or near normally excitable state. That small-amplitude electrical activity is noticed more frequently or, perhaps, sooner in the deeper layers as measured by these plunge electrodes than on the surface as detected by the surface electrocardiogram, as a rule, is entirely logical. First, the inherent pacemaker rate or rate of diastolic depolarization in the deeper layer.tissues or the subendocardial layer is more rapid and greater than that in ventricular myocardium itself. Second, the endocardial or deeper layers of the ventricle are much more likely to be warmer and to warm more quickly
Volume 91 Number 5 May, 1986
than the ventricular muscle itself. These facts still do not answer the question of why some animals or some heart exhibit this type of activity and others do not. In the absence of knowing the exact intracellular and extracellular potassium concentratons of these cells, I doubt that we are about to find out. I have one suggestion for the authors and one question of them. First, I suggest that another study be done, comparing antegrade cardioplegic administration, the way it was carried out in this study, with retrograde cardioplegic perfusion of the coronary sinus, to see if this alternative technique, at least in the canine model, will influence this small amplitude electrical activity. My question is this: You have significantly frightened us today by telling us that something that we cannot normally detect is likely to produce harm to the patients that we are operating on. How can we in the normal operating room situation detect this small-amplitude electrical activity, and what are your suggestions as to how to prevent it? DR. HILLEL LAKS Los Angeles, Calif
I would like to suggest that one of the reasons for the return of the small-amplitude electrical activity is the noncoronary collateral flow, and that the reason for the variability in some animals, may be an individual difference in the amount of noncoronary collateral flow. I also wonder whether the perfusion pressure of cardiopulmonary bypass, which also influences the amount of noncoronary collateral flow, could have varied in the different animals. Was such a difference noted in those who did and those who did not get return of activity? DR. LANDYMORE (Closing) Dr. Gay has suggested that retrograde coronary perfusion might be an effective method of preventing small-amplitude electrical activity. Retrograde perfusion is an effective method of delivering cardioplegia in the presence of coronary artery stenosis, but I doubt whether retrograde coronary perfusion
Small-amplitude electrical activity
689
would affect the presence of small-amplitude electrical activity in our model, because the animals all have a normal coronary circulation. The second and more important question was, "How do we prevent small-amplitude electrical activity during cardioplegic arrest?" Small-amplitude electrical activity cannot be observed visually and the electrocardiogram is isoelectric; therefore there are at present no monitoring techniques that may be used to determine the presence or absence of continuous electrical activity after the infusion of cardioplegic solution. Recording electrical activity in our laboratory has required a very complex measurement system to prevent mechanical and electrical artifact from interfering with. the small-amplitude electrical signal. I therefore doubt whether this type of measurement would be applicable to the operating room. However, I believe with the further investigations that although we may not be able to measure the electrical activity in the operating room, we may be able to develop improved cardioplegic solutions that will prevent continued electrical activity. Preliminary experiments in our laboratory indicate that the activity may be abolished by the addition of a calcium-channel blocker to potassium cardioplegia or by increasing the concentration of potassium in the cardioplegic solution to 30 mliq/L. Dr. Laks has questioned whether or not noncoronary collateral flow may have resulted in cardioplegic washout with the spontaneous return of electrical activity. The model that we are using for this experiment is essentially an isolated heart preparation; both ventricles are vented during the 90 minutes of arrest, the cavae and azygos vein are snared, and the aorta and pulmonary artery are cross-clamped. There is very little return from the left and right ventricular vents during the arrest. Thus there is a negligible amount of noncoronary collateral circulation. I have also been asked whether or not the perfusion pressure during bypass was significantly different between the two animal groups. Perfusion pressure was not statistically different between the two groups and was in the range of 80 to 100 mm Hg during the entire perfusion.