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Protection of the myocardium during ischemic arrest
J THORAC CARDIOVASC SURG 81:873-879, 1981
Protection of the myocardium during ischemic arrest Dose-response curves for procaine and lignocaine in cardioplegic solutions The dose-response curve of procaine or lignocaine (lidocaine) added to the St. Thomas' Hospital cardioplegic solution was investigated with an isolated working rat heart preparation. In the absence of any cold cardioplegic protection. hearts failed to recover after as little as 30 minutes of ischemia. A single infusion (20 0 C) of the basic St. Thomas' Hospital cardioplegic solution allowed hearts to recover to 60% or more of their preischemic control aortic flow after a 120 minute period of ischemia. Addition of procaine to the cardioplegic solution either increased or reduced the apparent protective properties of the solution with a bell-shaped dose-response curve being obtained. The optimum procaine concentration was 0.05 mM /L. At this concentration the protection afforded by the St. Thomas' Hospital solution was increased by up to two thirds. Substitution of lignocaine for procaine resulted in a similar dose-response curve with its optimum also at 0.05 mM /L. If a similar optimum exists for the human heart. the doses in current clinical use would appear to be too high. These results argue for determining the dose-response characteristics of all substances used in cardioplegic solutions.
David 1. Hearse, Ph.D., Kym O'Brien, B.Sc., and Mark V. Braimbridge, F.R.C.S., London. United Kingdom
T
he current growth of interest in the use of various cardioplegic and protective infusion solutions during cardiac operations has resulted in the development of a number of different solutions. 1-10 Although their composition varies, the basic principles underlying their use are similar': Cardioplegic agents induce arrest rapidly; hypothermia slows metabolic processes and the development of tissue injury; protective agents are included to combat one or more of the deleterious effects of ischemia. One agent which has been included in many cardioplegic solutions, particularly the early German formulations, is the local anesthetic agent, procaine.
From the Myocardial Metabolism Research Laboratories. The Rayne Institute. SI. Thomas' Hospital, London SEI, United Kingdom. Supported in part by grants from the British Heart Foundation, the Wellcome trust, and St. Thomas' Hospital Research Endowments Fund. Received for publication June 19, 1980. Accepted for publication Nov. 6, 1980. Address for reprints: Dr. D. J. Hearse, The Rayne Institute, SI. Thomas' Hospital, London SEI, United Kingdom.
Bretschneider and associates" and Holscher!' used 7.4 mM/L and Kirsch, Rodewald, and Kalmar' used 11.0 mM/L. The inclusion of procaine was based upon its cardioplegic effect, maintaining depolarization by blocking sodium efflux, and upon its antidysrhythmic properties, which were felt to be of value during postischemic reperfusion. Procaine was also added to a number of other European and North American solutions with a view to improving myocardial protection. These solutions, however, induced arrest primarily through their raised potassium content. The procaine was not added in cardioplegic doses, and concentrations in the order of I mM/L were usual. The wider use of procaine was limited by three factors: differing surgical experience, the absence of specific characterization or dose-response studies of its effects, and, in the United States, the lack of Food and Drug Administration approval for its intravenous use. Lignocaine (lidocaine), however, is approved for use in North America and might be expected to exhibit the same spectrum of cardiovascular effects as procaine. Therefore, we have carried out a preliminary study in which the effect of the inclusion of these two agents in
0022-5223/81/060873+07$00.70/0 © 1981 The C. V. Mosby Co.
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Fig. 1. Basic cardioplegic protection. Hearts were subjected to 120 minutes of hypothermic (200 C) ischemic arrest: (0) control group; (0) preischemic infusion of St. Thomas' Hospital cardioplegic solution. Recovery of aortic flow during a 30 minute postischemic reperfusion period is expressed as a percentage of its preischemic control value. Six hearts were used for each group and the bars represent the standard error of the mean. There was no recovery in the control group.
Table I. The St. Thomas' Hospital cardioplegic solution without procaine Compound
Sodium chloride (mM/L) Potassium chloride (mM/L) Magnesium chloride (mM/L) Calcium chloride (mM/L) Sodium bicarbonate (mM/L)
Concentration
110.0 16.0 16.0 1.2 10.0
pH adjusted to 7.8 Osmolarity = 324 mOsm/kg H20.
various concentrations in the St. Thomas' Hospital cardioplegic solution has been assessed using an isolated rat heart preparation.
Materials and methods Hearts. Hearts were obtained from male rats (280 to 320 gm of body weight) of the Wistar strain. Experimental model. The isolated, perfused, working rat heart model has already been described in detail. 12. 13 It is a left heart preparation in which oxygen-
ated perfusion medium (at 37° C) enters the cannulated left atrium at a pressure of 20 em H 20 and is passed to the ventricle, from which it is spontaneously ejected at 40 to 65 ml/min via an aortic cannula against a hydrostatic pressure of 100 cm H 20 . Electrical pacing was not used in this study in order to assess the effect of the local anesthetics on heart rate. Coronary effluent can be sampled for biochemical analysis or pooled and recirculated with the aortic outflow. Total cardiopulmonary bypass with maintained coronary perfusion may be simulated by clamping the left atrial cannula and introducing perfusion fluid at 37° C into the aorta from a reservoir located 100 em above the heart. This preparation, which is essentially that described by Langendorff, 14 will continue to beat but does not perform any external work. Ischemic cardiac arrest may be induced in this preparation by clamping the aortic cannula. Short periods of preischemic coronary infusion (at any degree of hypothermia) of the cardioplegic solution may be achieved by use of a reservoir (located 60 em above the heart) attached to a side arm of the aortic cannula. Experimental time course. Immediately after exci-
Volume 81
Cardioplegia: Procaine and lignocaine
Number 6
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June, 1981
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0.01 O. 05 0.2 1. 0 2.0 10.020. 0 PROCAINE CONCENTRATION (mmoles/litre I logarithm ic Scale
Fig. 2. Procaine dose-response study. The relationship between the concentration of procaine in the cardioplegic solution (mM/L; note the logarithmic scale) and the postischemic recovery of aortic flow (expressed as a percent of the preischernie control value) measured at the end of a 30 minute period of reperfusion following a 120 minute period of hypothermic (200 C) ischemic cardiac arrest. Each point represents the mean of six hearts and the bars indicate the standard error of the mean. sion of the heart, the aorta was connected to the aortic cannula and Langendorff perfusion was initiated for a 5 minute washout and equilibration period. During this 5 minute period, left atrial cannulation was completed. During this and subsequent perfusion periods, the circulating fluid was Krebs-Henseleit bicarbonate buffer;": 16 pH 7.4, containing glucose (Il.l mM/L) and gassed with 95% oxygen and 5% carbon dioxide. The heart was then converted to a working preparation by terminating the retrograde aortic perfusion and initiating left atrial perfusion. During a 15 minute period, control values for aortic and coronary flow rates, peak aortic pressure, and heart rate were recorded. At the
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Fig. 3. Lignocaine dose-response study. The relationship between the concentration of lignocaine in the cardioplegic solution (mM/L; note the logarithmic scale) and the postischernie recovery of aortic flow (expressed as a percent of the preischemic control value) measured at the end of a 30 minute period of reperfusion following a 120 minute period of hypothermic (20 C) ischemic cardiac arrest. Each point represents the mean of six hearts and the bars indicate the standard error of the mean. 0
end of this control period, the atrial and aortic cannulas were clamped and the heart was subjected to a 3 minute period of coronary infusion (20 0 C) with the cardioplegic solution under study. Infusion was then terminated and the entire heart was maintained hypothermically (20 0 C) in an ischemic state for 120 minutes. After this period the hearts were reperfused initially in the Langendorff mode for 15 minutes and then in the working mode for a further 15 minutes. During this latter period the recovery of cardiac function was monitored. Expression of results. During the preischemic working control period the following variables were recorded: heart rate, coronary flow, aortic flow, and aortic pressure. The cardiac output was derived from the sum of aortic and coronary flow and the stroke
The Journal of Thoracic and Cardiovascular Surgery
876 Hearse, O'Brien, Braimbridge
Table II. Procaine dose-response study: The effect of procaine concentration in the cardioplegic solution upon the postischemic recovery of various parameters of cardiac function after 120 minutes of ischemia Procaine concentration (mM/L) 20.0 10.0 2.0 1.0 0.2 0.05 0.01 0.001
o (control)
Aortic pressure
Aortic flow Control (mllmin) 53.5 52.0 52.0 48.3 49.0 52.0 50.4 50.0 52.8
± ± ± ± ± ± ± ± ±
I
3.8 2.5 0.8 3.7 1.7 3.1 2.1 2.4 1.9
Recovery after 30 min of reperfusion (%) 22.6 40.9 52.7 68.6 78.4 90.4 74.3 78.3 67.2
± ± ± ± ± ± ± ± ±
2.0* 3.4* 7.4t 6.0:1: 5.1 4.5 4.0§ 5.3 3.4*
Control (cm H2O) 192 198 199 150 180 160 186 198 189
± ± ± ± ± ± ± ± ±
I
Recovery after 30 min of reperfusion (%) 84.7 90.0 90.2 95.3 88.7 98.1 94.1 92.8 92.7
7.2 11 3.9 1.8 6.8 7.9 3.7 4.6 6.9
Heart rate
± ± ± ± ± ± ± ± ±
1.5t 1.6§ 2.7§ 0.8 4.3 2.7 1.5 1.0 1.9
Control (beats/min) 251 249 268 274 233 267 257 244 267
± ± ± ± ± ± ± ± ±
I
Recovery after 30 min of reperfusion (%) 83.3 88.5 95.6 98.0 105.0 105.0 93.9 102.0 100.0
11.0 8.8 7.2 13.0 9.3 14.0 8.6 7.1 6.2
± ± ± ± ± ± ± ± ±
3.4t 3.4§ 1.7 3.5 2.6 8.1 2.6 5.0 3.7
Statistical analysis: Percent recovery for each concentration group and for each variable has been compared (Student's t test) with optimal recovery observed. In all instances this involved a comparison of percent recovery with that found in 0.05 mM group. *p < 0.001.
tp < om. tp < 0.02. §p < 0.05.
Table III. Lignocaine dose-response study: The effect of lignocaine concentration in the cardioplegic solution upon the postischemic recovery of various parameters of cardiac function after 120 minutes of ischemia Lignocaine concentration (mM/L) 20.0 2.0 0.05 0.01
o (control)
Aortic flow Control (mllmin) 54.8 47.3 54.6 61.6 52.8
± ± ± ± ±
2.7 2.7 1.9 3.2 1.9
I
Aortic pressure
Recovery after 30 min of reperfusion (%) 38.9 65.5 86.2 79.3 67.2
± ± ± ± ±
6.9* 8.1§ 3.0 4.3 3.4t
Control (cm H2O) 202 176 206 193 189
± ± ± ± ±
4.2 4.2 4.7 8.8 6.9
I
Heart rate
Recovery after 30 min of reperfusion (%) 84.5 95.7 92.9 92.9 92.7
± ± ± ± ±
1.9§ 1.6 2.7 2.2 1.9
Control (beats/min) 255 270 284 262 267
± ± ± ± ±
12.3 14.0 20.0 8.3 6.2
I
Recovery after 30 min of reperfusion (%) 91.1 89.4 102.0 96.8 100.0
4.6 1.0 5.4 3.4 ± 3.7
± ± ± ±
Statistical analysis: Percent recovery for each concentration group and for each variable has been compared (Student's t test) with optimal recovery observed. In all instances this involved a comparison of percent recovery with that found in 0.05 mM group. *p < 0.001. tp < 0.01. tp < 0.02. §p < 0.05.
volume by dividing cardiac output by heart rate. During the recovery period these variables again were measured and expressed as a percent of their individual preischemic control values. In this way the postischemic recovery of function could be expressed as a percentage and related to the duration of ischemia, to the nature of the cardioplegic solution, and in particular to the nature and concentration of any specific additives. Six hearts were used for each condition studied, and all data were expressed as the mean ± the standard error. Cardioplegic solution. The basic St. Thomas' Hospital cardioplegic solution with the omission of procaine was used; the composition is shown in Table I. To this was added various concentrations of procaine hydrochloride or lignocaine hydrochloride.
Results Basic cardioplegic protection. To ascertain the degree of protection afforded by the unmodified St. Thomas' Hospital cardioplegic solution, we undertook a series of studies in which the postischemic recovery of function was related to the duration of ischemia and the presence or absence of the cardioplegic solution. The objective of this series of studies was to define a duration of ischemic arrest at which tissue injury was sufficient to prevent complete postischemic recovery but was not so severe as to prevent any recovery. In other words, conditions were established to permit a 60% to 70% recovery of pump function. In this way any protective or injurious effects arising from the inclusion of procaine or lignocaine in the cardioplegic
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Cardiac output
Coronary flow rate
I
Control (ml/min) 22.5 22.3 24.9 22.8 23.8 25.3 23.0 24.8 24.8
± ± ± ± ± ± ± ± ±
Recovery after 30 min of reperfusion (%) 83.5 98.4 105.0 101.0 97.5 94.1 95.8 99.4 104.0
0.8 0.9 J.I 1.4 1.3 0.4 J.I 0.9 0.8
± ± ± ± ± ± ± ± ±
5.9 5.0 4.3 2.2 8.4 2.8 2.5 4.0 6.3
Control (ml lmin}
74.3 74.3 76.9 71.2 72.8 77.2 73.2 74.8 77.5
± ± ± ± ± ± ± ± ±
22.8 23.5 22.6 23.8 24.8
± ± ± ± ±
0.8 1.0 1.0 0.9 0.8
I
Recovery after 30 min of reperfusion (%) 71.8 ± 6.2 95.9 ± 3.8 95.3 ± 5.6 96.4 ± 2.5 104.0 ± 6.3
Recovery after 30 min of reperfusion (%) 40.2 58.6 69.9 74.4 85.5 91.6 81.4 85.5 79.5
2.5 2.2 1.7 4.8 1.5 3.2 2.1 2.6 2.5
Coronary flow rate Control (ml/min)
I
Stroke volume
± ± ± ± ± ± ± ± ±
4.4* 3.2t 5.6* 6.2§ 3.7 3.7 2.9 2.5 2.7§
Control (ml/beat) 0.30 0.30 0.29 0.26 0.31 0.29 0.29 0.31 0.29
± ± ± ± ± ± ± ± ±
77.6 70.8 77.3 85.5 77.5
± ± ± ± ±
I
3.1 2.6 2.8 3.6 2.5
solution could be readily detected and quantitated. The results (Fig. 1) revealed that 120 minutes was the ideal ischemic interval. Hearts (n = 6) subjected to ischemic arrest without preischemic cardioplegic infusion failed to recover any pump function upon reperfusion and were observed to be in a state of contracture. By contrast, hearts subjected to preischemic coronary infusion (3 minutes) with the St. Thomas' Hospital cardioplegic solution (without procaine) recovered 67.2% ± 3.4% of their preischemic aortic flow and 79.5% ± 2.7% of their preischemic cardiac output. Inclusion of procaine. Procaine hydrochloride was added to the St. Thomas' Hospital cardioplegic solution to a final concentration of 1.0 mM or 10.0 mM. Hearts (n = 6 for each group) were infused for a 3 minute period with the cardioplegic solution at 20° C. The hearts were then subjected to 120 minutes of hypothermic ischemic arrest. There were no secondary infusions of cardioplegic solution. Upon reperfusion a
± ± ± ± ± ± ± ± ±
5.8* 3.3t 5.5 4.6 4.9 5.8 3.9 3.5 3.7
Stroke volume
Recovery after 30 min of reperfusion (%) 48.8 76.7 84.1 84.1 79.5
Recovery after 30 min of reperfusion (%) 48.9 66.4 73.1 75.4 73.9 88.8 86.9 84.8 80.3
0.01 0.005 0.01 0.02 0.01 0.01 0.01 0.01 0.01
Cardiac output Control (ml/min)
-\
± ± ± ± ±
6.6* 4.3 3.5 3.5 2.7
Control (ml/beat) 0.31 0.26 0.28 0.33 0.29
± ± ± ± ±
0.01 0.01 0.01 0.01 0.01
I
Recovery after 30 min of reperfusion (%) 53.5 86.1 88.8 87.0 80.3
± 6.7t ±4.3 ± 6.8 ± 2.2 ± 3.7
surprising result was obtained. At 1.0 mM, procaine addition increased postischemic functional recovery when compared with a procaine-free control, whereas at 10.0 mM, procaine addition reduced postischemic recovery. These results indicated that procaine may exhibit a complex dose-response profile and that concentrations hitherto used may not have been in the correct range for optimal protection. A dose-response curve for procaine was therefore constructed. Hearts (n = 6 for each group) were given a 3 minute infusion at 20° C of the St. Thomas' Hospital cardiop1egic solution to which procaine had been added in the following concentrations: 0, 0.001, 0.01, 0.05, 0.2, 1.0, 2.0, 10.0, and 20.0 mM/L. The hearts were then subjected to 120 minutes of ischemia at 20° C followed by 30 minutes of reperfusion. The final recovery of function in relation to the concentration of procaine in the cardiop1egic solution is shown in Table II and Fig. 2. The results showed a bell-shaped dose-response
The Journal of
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Hearse, O'Brien, Braimbridge
curve. As the procaine concentration increased from a to 0.05 mM/L, there was a progressive increase in protective properties (p < 0.001 with respect to control). Beyond this point, recovery decreased with increasing procaine concentrations, and above 2 mM procaine reduced the apparent efficacy of the cardioplegic solution (p < 0.001 with respect to control). The results indicate that when procaine is included in the cardioplegic solution at the noncardioplegic concentration of 0.05 mM/L, the postischemic recovery of aortic flow is increased from less than 70% to greater than 90% of its preischemic value. At procaine concentrations of 10 mM/L and above, there was a significant reduction in heart rate during the reperfusion period. However, calculation of the stroke volume, rather than aortic flow, made little difference to the shape of the dose-response curve (Table II), though tending to flatten it somewhat. The added protection resulting from the inclusion of procaine in a concentration of 0.05 mM/L may appear relatively small, but, as the recovery of the procaine group approaches 100%, the full potential for the additional protection might not have been revealed. In order to test this last point, we carried out a series of experiments in which hearts (n = 6 for each group) were subjected to 150 minutes of ischemic arrest with procaine included in the cardioplegic solution at concentrations of 0, 0.01, and 0.05 mM/L. In the procainefree group, the final postischemic recovery of aortic flow was 33.1 % ± 7.8% of its preischemic value. Inclusion of procaine at 0.01 mM/L improved this figure to 50.1 % ± 7.8% and at 0.05 mM/L to 53.6% ± 4.9%. Thus it would appearthat the inclusion of procaine at its optimal concentration increased the protective properties of the St. Thomas' Hospital cardioplegic solution by approximately two thirds. Inclusion of lignocaine. In order to ascertain whether lignocaine (lidocaine) affords a similar improvement in the protective properties of the St. Thomas' Hospital cardioplegic solution and also to investigate its dose-response characteristics, we conducted the following studies. Lignocaine hydrochloride was included in the cardioplegic solution at the following concentrations: 0, 0.01, 0.05, 2.0, and 20.0 mM/L. Hearts (n = 6 for each group) were subjected to 120 minutes of ischemia (20 C) and 30 minutes of reperfusion. The results for the postischemic recovery of function in relation to the concentration of lignocaine in the cardioplegic solution are detailed in Table III and Fig. 3. As with procaine, a bell-shaped dose-response curve was obtained with an optimal protective concentration 0
Thoracic and Cardiovascular Surgery
of 0.05 mM/L. At this concentration, protection was significantly (p < 0.01) improved, with aortic flow increasing from 67.2% ± 3.4% to 86.2% ± 3.0%. At concentrations above 2.0 mM/L, lignocaine reduced the apparent protective properties of the cardioplegic solution, so that at 20.0 mM the recovery of aortic flow fell significantly (p < 0.001) to 38.9% ± 6.9%. There was a reduction in heart rate at the lignocaine concentration of 20 mM/L, although this reduction was less than that with procaine. Again, calculation of stroke volume tended to flatten the dose-response curve but not to alter it significantly (Table III).
Discussion The results of this study with the isolated, perfused, working rat heart indicate that the inclusion of local anesthetic agents such as procaine or lignocaine (lidocaine) in the St. Thomas' Hospital cardioplegic solution can have a variable effect upon the ability of the solution to protect the heart against extended periods of ischemia. This variability can be attributed to the complex dose-response characteristics of these agents. Thus, at concentrations in the range of O. 00 I to O. I mM/L, these agents improved the protective properties of the solution: For both procaine and lignocaine the optimal concentration was 0.05 mM, and at this level the protective properties of the solution could be improved substantially. From a number of studies it appears that the added protection was such that, when the drug was used at an optimal concentration, an additional 20% of preischemic function could be restored after 2 or 2V2 hours of ischemia. At concentrations above I to 2 mM, the use of procaine or lignocaine appeared to reduce the protective properties of the cardioplegic solution. Thus, in the 20.0 mM group, postischemic recovery of aortic flow was less than half that of control. In considering the beneficial and possibly detrimental effects of local anesthetics, it would appear likely that the additional protection at low, noncardioplegic doses is achieved through the ability of procaine to reduce deleterious, ischemia-induced changes in cell membrane activity, possibly through the so-called "membrane stabilizing" action of the drug. The apparent depressive effects of the drugs at high concentrations are less readily explained but may be attributable to some direct membrane action during ischemia or to some residual activity during reperfusion. This latter possibility might be supported by the observation of a sustained depression of heart rate that occurred in the high-dose groups for as long as 30 minutes after reperfusion (this reduction in rate did not significantly alter
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Cardioplegia: Procaine and lignocaine
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June. 1981
the dose-response curves beside flattening them somewhat). Since it is conceivable that extended periods of reperfusion might have reversed a depression of function, it is not possible in these studies to conclusively equate the depression of function with the induction of damage. Although these results were obtained in the isolated rat heart, they stress the importance of determining the dose-response characteristics of any agent included in a cardioplegic solution. The observation of bell-shaped dose-response curves is not unusual; for example, we!" have obtained one for the concentration of magnesium in cardioplegic solutions. Although the optimum concentration of local anesthetic may vary between species, our results suggest that the currently used clinical dosage should be reduced in man. Our results also suggest that lignocaine (lidocaine) is an acceptable alternative to procaine as a component of cardioplegic solutions. The assistance of Mrs. C. Boles is gratefully acknowledged. REFERENCES
2
3
4
5
Hearse OJ, Stewart OA, Braimbridge MY: Cellular protection during myocardial ischemia. The development and characterization of a procedure for the induction of reversible ischemic arrest. Circulation 54: 193-202, 1976 Braimbridge MY, Chayen J, Bitensky L, Hearse OJ, Jynge P, Cankovic-Oarracott S: Cold cardioplegia or continuous coronary perfusion? Report on preliminary clinical experience as assessed cytochemically. J THORAC CARDIOVASC SURG 74:900-906. 1977 Jynge P, Hearse DJ, Braimbridge MY: Myocardial protection during ischemic cardiac arrest. A possible hazard with calcium-free cardioplegic infusates. J THORAC CARDIOVASC SURG 73:846-855, 1977 Bretschneider HJ, Hiibner G, Knoll D. Lohr B, Nordbeck H, Spieckermann PG: Myocardial resistance and tolerance to ischemia. Physiological and biochemical basis. J Cardiovasc Surg 16:241-260, 1975 Kirsch U, Rodewald G, Kalmar P: Induced ischemic arrest. Clinical experience with cardioplegia in open-heart
surgery. J THORAC CARDIOVASC SURG 63:121-130, 1972 6 Gay WA Jr, Ebert PA: Functional, metabolic, and morphologic effects of potassium-induced cardioplegia. Surgery 74:284-290, 1973 7 Nelson RL, Goldstein SM, McConnell DH, Maloney JY, Buckberg GO: Improved myocardial performance after aortic cross clamping by combining pharmacologic arrest with topical hypothermia. Circulation 54:Suppl 3: II , 1976 8 Raju S, Gibson WJ, Heath B, Lockhart Y, Conn H: Experimental evaluation of coronary infusates in dogs. Arch Surg 110:1374-1382,1975 9 Lolley DM, Hewitt RL, Drapanas T: Retroperfusion of the heart with a solution of glucose, insulin, and potassium during anoxic arrest. J THORAC CARDIOVASC SURG 67:364-370, 1974 10 Fisk RL, Gelfand ET, Callaghan JC: Hypothermic coronary perfusion for intraoperative cardioplegia. Ann Thorae Surg 23:58-61, 1977 II Holscher B: Studies by electron microscopy on the effects of magnesium chloride-procaine or potassium citrate on the myocardium in induced cardiac arrest. J Cardiovasc Surg 8:3-8, 1967 12 Hearse DJ, Stewart DA, Braimbridge MY: Myocardial protection during bypass and arrest. A possible hazard with lactate-containing infusates. J THORAC CARDIOVASC SURG 72:880-884, 1976 13 Hearse OJ, Stewart OA, Braimbridge MY: Hypothermic arrest and potassium arrest. Metabolic and myocardial protection during elective cardiac arrest. Circ Res 36: 481-489, 1975 14 Langendorff 0: Untersuchungen am iiberlebenden Saugetierherzen. Pflugers Arch 61:291, 1895 15 Krebs HA, Henseleit K: Untersuchungen iiber die Harnstoffbildung im Tierkorper. Hoppe Seylers Z Physiol Chern 210:33-66, 1932 16 Umbreit WW, Burris RH, Stauffer JF: Preparation of Krebs-Ringer phosphate and bicarbonate solution, Manometric Techniques, Minneapolis, 1969, Burgess Publishing Company, p 132 17 Hearse DJ, Stewart DA, Braimbridge MY: Myocardial protection during ischemic cardiac arrest. The importance of magnesium in cardioplegic infusates. J THORAC CARD10VASC SURG 75:877-885, 1978
Protection of the myocardium during ischemic arrest Dose-response curves for procaine and lignocaine in cardioplegic solutions The dose-response curve of procaine or lignocaine (lidocaine) added to the St. Thomas' Hospital cardioplegic solution was investigated with an isolated working rat heart preparation. In the absence of any cold cardioplegic protection. hearts failed to recover after as little as 30 minutes of ischemia. A single infusion (20 0 C) of the basic St. Thomas' Hospital cardioplegic solution allowed hearts to recover to 60% or more of their preischemic control aortic flow after a 120 minute period of ischemia. Addition of procaine to the cardioplegic solution either increased or reduced the apparent protective properties of the solution with a bell-shaped dose-response curve being obtained. The optimum procaine concentration was 0.05 mM /L. At this concentration the protection afforded by the St. Thomas' Hospital solution was increased by up to two thirds. Substitution of lignocaine for procaine resulted in a similar dose-response curve with its optimum also at 0.05 mM /L. If a similar optimum exists for the human heart. the doses in current clinical use would appear to be too high. These results argue for determining the dose-response characteristics of all substances used in cardioplegic solutions.
David 1. Hearse, Ph.D., Kym O'Brien, B.Sc., and Mark V. Braimbridge, F.R.C.S., London. United Kingdom
T
he current growth of interest in the use of various cardioplegic and protective infusion solutions during cardiac operations has resulted in the development of a number of different solutions. 1-10 Although their composition varies, the basic principles underlying their use are similar': Cardioplegic agents induce arrest rapidly; hypothermia slows metabolic processes and the development of tissue injury; protective agents are included to combat one or more of the deleterious effects of ischemia. One agent which has been included in many cardioplegic solutions, particularly the early German formulations, is the local anesthetic agent, procaine.
From the Myocardial Metabolism Research Laboratories. The Rayne Institute. SI. Thomas' Hospital, London SEI, United Kingdom. Supported in part by grants from the British Heart Foundation, the Wellcome trust, and St. Thomas' Hospital Research Endowments Fund. Received for publication June 19, 1980. Accepted for publication Nov. 6, 1980. Address for reprints: Dr. D. J. Hearse, The Rayne Institute, SI. Thomas' Hospital, London SEI, United Kingdom.
Bretschneider and associates" and Holscher!' used 7.4 mM/L and Kirsch, Rodewald, and Kalmar' used 11.0 mM/L. The inclusion of procaine was based upon its cardioplegic effect, maintaining depolarization by blocking sodium efflux, and upon its antidysrhythmic properties, which were felt to be of value during postischemic reperfusion. Procaine was also added to a number of other European and North American solutions with a view to improving myocardial protection. These solutions, however, induced arrest primarily through their raised potassium content. The procaine was not added in cardioplegic doses, and concentrations in the order of I mM/L were usual. The wider use of procaine was limited by three factors: differing surgical experience, the absence of specific characterization or dose-response studies of its effects, and, in the United States, the lack of Food and Drug Administration approval for its intravenous use. Lignocaine (lidocaine), however, is approved for use in North America and might be expected to exhibit the same spectrum of cardiovascular effects as procaine. Therefore, we have carried out a preliminary study in which the effect of the inclusion of these two agents in
0022-5223/81/060873+07$00.70/0 © 1981 The C. V. Mosby Co.
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Fig. 1. Basic cardioplegic protection. Hearts were subjected to 120 minutes of hypothermic (200 C) ischemic arrest: (0) control group; (0) preischemic infusion of St. Thomas' Hospital cardioplegic solution. Recovery of aortic flow during a 30 minute postischemic reperfusion period is expressed as a percentage of its preischemic control value. Six hearts were used for each group and the bars represent the standard error of the mean. There was no recovery in the control group.
Table I. The St. Thomas' Hospital cardioplegic solution without procaine Compound
Sodium chloride (mM/L) Potassium chloride (mM/L) Magnesium chloride (mM/L) Calcium chloride (mM/L) Sodium bicarbonate (mM/L)
Concentration
110.0 16.0 16.0 1.2 10.0
pH adjusted to 7.8 Osmolarity = 324 mOsm/kg H20.
various concentrations in the St. Thomas' Hospital cardioplegic solution has been assessed using an isolated rat heart preparation.
Materials and methods Hearts. Hearts were obtained from male rats (280 to 320 gm of body weight) of the Wistar strain. Experimental model. The isolated, perfused, working rat heart model has already been described in detail. 12. 13 It is a left heart preparation in which oxygen-
ated perfusion medium (at 37° C) enters the cannulated left atrium at a pressure of 20 em H 20 and is passed to the ventricle, from which it is spontaneously ejected at 40 to 65 ml/min via an aortic cannula against a hydrostatic pressure of 100 cm H 20 . Electrical pacing was not used in this study in order to assess the effect of the local anesthetics on heart rate. Coronary effluent can be sampled for biochemical analysis or pooled and recirculated with the aortic outflow. Total cardiopulmonary bypass with maintained coronary perfusion may be simulated by clamping the left atrial cannula and introducing perfusion fluid at 37° C into the aorta from a reservoir located 100 em above the heart. This preparation, which is essentially that described by Langendorff, 14 will continue to beat but does not perform any external work. Ischemic cardiac arrest may be induced in this preparation by clamping the aortic cannula. Short periods of preischemic coronary infusion (at any degree of hypothermia) of the cardioplegic solution may be achieved by use of a reservoir (located 60 em above the heart) attached to a side arm of the aortic cannula. Experimental time course. Immediately after exci-
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June, 1981
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0.01 O. 05 0.2 1. 0 2.0 10.020. 0 PROCAINE CONCENTRATION (mmoles/litre I logarithm ic Scale
Fig. 2. Procaine dose-response study. The relationship between the concentration of procaine in the cardioplegic solution (mM/L; note the logarithmic scale) and the postischemic recovery of aortic flow (expressed as a percent of the preischernie control value) measured at the end of a 30 minute period of reperfusion following a 120 minute period of hypothermic (200 C) ischemic cardiac arrest. Each point represents the mean of six hearts and the bars indicate the standard error of the mean. sion of the heart, the aorta was connected to the aortic cannula and Langendorff perfusion was initiated for a 5 minute washout and equilibration period. During this 5 minute period, left atrial cannulation was completed. During this and subsequent perfusion periods, the circulating fluid was Krebs-Henseleit bicarbonate buffer;": 16 pH 7.4, containing glucose (Il.l mM/L) and gassed with 95% oxygen and 5% carbon dioxide. The heart was then converted to a working preparation by terminating the retrograde aortic perfusion and initiating left atrial perfusion. During a 15 minute period, control values for aortic and coronary flow rates, peak aortic pressure, and heart rate were recorded. At the
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LIGNOCAINE CONCENTRATION (mmolesllitre) Logarithm ic Scale
Fig. 3. Lignocaine dose-response study. The relationship between the concentration of lignocaine in the cardioplegic solution (mM/L; note the logarithmic scale) and the postischernie recovery of aortic flow (expressed as a percent of the preischemic control value) measured at the end of a 30 minute period of reperfusion following a 120 minute period of hypothermic (20 C) ischemic cardiac arrest. Each point represents the mean of six hearts and the bars indicate the standard error of the mean. 0
end of this control period, the atrial and aortic cannulas were clamped and the heart was subjected to a 3 minute period of coronary infusion (20 0 C) with the cardioplegic solution under study. Infusion was then terminated and the entire heart was maintained hypothermically (20 0 C) in an ischemic state for 120 minutes. After this period the hearts were reperfused initially in the Langendorff mode for 15 minutes and then in the working mode for a further 15 minutes. During this latter period the recovery of cardiac function was monitored. Expression of results. During the preischemic working control period the following variables were recorded: heart rate, coronary flow, aortic flow, and aortic pressure. The cardiac output was derived from the sum of aortic and coronary flow and the stroke
The Journal of Thoracic and Cardiovascular Surgery
876 Hearse, O'Brien, Braimbridge
Table II. Procaine dose-response study: The effect of procaine concentration in the cardioplegic solution upon the postischemic recovery of various parameters of cardiac function after 120 minutes of ischemia Procaine concentration (mM/L) 20.0 10.0 2.0 1.0 0.2 0.05 0.01 0.001
o (control)
Aortic pressure
Aortic flow Control (mllmin) 53.5 52.0 52.0 48.3 49.0 52.0 50.4 50.0 52.8
± ± ± ± ± ± ± ± ±
I
3.8 2.5 0.8 3.7 1.7 3.1 2.1 2.4 1.9
Recovery after 30 min of reperfusion (%) 22.6 40.9 52.7 68.6 78.4 90.4 74.3 78.3 67.2
± ± ± ± ± ± ± ± ±
2.0* 3.4* 7.4t 6.0:1: 5.1 4.5 4.0§ 5.3 3.4*
Control (cm H2O) 192 198 199 150 180 160 186 198 189
± ± ± ± ± ± ± ± ±
I
Recovery after 30 min of reperfusion (%) 84.7 90.0 90.2 95.3 88.7 98.1 94.1 92.8 92.7
7.2 11 3.9 1.8 6.8 7.9 3.7 4.6 6.9
Heart rate
± ± ± ± ± ± ± ± ±
1.5t 1.6§ 2.7§ 0.8 4.3 2.7 1.5 1.0 1.9
Control (beats/min) 251 249 268 274 233 267 257 244 267
± ± ± ± ± ± ± ± ±
I
Recovery after 30 min of reperfusion (%) 83.3 88.5 95.6 98.0 105.0 105.0 93.9 102.0 100.0
11.0 8.8 7.2 13.0 9.3 14.0 8.6 7.1 6.2
± ± ± ± ± ± ± ± ±
3.4t 3.4§ 1.7 3.5 2.6 8.1 2.6 5.0 3.7
Statistical analysis: Percent recovery for each concentration group and for each variable has been compared (Student's t test) with optimal recovery observed. In all instances this involved a comparison of percent recovery with that found in 0.05 mM group. *p < 0.001.
tp < om. tp < 0.02. §p < 0.05.
Table III. Lignocaine dose-response study: The effect of lignocaine concentration in the cardioplegic solution upon the postischemic recovery of various parameters of cardiac function after 120 minutes of ischemia Lignocaine concentration (mM/L) 20.0 2.0 0.05 0.01
o (control)
Aortic flow Control (mllmin) 54.8 47.3 54.6 61.6 52.8
± ± ± ± ±
2.7 2.7 1.9 3.2 1.9
I
Aortic pressure
Recovery after 30 min of reperfusion (%) 38.9 65.5 86.2 79.3 67.2
± ± ± ± ±
6.9* 8.1§ 3.0 4.3 3.4t
Control (cm H2O) 202 176 206 193 189
± ± ± ± ±
4.2 4.2 4.7 8.8 6.9
I
Heart rate
Recovery after 30 min of reperfusion (%) 84.5 95.7 92.9 92.9 92.7
± ± ± ± ±
1.9§ 1.6 2.7 2.2 1.9
Control (beats/min) 255 270 284 262 267
± ± ± ± ±
12.3 14.0 20.0 8.3 6.2
I
Recovery after 30 min of reperfusion (%) 91.1 89.4 102.0 96.8 100.0
4.6 1.0 5.4 3.4 ± 3.7
± ± ± ±
Statistical analysis: Percent recovery for each concentration group and for each variable has been compared (Student's t test) with optimal recovery observed. In all instances this involved a comparison of percent recovery with that found in 0.05 mM group. *p < 0.001. tp < 0.01. tp < 0.02. §p < 0.05.
volume by dividing cardiac output by heart rate. During the recovery period these variables again were measured and expressed as a percent of their individual preischemic control values. In this way the postischemic recovery of function could be expressed as a percentage and related to the duration of ischemia, to the nature of the cardioplegic solution, and in particular to the nature and concentration of any specific additives. Six hearts were used for each condition studied, and all data were expressed as the mean ± the standard error. Cardioplegic solution. The basic St. Thomas' Hospital cardioplegic solution with the omission of procaine was used; the composition is shown in Table I. To this was added various concentrations of procaine hydrochloride or lignocaine hydrochloride.
Results Basic cardioplegic protection. To ascertain the degree of protection afforded by the unmodified St. Thomas' Hospital cardioplegic solution, we undertook a series of studies in which the postischemic recovery of function was related to the duration of ischemia and the presence or absence of the cardioplegic solution. The objective of this series of studies was to define a duration of ischemic arrest at which tissue injury was sufficient to prevent complete postischemic recovery but was not so severe as to prevent any recovery. In other words, conditions were established to permit a 60% to 70% recovery of pump function. In this way any protective or injurious effects arising from the inclusion of procaine or lignocaine in the cardioplegic
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Cardiac output
Coronary flow rate
I
Control (ml/min) 22.5 22.3 24.9 22.8 23.8 25.3 23.0 24.8 24.8
± ± ± ± ± ± ± ± ±
Recovery after 30 min of reperfusion (%) 83.5 98.4 105.0 101.0 97.5 94.1 95.8 99.4 104.0
0.8 0.9 J.I 1.4 1.3 0.4 J.I 0.9 0.8
± ± ± ± ± ± ± ± ±
5.9 5.0 4.3 2.2 8.4 2.8 2.5 4.0 6.3
Control (ml lmin}
74.3 74.3 76.9 71.2 72.8 77.2 73.2 74.8 77.5
± ± ± ± ± ± ± ± ±
22.8 23.5 22.6 23.8 24.8
± ± ± ± ±
0.8 1.0 1.0 0.9 0.8
I
Recovery after 30 min of reperfusion (%) 71.8 ± 6.2 95.9 ± 3.8 95.3 ± 5.6 96.4 ± 2.5 104.0 ± 6.3
Recovery after 30 min of reperfusion (%) 40.2 58.6 69.9 74.4 85.5 91.6 81.4 85.5 79.5
2.5 2.2 1.7 4.8 1.5 3.2 2.1 2.6 2.5
Coronary flow rate Control (ml/min)
I
Stroke volume
± ± ± ± ± ± ± ± ±
4.4* 3.2t 5.6* 6.2§ 3.7 3.7 2.9 2.5 2.7§
Control (ml/beat) 0.30 0.30 0.29 0.26 0.31 0.29 0.29 0.31 0.29
± ± ± ± ± ± ± ± ±
77.6 70.8 77.3 85.5 77.5
± ± ± ± ±
I
3.1 2.6 2.8 3.6 2.5
solution could be readily detected and quantitated. The results (Fig. 1) revealed that 120 minutes was the ideal ischemic interval. Hearts (n = 6) subjected to ischemic arrest without preischemic cardioplegic infusion failed to recover any pump function upon reperfusion and were observed to be in a state of contracture. By contrast, hearts subjected to preischemic coronary infusion (3 minutes) with the St. Thomas' Hospital cardioplegic solution (without procaine) recovered 67.2% ± 3.4% of their preischemic aortic flow and 79.5% ± 2.7% of their preischemic cardiac output. Inclusion of procaine. Procaine hydrochloride was added to the St. Thomas' Hospital cardioplegic solution to a final concentration of 1.0 mM or 10.0 mM. Hearts (n = 6 for each group) were infused for a 3 minute period with the cardioplegic solution at 20° C. The hearts were then subjected to 120 minutes of hypothermic ischemic arrest. There were no secondary infusions of cardioplegic solution. Upon reperfusion a
± ± ± ± ± ± ± ± ±
5.8* 3.3t 5.5 4.6 4.9 5.8 3.9 3.5 3.7
Stroke volume
Recovery after 30 min of reperfusion (%) 48.8 76.7 84.1 84.1 79.5
Recovery after 30 min of reperfusion (%) 48.9 66.4 73.1 75.4 73.9 88.8 86.9 84.8 80.3
0.01 0.005 0.01 0.02 0.01 0.01 0.01 0.01 0.01
Cardiac output Control (ml/min)
-\
± ± ± ± ±
6.6* 4.3 3.5 3.5 2.7
Control (ml/beat) 0.31 0.26 0.28 0.33 0.29
± ± ± ± ±
0.01 0.01 0.01 0.01 0.01
I
Recovery after 30 min of reperfusion (%) 53.5 86.1 88.8 87.0 80.3
± 6.7t ±4.3 ± 6.8 ± 2.2 ± 3.7
surprising result was obtained. At 1.0 mM, procaine addition increased postischemic functional recovery when compared with a procaine-free control, whereas at 10.0 mM, procaine addition reduced postischemic recovery. These results indicated that procaine may exhibit a complex dose-response profile and that concentrations hitherto used may not have been in the correct range for optimal protection. A dose-response curve for procaine was therefore constructed. Hearts (n = 6 for each group) were given a 3 minute infusion at 20° C of the St. Thomas' Hospital cardiop1egic solution to which procaine had been added in the following concentrations: 0, 0.001, 0.01, 0.05, 0.2, 1.0, 2.0, 10.0, and 20.0 mM/L. The hearts were then subjected to 120 minutes of ischemia at 20° C followed by 30 minutes of reperfusion. The final recovery of function in relation to the concentration of procaine in the cardiop1egic solution is shown in Table II and Fig. 2. The results showed a bell-shaped dose-response
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Hearse, O'Brien, Braimbridge
curve. As the procaine concentration increased from a to 0.05 mM/L, there was a progressive increase in protective properties (p < 0.001 with respect to control). Beyond this point, recovery decreased with increasing procaine concentrations, and above 2 mM procaine reduced the apparent efficacy of the cardioplegic solution (p < 0.001 with respect to control). The results indicate that when procaine is included in the cardioplegic solution at the noncardioplegic concentration of 0.05 mM/L, the postischemic recovery of aortic flow is increased from less than 70% to greater than 90% of its preischemic value. At procaine concentrations of 10 mM/L and above, there was a significant reduction in heart rate during the reperfusion period. However, calculation of the stroke volume, rather than aortic flow, made little difference to the shape of the dose-response curve (Table II), though tending to flatten it somewhat. The added protection resulting from the inclusion of procaine in a concentration of 0.05 mM/L may appear relatively small, but, as the recovery of the procaine group approaches 100%, the full potential for the additional protection might not have been revealed. In order to test this last point, we carried out a series of experiments in which hearts (n = 6 for each group) were subjected to 150 minutes of ischemic arrest with procaine included in the cardioplegic solution at concentrations of 0, 0.01, and 0.05 mM/L. In the procainefree group, the final postischemic recovery of aortic flow was 33.1 % ± 7.8% of its preischemic value. Inclusion of procaine at 0.01 mM/L improved this figure to 50.1 % ± 7.8% and at 0.05 mM/L to 53.6% ± 4.9%. Thus it would appearthat the inclusion of procaine at its optimal concentration increased the protective properties of the St. Thomas' Hospital cardioplegic solution by approximately two thirds. Inclusion of lignocaine. In order to ascertain whether lignocaine (lidocaine) affords a similar improvement in the protective properties of the St. Thomas' Hospital cardioplegic solution and also to investigate its dose-response characteristics, we conducted the following studies. Lignocaine hydrochloride was included in the cardioplegic solution at the following concentrations: 0, 0.01, 0.05, 2.0, and 20.0 mM/L. Hearts (n = 6 for each group) were subjected to 120 minutes of ischemia (20 C) and 30 minutes of reperfusion. The results for the postischemic recovery of function in relation to the concentration of lignocaine in the cardioplegic solution are detailed in Table III and Fig. 3. As with procaine, a bell-shaped dose-response curve was obtained with an optimal protective concentration 0
Thoracic and Cardiovascular Surgery
of 0.05 mM/L. At this concentration, protection was significantly (p < 0.01) improved, with aortic flow increasing from 67.2% ± 3.4% to 86.2% ± 3.0%. At concentrations above 2.0 mM/L, lignocaine reduced the apparent protective properties of the cardioplegic solution, so that at 20.0 mM the recovery of aortic flow fell significantly (p < 0.001) to 38.9% ± 6.9%. There was a reduction in heart rate at the lignocaine concentration of 20 mM/L, although this reduction was less than that with procaine. Again, calculation of stroke volume tended to flatten the dose-response curve but not to alter it significantly (Table III).
Discussion The results of this study with the isolated, perfused, working rat heart indicate that the inclusion of local anesthetic agents such as procaine or lignocaine (lidocaine) in the St. Thomas' Hospital cardioplegic solution can have a variable effect upon the ability of the solution to protect the heart against extended periods of ischemia. This variability can be attributed to the complex dose-response characteristics of these agents. Thus, at concentrations in the range of O. 00 I to O. I mM/L, these agents improved the protective properties of the solution: For both procaine and lignocaine the optimal concentration was 0.05 mM, and at this level the protective properties of the solution could be improved substantially. From a number of studies it appears that the added protection was such that, when the drug was used at an optimal concentration, an additional 20% of preischemic function could be restored after 2 or 2V2 hours of ischemia. At concentrations above I to 2 mM, the use of procaine or lignocaine appeared to reduce the protective properties of the cardioplegic solution. Thus, in the 20.0 mM group, postischemic recovery of aortic flow was less than half that of control. In considering the beneficial and possibly detrimental effects of local anesthetics, it would appear likely that the additional protection at low, noncardioplegic doses is achieved through the ability of procaine to reduce deleterious, ischemia-induced changes in cell membrane activity, possibly through the so-called "membrane stabilizing" action of the drug. The apparent depressive effects of the drugs at high concentrations are less readily explained but may be attributable to some direct membrane action during ischemia or to some residual activity during reperfusion. This latter possibility might be supported by the observation of a sustained depression of heart rate that occurred in the high-dose groups for as long as 30 minutes after reperfusion (this reduction in rate did not significantly alter
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June. 1981
the dose-response curves beside flattening them somewhat). Since it is conceivable that extended periods of reperfusion might have reversed a depression of function, it is not possible in these studies to conclusively equate the depression of function with the induction of damage. Although these results were obtained in the isolated rat heart, they stress the importance of determining the dose-response characteristics of any agent included in a cardioplegic solution. The observation of bell-shaped dose-response curves is not unusual; for example, we!" have obtained one for the concentration of magnesium in cardioplegic solutions. Although the optimum concentration of local anesthetic may vary between species, our results suggest that the currently used clinical dosage should be reduced in man. Our results also suggest that lignocaine (lidocaine) is an acceptable alternative to procaine as a component of cardioplegic solutions. The assistance of Mrs. C. Boles is gratefully acknowledged. REFERENCES
2
3
4
5
Hearse OJ, Stewart OA, Braimbridge MY: Cellular protection during myocardial ischemia. The development and characterization of a procedure for the induction of reversible ischemic arrest. Circulation 54: 193-202, 1976 Braimbridge MY, Chayen J, Bitensky L, Hearse OJ, Jynge P, Cankovic-Oarracott S: Cold cardioplegia or continuous coronary perfusion? Report on preliminary clinical experience as assessed cytochemically. J THORAC CARDIOVASC SURG 74:900-906. 1977 Jynge P, Hearse DJ, Braimbridge MY: Myocardial protection during ischemic cardiac arrest. A possible hazard with calcium-free cardioplegic infusates. J THORAC CARDIOVASC SURG 73:846-855, 1977 Bretschneider HJ, Hiibner G, Knoll D. Lohr B, Nordbeck H, Spieckermann PG: Myocardial resistance and tolerance to ischemia. Physiological and biochemical basis. J Cardiovasc Surg 16:241-260, 1975 Kirsch U, Rodewald G, Kalmar P: Induced ischemic arrest. Clinical experience with cardioplegia in open-heart
surgery. J THORAC CARDIOVASC SURG 63:121-130, 1972 6 Gay WA Jr, Ebert PA: Functional, metabolic, and morphologic effects of potassium-induced cardioplegia. Surgery 74:284-290, 1973 7 Nelson RL, Goldstein SM, McConnell DH, Maloney JY, Buckberg GO: Improved myocardial performance after aortic cross clamping by combining pharmacologic arrest with topical hypothermia. Circulation 54:Suppl 3: II , 1976 8 Raju S, Gibson WJ, Heath B, Lockhart Y, Conn H: Experimental evaluation of coronary infusates in dogs. Arch Surg 110:1374-1382,1975 9 Lolley DM, Hewitt RL, Drapanas T: Retroperfusion of the heart with a solution of glucose, insulin, and potassium during anoxic arrest. J THORAC CARDIOVASC SURG 67:364-370, 1974 10 Fisk RL, Gelfand ET, Callaghan JC: Hypothermic coronary perfusion for intraoperative cardioplegia. Ann Thorae Surg 23:58-61, 1977 II Holscher B: Studies by electron microscopy on the effects of magnesium chloride-procaine or potassium citrate on the myocardium in induced cardiac arrest. J Cardiovasc Surg 8:3-8, 1967 12 Hearse DJ, Stewart DA, Braimbridge MY: Myocardial protection during bypass and arrest. A possible hazard with lactate-containing infusates. J THORAC CARDIOVASC SURG 72:880-884, 1976 13 Hearse OJ, Stewart OA, Braimbridge MY: Hypothermic arrest and potassium arrest. Metabolic and myocardial protection during elective cardiac arrest. Circ Res 36: 481-489, 1975 14 Langendorff 0: Untersuchungen am iiberlebenden Saugetierherzen. Pflugers Arch 61:291, 1895 15 Krebs HA, Henseleit K: Untersuchungen iiber die Harnstoffbildung im Tierkorper. Hoppe Seylers Z Physiol Chern 210:33-66, 1932 16 Umbreit WW, Burris RH, Stauffer JF: Preparation of Krebs-Ringer phosphate and bicarbonate solution, Manometric Techniques, Minneapolis, 1969, Burgess Publishing Company, p 132 17 Hearse DJ, Stewart DA, Braimbridge MY: Myocardial protection during ischemic cardiac arrest. The importance of magnesium in cardioplegic infusates. J THORAC CARD10VASC SURG 75:877-885, 1978