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Clinical trial of nicardipine cardioplegia in pediatric cardiac surgery
Clinical Trial of Nicardipine Cardioplegia in Pediatric Cardiac Surgery Fumiki Mori, MD, Masaki Miyamoto, MD, Hidetoshi Tsuboi, MD, Hiroshi Noda, MD, and Kensuke Esato, MD First Department of Surgery, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan
To clarify the effectiveness of nicardipine, one of the dihydropyridine calcium-channel blockers, for myocardial protection during cold potassium cardioplegic arrest in pediatric cardiac surgery, a clinical trial of nicardipine (0.25 mg/L) added to potassium cardioplegic solution was performed in children undergoing surgical repair of congenital heart diseases. Twenty patients were selected to receive nicardipine cardioplegia and 13 patients received a standard potassium cardioplegia, serving as a
F
or the last decade, cold potassium cardioplegia has been widely accepted as protecting the ischemic myocardium during cardiac operations. This cardioplegia is not optimal, however, and further improvement of myocardial protection is needed. More recently, slowcalcium-channel blockers have been suggested to provide additional protection when included in cardioplegic solutions used during aortic cross-clamping [ 1-51. Slow-calcium-channel blockers, which inhibit the influx of calcium ions into myocardial cells by blockade of the slow channel, provide myocardial electrical arrest and are potent coronary vasodilators. In addition, slow-calcium-channel blockers may provide a cytoprotective effect by inhibiting calcium overload in the ischemic myocardium. Use of calcium-channel blockers is still controversial, however. Recent reports [6] have suggested that calciumchannel blockers failed to afford any additional protection because of a temperature dependency for the effectiveness of these agents when used under the clinically relevant condition of hypothermic ischemic arrest in cardiac surgery. Furthermore, little is known regarding clinical use of calcium antagonists for intraoperative myocardial protection in children with congenital heart disease. The present study was designed to evaluate the efficacy of nicardipine, one of the dihydropyridine calcium-channel blockers, for myocardial protection during hypothermic cardioplegic arrest in pediatric cardiac surgery.
Material and Methods Thirty-three patients aged less than 10 years underwent repair of a variety of types of congenital heart disease at Yamaguchi University Hospital from September 1986 to May 1987. Patients were randomly assigned by hospital Accepted for publication Sep 27, 1989. Address reprint requests to Dr Mori, First Department of Surgery, Yamaguchi University School of Medicine, Ube, Yamaguchi 755, Japan.
0 1990 by The Society of Thoracic Surgeons
control group. Nicardipine cardioplegia provided better cardiac performance in the early postoperative period and reduced release of the MB isozyme of creatine kinase, as determined during a 46-hour postoperative period. These results suggest that nicardipine added to cold potassium cardioplegic solution offers additional protection for the myocardium during ischemia and postischemic reperfusion in pediatric cardiac surgery. (Ann Thorac Surg 1990;49:413-8)
number to one of two groups. Twenty patients received nicardipine in cardioplegic solution and 13 patients received our standard cardioplegic solution as a control group. The study protocol was approved by the institutional human research committee at Yamaguchi University Hospital. Type of operation and number of patients are shown in Table 1. On the whole, there were no differences in the severity and complexity of disease between the two patient groups.
Operative Technique After performance of a median sternotomy, the aorta was cannulated at the ascending aorta, and the superior and inferior venae cavae were cannulated through the right atrium. Cardiopulmonary bypass was established with a standard bubble oxygenator and roller pump at flows of 2.0 to 2.5 L/min/m2. Hypothermic perfusion was used to cool the patients to 25°C or less. In all patients, myocardial protection during aortic cross-clamping was assured by the combination of cold potassium cardioplegia and topical cooling of the heart with ice-cold saline solution. The composition of the cardioplegic solution was as follows: Na, 25.2 mEq/L; K, 23.0 mEq/L; Mg, 5.0 mEq/L; C1, 26.6 mEq/L; glucose, 48.1 g/L; Tris buffer, 3.0 mM; pH (37"C), 7.4; osmolarity, 345 mosm. The cardioplegic solution was infused into the aortic root at an initial volume of 15 mL/kg of body weight, and an additional 10 mL/kg of cardioplegic solution was infused every 20 minutes during aortic clamping. The patients in the nicardipine group received cardioplegic solution containing 0.25 mg/L of nicardipine (Fig 1).
Postoperative Care After termination of cardiopulmonary bypass, a SwanGanz catheter was inserted into the pulmonary artery to determine cardiac output postoperatively by thermodilution method, using in each instance the means of triplicate measurements. During the first 24 hours after operation, 0003-4975/90/$3.50
414
MORIETAL NICARDII'INE CARDIOPLEGIA IN CHILDREN
Ann Thorac Surg 1990;49:4134
Table 1. Profile of Operations and Number of Patients Control Group
Operations Atrial septal defect Ventricular septal defect Pulmonary stenosis Endocardia1 cushion defect Tetralogy of Fallot Fontan operation Total
Table 2 . Variables in 33 Study Patients"
Nicardipine Group
3 6 2 1 1 0
1 10 2 3 3 1
13
20
intravenous fluid was restricted to 750 mL/m2/24 h and blood, plasma, or both was transfused to maintain hemodynamic stability and hematocrit at approximately 35%. Arterial pressure, central venous pressure, and pulmonary arterial pressure were monitored continuously during the early postoperative period. Twelve patients required inotropic support with 5 to 15 pg/kg/min of dopamine or dobutamine, and 3 of them required combined use of vasodilators. As an indicator of myocardial injury during operation, serial changes in serum activity of the MB isoenzyme of creatine kinase (CK-MB) were measured for 48 hours after termination of cardiopulmonary bypass. Creatine kinase activity was determined by a spectrophotometric kinetic method, and the isozymes were separated according to the electrophoresis technique. The total amount of CK-MB release was calculated by the following formula [7]: Total CK-MB release (IU/L) = E(T) + kdJE(t)dt, where total CK-MB release = cumulative activity of CK-MB released by heart up to time T, E(t) = activity of CK-MB in serum (IU/L)at time t, and kd = the fractional rate of disappearance of CK-MB from blood. Statistical Analysis Statistical analyses of time-related data were performed by two-way analysis of variance. Other data were analyzed by Student's t test or x2 test where appropriate. Probability values less than 0.05 were considered statistically significant. Data are expressed as mean 5 standard deviation of the mean.
W H
CwHwN&o*HCI = 516.0 2, 6 -dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine- 3, 5 - dicarboxylic acid 3- { 2-( N benzylN-methylamino); -ethyl ester 5-methyl ester hydrochloride
-
Fig 1. Chemical structure of nicardipine.
Variable Age (yr) Total bypass time (min) Aortic cross-clamp time (min) Temperatures ("C) Esophageal Rectal Spontaneous defibrillation (%) Inotropic support (%) a
Control Group
Nicardipine Group
p Value
&
4.8 f 3.3 84 f 33 49 f 23
NS NS NS
23 f 3 27 f 3 53.8 (7113)
22 f 4 26 f 3 75.0 (15/20)
NS NS NS
38.5 (5/13)
35.0 (7/20)
NS
4.4 68 40
3.0 23 f 17 f
Data are shown as the mean t standard deviation.
NS = not significant.
Results
There were no operative deaths, and all patients are alive and well after hospital discharge. Variables analyzed were age, total bypass time, aortic cross-clamp time, body temperatures, spontaneous defibrillation, use of inotropic agents, and early postoperative hemodynamics (Table 2). Ages ranged from 6 months to 10 years. Twelve patients were girls and 21 were boys. There were no significant differences in average age, total bypass time, aortic crossclamp time, body temperatures, incidence of spontaneous defibrillation, or use of inotropic agents between the two groups.
Postoperative Hemodynamics Selected hemodynamic variables at three hours after bypass are shown in Table 3. Heart rate, central venous pressure, and pulmonary capillary wedge pressure were nearly identical between the two groups. Mean arterial pressure was 70 & 13 mm Hg in the control group and 79 Table 3. Selected Hemodynamic Variables at Three Hours After Bypass" Hemodynamic Variable
Control Group
121 +. 19 Heart rate (beats/min) 9.3 f 2.6 CVP (mm Hg) 8.7 ? 3.2 PCWP (mm Hg) 70 ? 13 MAP (mm Hg) 2.80 f 0.84 Cardiac index (L/min/m2) 21.5 ? 14.3 LVSWI (g . m/ beats/m*) 2,000 2 671 SVRI (dynes * s * ~ m - ~ )
p
Nicardipine Group
Value
120 ? 17 8.9 f 2.9 7.7 f 2.8 79 f 13 4.00 f 0.89
NS NS NS NS <0.01
34.6
(0.05
f
15.3
1,566 f 434
NS
Data are shown as the mean t standard deviation. LVSWI = left ventricular stroke work CVP = central venous pressure; index; MAP = mean arterial pressure; NS = not significant; PCWP = pulmonary capillary wedge pressure; SVRI = systemic vascular resistance index.
415
MORIETAL NICARDIPINE CARDIOPLEGIA IN CHILDREN
Ann Thorac Surg 1990;49:413-8
IU/L 150 [
L/min/m2
.--+
T'
Control(N=13)
5t
Nicardipine(N=ZO)
Mean f lSEM
Y
$j100
-
Control (N=13)
0 1-
t-4
* p< 0.02 ** p
"E
P<0.05
50
2
Nicardipine (N=20)
.
'I-----
Mean 2 lSEM 0
---3
Before
1 3
12
6
Bypass
24
48 HR
After Bypass
Fig 4. Mean and standard error (SEM) of sequential serum CK-MB isozyme measurements in the postoperative period. The serum activity curve for 48 hours in the nicardipine group was significantly lower than that in the control group (p < 0.01 by analysis of variance). (*p < 0.05 versus the nicardipine group [by t test].) & 13 mm Hg in the nicardipine group, which was not significant. At a comparable preload and heart rate, however, the nicardipine group had a greater cardiac index (4.00 f 0.89 versus 2.80 f 0.84 L/min/m2) and left ventricular stroke work index (34.6 f 15.3 versus 21.5 f 14.3 g . m/beats/m2) than the control group. The time courses of two variables, cardiac index and pulmonary capillary wedge pressure, are shown in Figures 2 and 3. Postoperative cardiac indexes were 3.28 f 0.88 at 6 hours, 3.26 ? 0.66 at 12 hours, and 3.22 2 0.54 L/min/m2 at 24 hours in the control group, and 4.09 & 0.89 at 6 hours, 3.93 ? 0.59 at 12 hours, and 3.86 f 0.50 L/min/m2 at 24 hours in the nicardipine group. Cardiac indexes in the nicardipine group remained significantly higher than those in the control group during the 24-hour postoperative period ( p < 0.01 by analysis of variance). Pulmonary capillary wedge pressures were 9.1 f 3.1 at 6 hours, 9.0 f 2.9 at 12 hours, and 9.2 & 3.5 mm Hg at 24 hours in the control group, and 7.7 f 3.1 at 6 hours, 7.4 f 2.9 at 12 hours, and 6.6 f 3.0 mm Hg at 24 hours in the nicardipine group. Pulmonary capillary wedge pressures in the nicardipine group were significantly lower than
;"i tON
2
those in the control group ( p < 0.01 by analysis of variance). Heart rate and mean arterial pressure were statistically identical during the 24-hour study period. These data show that the nicardipine group had improved cardiac performance in the early postoperative period as compared with the control group.
Creatine Kinase M B Assays As an indicator of myocardial ischemic injury during operation, serial changes in serum CK-MB isozyme activity were monitored for 48 hours after termination of cardiopulmonary bypass (Fig 4). In the control group, the peak in average CK-MB activity was 121 f 97 IU/L at 12 hours after termination of cardiopulmonary bypass. In the nicardipine group, the peak activity was 78 & 50 IU/L at six hours. The serum CK-MB activity curve for 48 hours in the nicardipine group was significantly lower than that in the control group ( p < 0.01 by analysis of variance). For quantitative evaluation of myocardial leakage of CK-MB, the average peak CK-MB activity in individual patients and total CK-MB releases were calculated (Table 4). The total CK-MB release in the nicardipine group was significantly less than that of the control group ( p < 0.05), indicating less myocardial damage during cardioplegic arrest.
'-
Comment
-
In the last few years, numerous investigations of myocardial protection during cardiac operations have focused on
r--I--- --I ---------1 Control
P<0.05
Table 4. Quantitative Evaluation of Creatine Kinase M B Fraction Release"
c-4Nicardipine
Mean ? lSEM 3
6
12
24 HR
After Bypass
Fig 3. Mean and standard error (SEM) of sequential pulmonary capillay wedge pressure (PCWP) measurements in the postoperative period. Pulmona y capillary wedge pressures in the nicardipine group were lower than those in the control group during the postoperative 24 hours (p < 0.01 by analysis of variance). (*p < 0.05 versus the nicardipine group [by t test].)
Variable Peak CK-MB (IU/L) Total CK-MB release (IU/L)
Control Group
Nicardipine Group
140 2 90 272 ? 183
88 -+ 51 126 -+ 80b
*
Data are shown as the mean standard deviation. compared with the control group.
a
CK-MB = MB isoenzyme of creatine kinase.
p < 0.05 as
416
MORIETAL NICARDIPINE CARDIOPLEGIA IN CHILDREN
calcium metabolism during ischemia and reperfusion. In 1972, Shen and Jennings [8] first proposed the hypothesis that intracellular calcium influx was the critical event in the transition from reversible to irreversible tissue damage of ischemic and reperfused myocardium. The intracellular calcium overloading produces a deterioration of mitochondrial function, which can be quantitated in terms of a reduced oxidative phosphorylating activity and an impaired adenosine triphosphate-generating capacity [9]. In the ischemic myocardium, decrease in the tissue stores of adenosine triphosphate occurs through depressed aerobic glycolysis and impairs the integrity of cell membrane and the maintenance of intracellular calcium homeostasis [101. The excessive calcium influx leads to ischemic contracture, the ”stone heart” syndrome, which is a life-threatening event. Calcium is an essential element in the myocardial cell. It is required for integrity of cell membranes and the enzyme system and for activation of the contraction apparatus. Four pathways exist for calcium ions to enter the cell: passive diffusion, exchange with sodium, voltageactivated transport, and possibly also exchange with potassium. The calcium ions carried by these pathways to the interior of the myocardial cell generally serve as a chemical and electrical messenger. Calcium antagonists mainly inhibit entry of calcium ions during the plateau phase of the action potential and thereby exert a negative inotropic effect on the heart and cause vasodilatation in the vascular vessels [ll]. The elements necessary for effective myocardial protection during cardioplegic arrest play an important role: energy sparing by rapid induction of electromechanical cardiac arrest, slowing down of energy consumption during ischemia by hypothermia, and combating of harmful changes caused by ischemia and reperfusion with protective agents. Inadequate protection may have resulted from heterogeneous cardioplegic delivery, incomplete electrical and mechanical arrest, or loss of highenergy phosphates during ischemia. In view of these considerations, calcium antagonists may offer substantial advantages in myocardial protection during surgically induced arrest. The possible role of calcium antagonist cardioplegia appears to be that of ensuring homogeneous delivery of cardioplegic solution, profound electromechanical cardiac arrest, and preservation of high-energy phosphates through inhibition of intracellular calcium overload. Calcium antagonists are potent coronary vasodilators and have been reported to improve cardioplegic delivery in an animal model of limited coronary flow [12]. Persistent microfibrillatory electrical activity and resultant mechanical activity were reported despite apparently adequate hypothermic potassium cardioplegic arrest [13]. Calcium antagonists may augment the electrical and mechanical arrest achieved with hypothermia and potassium [l, 41. Preventing intracellular calcium accumulation reduces adenosine triphosphate hydrolysis, improves oxidative phosphorylation during reperfusion, and promotes adenosine triphosphate restoration [lo, 141. Experimental studies [4, 5, 151 have shown that calcium antagonists preserve high-energy phosphate stores after cardioplegic arrest.
Ann Thorac Surg
1990;49:41%3
The most widely used calcium antagonists (nifedipine, verapamil, and diltiazem) have been studied to evaluate their protective effects on myocardial ischemia and reperfusion in animals. Nicardipine is a dihydropyridine calcium antagonist similar to nifedipine and is as potent a coronary vasodilator as nifedipine. Hashimoto and associates [16] showed that nicardipine limited myocardial infarct size in baboons and dogs. Possible mechanisms of beneficial effects on the ischemic myocardium reported were an increase in myocardial oxygen tension, which is caused mainly by increased regional blood flow, and some direct protective effects on ischemic myocardial cells [17]. Nicardipine has much less effect on atrioventricular conduction and myocardial contractility than do verapamil and diltiazem [16]. With regard to myocardial protection during open heart operations, many investigators [l, 3-5, 12, 151 have reported additional protective effects of calcium antagonists as adjuncts to potassium cardioplegia in anesthetized animals and isolated perfused hearts of several species. In some studies, however, calcium antagonists did not significantly ameliorate protection by hypothermic potassium cardioplegia. Most of the negative studies were done by Hearse and colleagues [6], who reported a temperature dependency for the effectiveness of calcium antagonists and merely a redundant effect of the agent under conditions of hypothermia. On the other hand, Nayler [3] showed that the protective effects of hypothermia and nifedipine are additive, and the protective effect of nifedipine was more demonstrable in an extended period of ischemia. Boe and co-workers [18] reported that nifedipine in combination with hypothermic potassium cardioplegia effectively controlled myocardial calcium sequestration during ischemia and reperfusion. Few clinical trials of calcium antagonists added to a cardioplegic solution have been published. Clark and associates reported the first clinical experience with nifedipine cardioplegia [2] and later reported that nifedipine and cold potassium cardioplegia improved cardiac performance immediately after operation and reduced the incidence of acute low cardiac output death in a group of high-risk patients [19]. Hicks and colleagues [20] reported that verapamil in cold potassium cardioplegia and nifedipine instituted postoperatively resulted in a reduction in postoperative creatine kinase release and fatal arrhythmias. Grondin and colleagues [21] reported excellent protective effects of diltiazem as the sole arresting agent in cold crystalloid cardioplegia in patients undergoing coronary artery bypass grafting. The potential benefits of calcium antagonist cardioplegia must be balanced by the potential risks. Christakis and colleagues [22] documented that diltiazem cardioplegia may not be beneficial for patients with poor ventricular function because diltiazem was a potent negative inotrope and produced prolonged electromechanical arrest. In the present study using nicardipine cardioplegia, however, there was no deterioration in ventricular function or atrioventricular conduction in the perioperative and postoperative periods. Age-related differences appear to exist with respect to myocardial calcium metabolism. These differences include affinity of the sarcoplasmic reticulum for calcium ion, the
Ann Thorac Surg 1990;49:41>8
calcium regulatory function of the sarcolemma, the relative inotropic response to exogenous calcium, and the effect of hypoxia on calcium influx and resulting depression of contractile function [23, 241. Boucek and associates [25] found a greater sensitivity to calcium antagonists in the immature heart. Lupinetti and co-workers [15] showed that addition of verapamil to a potassium cardioplegic solution enhanced myocardial protection in the immature canine heart after normothermic global ischemia. In our clinical trial, addition of nicardipine to a cold potassium cardioplegic solution improved immediate postoperative cardiac performance and lessened myocardial CK-MB release in children undergoing surgical repair of congenital heart diseases. A dose of 0.25 mg of nicardipine in 1 L of cardioplegic solution did not produce the disadvantageous sequelae of calcium antagonists clinically. These results suggest the usefulness of nicardipine as an adjunct to potassium cardioplegia for cardiac surgery in children.
References 1. Magovern GJ, Dixon CM, Burkholder JA. Improved myocardial protection with nifedipine and potassium-based cardioplegia. J Thorac Cardiovasc Surg 1981;82:23944. 2. Clark RE, Christlieb IY, Ferguson TB, et al. The first American clinical trial of nifedipine in cardioplegia. A report of the first 12-month experience. J Thorac Cardiovasc Surg 1981;82: 848-59. 3. Nayler WG. Protection of the myocardium against postischemic reperfusion damage. The combined effect of hypothermia and nifedipine. J Thorac Cardiovasc Surg 1982;84: 897-905. 4. Standeven JW, Jellinek M, Menz LJ, Kolata RJ, Barner HB. Cold blood potassium diltiazem cardioplegia. J Thorac Cardiovasc Surg 1984;87:201-12. 5. Balderman SC, Chan AK, Gage AA. Verapamil cardioplegia: improved myocardial preservation during global ischemia. J Thorac Cardiovasc Surg 1984;88:5746. 6. Hearse DJ, Yamamoto F, Shattock MJ. Calcium antagonists and hypothermia: the temperature dependency of the negative inotropic and anti-ischemic properties of verapamil in the isolated rat heart. Circulation 1984;7O(Suppl 1):54-64. 7. Shell WE, Sobel BE. Biochemical markers of ischemic injury. Circulation 1976;53(Suppl 1):98-106. 8. Shen AC, Jennings RB. Kinetics of calcium accumulation in acute myocardial ischemic injury. Am J Pathol 1972;67: 441-52. 9. Murphy JG, Marsh JD, Smith TW. The role of calcium in ischemic myocardial injury. Circulation 1987;75(Suppl 5): 15-24. 10. Nayler WG, Ferrari R, Williams A. The protective effect of pretreatment with verapamil, nifedipine and propranolol on mitochondria1 function in the ischemic and reperfused myocardium. Am J Cardiol 1980;46:242-8.
MORIETAL NICARDIPINE CARDIOPLEGIA IN CHILDREN
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11. Katz AM, Pappano AJ, Messineo FC, Smilowitz H, NashAdler P. Calcium channel blocking drugs. In: Fozzard HA, Haber E, Jenning RB, Katz AM, Morgan HE, eds. The heart and cardiovascular system. New York: Raven Press, 1986: 1597-611. 12. Guyton RA, Dorsey LM, Colgan TK, Hatcher CR. Calciumchannel blockade as an adjunct to heterogenous delivery of cardioplegia. Ann Thorac Surg 1983;35:62&32. 13. Tchervenkov CI, Wynands JE, Symes JF, Malcolm ID, Dobell ARC, Morin JE. Electrical behavior of the heart following high-potassium cardioplegia. Ann Thorac Surg 1983;36: 314-9. 14. Jolly SR, Mehahan LA, Gross GJ. Diltiazem in myocardial recovery from global ischemia and reperfusion. J Mol Cell Cardiol 1981;13:359-72. 15. Lupinetti FM, Hammon JW, Huddleston CB, Boucek RJ, Bender HW. Global ischemia in the immature canine ventricle. Enhanced protective effect of verapamil and potassium. J Thorac Cardiovasc Surg 1984;87:213-9. 16. Endo T, Nejima J, Fujita S, et al. Comparative effects of nicardipine, a new calcium antagonist, on size of myocardial infarction after coronary artery occlusion in dogs. Circulation 1986;74:42@-30. 17. Hashimoto H, Asano M, Takiguchi Y, Katoh H, Nakashima M. Effects of nicardipine, a dihydropyridine calcium antagonist, on regional myocardial blood flow, myocardial oxygen tension, and electrical abnormalities during acute coronary artery occlusion in dogs. J Cardiovasc Pharmacol 1985;7: 613-21. 18. Boe SL, Dixon CM, Sakert TA, Magovern GJ. The control of myocardial Ca++ sequestration with nifedipine cardioplegia. J Thorac Cardiovasc Surg 1982;84:678-84. 19. Clark RE, Magovern GJ, Christlieb IY, Boe SL. Nifedipine cardioplegia experience: results of a 3-year co-operative clinical study. Ann Thorac Surg 1983;36:65+63. 20. Hicks GL Jr, Salley RK, DeWeese JA. Calcium channel blockers: an intraoperative and postoperative trial in women. Ann Thorac Surg 1984;37:319-23. 21. Grondin CM, Poman JL, Vouhe PR, Hebert Y. Cold cardioplegia with diltiazem, a calcium channel blocker, during coronary revascularization [Abstract]. J Cardiovasc Surg 1983;24:291. 22. Christakis GT, Fremes SE, Weisel RD, et al. Diltiazem cardioplegia: a balance of risk and benefit. J Thorac Cardiovasc Surg 1986;91:647-61. 23. Nishioka K, Nakanishi T, George BL, Jarmakani JM. The effect of calcium on the inotropy of catecholamine and paired electrical stimulation in the newborn and adult myocardium. J Mol Cell Cardiol 1981;13:511-20. 24. Nakanishi T, Young HH, Shimiza T, Nishioka K, Jarmakani JM. Effects of hypoxia and reoxygenation(re-0,) on creatine kinase (CK) release and tissue Ca uptake in the newborn myocardium [Abstract]. Pediatr Res 1981;15:468. 25. Boucek RJ Jr, Shelton M, Artman M, Musklin PS, Starnes VA, Olson RD. Comparative effects of verapamil, nifedipine and diltiazem on contractile function in the isolated immature and adult rabbit heart. Pediatr Res 1984;18:948-52.
INVITED COMMENTARY In this article Mori and colleagues examined the effectiveness of nicardipine as an additive to cardioplegic arrest in pediatric cardiac surgery. It was concluded that nicardipine offers additional protection for the myocardium. This conclusion was based on the observations that (1)
indices of mechanical function were improved by nicardipine three to 24 hours after reperfusion and (2) reperfusion-induced elevation of serum CK-MB level was reduced by nicardipine. Is this conclusion justified? In my view it is not.
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MORIETAL NICARDIPINE CARDIOPLEGIA IN CHILDREN
48h Time aiter reperfusion
48h
Time aHer reperfusion
Fig I . Hypothetical relationship between recovery of cardiac function (eg, cardiac output or slope of the Frank-Starling curve) and time after reperfusion. Filled circles are controls and open circles represent an intervention group. In (A) the intervention is shown providing sustained improvement of function. In ( B ) the intervention is shown providing transient protection representing an action best described as a hastening of recovey from stunning. Note that comparative assessment of function at least two days after reperfusion (sufficient to allow a stable level of function to be reached) is necessay to allow distinction between these alternative effcts [31. Part (A) defines a type-A intervention as one providing additional protection to that resulting from recovey from stunning. Part (B)defines a type-B intervention as one that merely hastens recovery from stunning.
There are two pieces of information pertaining to Mori and colleagues’ data that must be emphasized. First, hemodynamic status was monitored for only 24 hours during reperfusion. Second, “all patients are alive and well after hospital discharge.” It is unquestionably the case that survival and good health are ultimate arbiters of the adequacy of myocardial protection. Therefore the present study indicates that although laboratory indices of myocardial function were improved by nicardipine in the short term, the ability of the myocardium to function effectively in the long term was de facto unmodified. In view of this apparent paradox a degree of circumspection is appropriate in the interpretation of the data. A factor not considered by Mori and colleagues but that may have considerable relevance to the present study is myocardial stunning [11. Recovery of myocardial function during reperfusion often requires several days for completion [2]. Bolli and associates (3, 41 have shown that even when ischemia-induced mechanical dysfunction is 100% reversible it takes at least 48 hours of reperfusion for systolic and diastolic function to recover maximally from
Ann Thorac Surg 1990;49:413-8
stunning. Mechanical function was monitored only during the first 24 hours of reperfusion in the present study. This does not permit an assessment of whether the hemodynamic improvement provided by nicardipine was sustained or whether the effect of nicardipine merely reflected a hastening of recovery from stunning. In Figure 1 I have defined a type-A intervention as one that provides additional protection to that resulting from recovery from stunning and a type-B intervention as one that merely hastens recovery from stunning. If we accept that equivalent patient survival and recovery of health both with and without nicardipine is indicative of equivalent recovery of myocardial function, then it could be argued from the data of Mori and associates that nicardipine is more likely to be a type-B intervention than a type-A. However, in reality it is not possible to draw any definite conclusion from the present data because cardiac function was not assessed after 24 hours. If it were the case that ultimate recovery from stunning in the drug-free control patients was 100% then the present protocol could be criticized on the grounds that it offered no scope for distinguishing between type-A and type-B activity, because demonstration of type-A activity requires a recovery of function in controls of less than 100%. Finally, if we consider the obvious improvement in laboratory variables (hemodynamic status and CK-MB release) afforded by nicardipine during the first 24 hours of reperfusion in relation to the final clinical outcome then two factors arise. First, it would appear that the laboratory variables have no prognostic significance in the present setting, and second, it would seem clear that the protocol of cardioplegia presently employed is perfectly adequate and without the need for any additives.
Michael 1. Curtis, PhD Cardiovascular Research Laboratories Department of Pharmacology Division of Biomedical Sciences King‘s College London Manresa Rd London SW3 6 L X , United Kingdom
References 1. Heyndrickx GR, Millard RW, McRitchie RJ, Maroko PR, Vatner SF. Regional myocardial function and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest 1975;56:978-85. 2. Braunwald E, Kloner RA. The stunned myocardium: prolonged postischemic ventricular dysfunction. Circulation 1982;66:1146-9. 3. Bolli R, Zhu WX, Thornby JI, ONeill PG, Roberts R. Timecourse and determinants of recovery of function after reversible ischemia in conscious dogs. Am J Physiol 1988;254: H102-14. 4. Bolli R, Jeroudi MO, Patel BS, et al. Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial “stunning” is a manifestation of reperfusion injury. Circ Res 1989;65:607-22.
To clarify the effectiveness of nicardipine, one of the dihydropyridine calcium-channel blockers, for myocardial protection during cold potassium cardioplegic arrest in pediatric cardiac surgery, a clinical trial of nicardipine (0.25 mg/L) added to potassium cardioplegic solution was performed in children undergoing surgical repair of congenital heart diseases. Twenty patients were selected to receive nicardipine cardioplegia and 13 patients received a standard potassium cardioplegia, serving as a
F
or the last decade, cold potassium cardioplegia has been widely accepted as protecting the ischemic myocardium during cardiac operations. This cardioplegia is not optimal, however, and further improvement of myocardial protection is needed. More recently, slowcalcium-channel blockers have been suggested to provide additional protection when included in cardioplegic solutions used during aortic cross-clamping [ 1-51. Slow-calcium-channel blockers, which inhibit the influx of calcium ions into myocardial cells by blockade of the slow channel, provide myocardial electrical arrest and are potent coronary vasodilators. In addition, slow-calcium-channel blockers may provide a cytoprotective effect by inhibiting calcium overload in the ischemic myocardium. Use of calcium-channel blockers is still controversial, however. Recent reports [6] have suggested that calciumchannel blockers failed to afford any additional protection because of a temperature dependency for the effectiveness of these agents when used under the clinically relevant condition of hypothermic ischemic arrest in cardiac surgery. Furthermore, little is known regarding clinical use of calcium antagonists for intraoperative myocardial protection in children with congenital heart disease. The present study was designed to evaluate the efficacy of nicardipine, one of the dihydropyridine calcium-channel blockers, for myocardial protection during hypothermic cardioplegic arrest in pediatric cardiac surgery.
Material and Methods Thirty-three patients aged less than 10 years underwent repair of a variety of types of congenital heart disease at Yamaguchi University Hospital from September 1986 to May 1987. Patients were randomly assigned by hospital Accepted for publication Sep 27, 1989. Address reprint requests to Dr Mori, First Department of Surgery, Yamaguchi University School of Medicine, Ube, Yamaguchi 755, Japan.
0 1990 by The Society of Thoracic Surgeons
control group. Nicardipine cardioplegia provided better cardiac performance in the early postoperative period and reduced release of the MB isozyme of creatine kinase, as determined during a 46-hour postoperative period. These results suggest that nicardipine added to cold potassium cardioplegic solution offers additional protection for the myocardium during ischemia and postischemic reperfusion in pediatric cardiac surgery. (Ann Thorac Surg 1990;49:413-8)
number to one of two groups. Twenty patients received nicardipine in cardioplegic solution and 13 patients received our standard cardioplegic solution as a control group. The study protocol was approved by the institutional human research committee at Yamaguchi University Hospital. Type of operation and number of patients are shown in Table 1. On the whole, there were no differences in the severity and complexity of disease between the two patient groups.
Operative Technique After performance of a median sternotomy, the aorta was cannulated at the ascending aorta, and the superior and inferior venae cavae were cannulated through the right atrium. Cardiopulmonary bypass was established with a standard bubble oxygenator and roller pump at flows of 2.0 to 2.5 L/min/m2. Hypothermic perfusion was used to cool the patients to 25°C or less. In all patients, myocardial protection during aortic cross-clamping was assured by the combination of cold potassium cardioplegia and topical cooling of the heart with ice-cold saline solution. The composition of the cardioplegic solution was as follows: Na, 25.2 mEq/L; K, 23.0 mEq/L; Mg, 5.0 mEq/L; C1, 26.6 mEq/L; glucose, 48.1 g/L; Tris buffer, 3.0 mM; pH (37"C), 7.4; osmolarity, 345 mosm. The cardioplegic solution was infused into the aortic root at an initial volume of 15 mL/kg of body weight, and an additional 10 mL/kg of cardioplegic solution was infused every 20 minutes during aortic clamping. The patients in the nicardipine group received cardioplegic solution containing 0.25 mg/L of nicardipine (Fig 1).
Postoperative Care After termination of cardiopulmonary bypass, a SwanGanz catheter was inserted into the pulmonary artery to determine cardiac output postoperatively by thermodilution method, using in each instance the means of triplicate measurements. During the first 24 hours after operation, 0003-4975/90/$3.50
414
MORIETAL NICARDII'INE CARDIOPLEGIA IN CHILDREN
Ann Thorac Surg 1990;49:4134
Table 1. Profile of Operations and Number of Patients Control Group
Operations Atrial septal defect Ventricular septal defect Pulmonary stenosis Endocardia1 cushion defect Tetralogy of Fallot Fontan operation Total
Table 2 . Variables in 33 Study Patients"
Nicardipine Group
3 6 2 1 1 0
1 10 2 3 3 1
13
20
intravenous fluid was restricted to 750 mL/m2/24 h and blood, plasma, or both was transfused to maintain hemodynamic stability and hematocrit at approximately 35%. Arterial pressure, central venous pressure, and pulmonary arterial pressure were monitored continuously during the early postoperative period. Twelve patients required inotropic support with 5 to 15 pg/kg/min of dopamine or dobutamine, and 3 of them required combined use of vasodilators. As an indicator of myocardial injury during operation, serial changes in serum activity of the MB isoenzyme of creatine kinase (CK-MB) were measured for 48 hours after termination of cardiopulmonary bypass. Creatine kinase activity was determined by a spectrophotometric kinetic method, and the isozymes were separated according to the electrophoresis technique. The total amount of CK-MB release was calculated by the following formula [7]: Total CK-MB release (IU/L) = E(T) + kdJE(t)dt, where total CK-MB release = cumulative activity of CK-MB released by heart up to time T, E(t) = activity of CK-MB in serum (IU/L)at time t, and kd = the fractional rate of disappearance of CK-MB from blood. Statistical Analysis Statistical analyses of time-related data were performed by two-way analysis of variance. Other data were analyzed by Student's t test or x2 test where appropriate. Probability values less than 0.05 were considered statistically significant. Data are expressed as mean 5 standard deviation of the mean.
W H
CwHwN&o*HCI = 516.0 2, 6 -dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine- 3, 5 - dicarboxylic acid 3- { 2-( N benzylN-methylamino); -ethyl ester 5-methyl ester hydrochloride
-
Fig 1. Chemical structure of nicardipine.
Variable Age (yr) Total bypass time (min) Aortic cross-clamp time (min) Temperatures ("C) Esophageal Rectal Spontaneous defibrillation (%) Inotropic support (%) a
Control Group
Nicardipine Group
p Value
&
4.8 f 3.3 84 f 33 49 f 23
NS NS NS
23 f 3 27 f 3 53.8 (7113)
22 f 4 26 f 3 75.0 (15/20)
NS NS NS
38.5 (5/13)
35.0 (7/20)
NS
4.4 68 40
3.0 23 f 17 f
Data are shown as the mean t standard deviation.
NS = not significant.
Results
There were no operative deaths, and all patients are alive and well after hospital discharge. Variables analyzed were age, total bypass time, aortic cross-clamp time, body temperatures, spontaneous defibrillation, use of inotropic agents, and early postoperative hemodynamics (Table 2). Ages ranged from 6 months to 10 years. Twelve patients were girls and 21 were boys. There were no significant differences in average age, total bypass time, aortic crossclamp time, body temperatures, incidence of spontaneous defibrillation, or use of inotropic agents between the two groups.
Postoperative Hemodynamics Selected hemodynamic variables at three hours after bypass are shown in Table 3. Heart rate, central venous pressure, and pulmonary capillary wedge pressure were nearly identical between the two groups. Mean arterial pressure was 70 & 13 mm Hg in the control group and 79 Table 3. Selected Hemodynamic Variables at Three Hours After Bypass" Hemodynamic Variable
Control Group
121 +. 19 Heart rate (beats/min) 9.3 f 2.6 CVP (mm Hg) 8.7 ? 3.2 PCWP (mm Hg) 70 ? 13 MAP (mm Hg) 2.80 f 0.84 Cardiac index (L/min/m2) 21.5 ? 14.3 LVSWI (g . m/ beats/m*) 2,000 2 671 SVRI (dynes * s * ~ m - ~ )
p
Nicardipine Group
Value
120 ? 17 8.9 f 2.9 7.7 f 2.8 79 f 13 4.00 f 0.89
NS NS NS NS <0.01
34.6
(0.05
f
15.3
1,566 f 434
NS
Data are shown as the mean t standard deviation. LVSWI = left ventricular stroke work CVP = central venous pressure; index; MAP = mean arterial pressure; NS = not significant; PCWP = pulmonary capillary wedge pressure; SVRI = systemic vascular resistance index.
415
MORIETAL NICARDIPINE CARDIOPLEGIA IN CHILDREN
Ann Thorac Surg 1990;49:413-8
IU/L 150 [
L/min/m2
.--+
T'
Control(N=13)
5t
Nicardipine(N=ZO)
Mean f lSEM
Y
$j100
-
Control (N=13)
0 1-
t-4
* p< 0.02 ** p
"E
P<0.05
50
2
Nicardipine (N=20)
.
'I-----
Mean 2 lSEM 0
---3
Before
1 3
12
6
Bypass
24
48 HR
After Bypass
Fig 4. Mean and standard error (SEM) of sequential serum CK-MB isozyme measurements in the postoperative period. The serum activity curve for 48 hours in the nicardipine group was significantly lower than that in the control group (p < 0.01 by analysis of variance). (*p < 0.05 versus the nicardipine group [by t test].) & 13 mm Hg in the nicardipine group, which was not significant. At a comparable preload and heart rate, however, the nicardipine group had a greater cardiac index (4.00 f 0.89 versus 2.80 f 0.84 L/min/m2) and left ventricular stroke work index (34.6 f 15.3 versus 21.5 f 14.3 g . m/beats/m2) than the control group. The time courses of two variables, cardiac index and pulmonary capillary wedge pressure, are shown in Figures 2 and 3. Postoperative cardiac indexes were 3.28 f 0.88 at 6 hours, 3.26 ? 0.66 at 12 hours, and 3.22 2 0.54 L/min/m2 at 24 hours in the control group, and 4.09 & 0.89 at 6 hours, 3.93 ? 0.59 at 12 hours, and 3.86 f 0.50 L/min/m2 at 24 hours in the nicardipine group. Cardiac indexes in the nicardipine group remained significantly higher than those in the control group during the 24-hour postoperative period ( p < 0.01 by analysis of variance). Pulmonary capillary wedge pressures were 9.1 f 3.1 at 6 hours, 9.0 f 2.9 at 12 hours, and 9.2 & 3.5 mm Hg at 24 hours in the control group, and 7.7 f 3.1 at 6 hours, 7.4 f 2.9 at 12 hours, and 6.6 f 3.0 mm Hg at 24 hours in the nicardipine group. Pulmonary capillary wedge pressures in the nicardipine group were significantly lower than
;"i tON
2
those in the control group ( p < 0.01 by analysis of variance). Heart rate and mean arterial pressure were statistically identical during the 24-hour study period. These data show that the nicardipine group had improved cardiac performance in the early postoperative period as compared with the control group.
Creatine Kinase M B Assays As an indicator of myocardial ischemic injury during operation, serial changes in serum CK-MB isozyme activity were monitored for 48 hours after termination of cardiopulmonary bypass (Fig 4). In the control group, the peak in average CK-MB activity was 121 f 97 IU/L at 12 hours after termination of cardiopulmonary bypass. In the nicardipine group, the peak activity was 78 & 50 IU/L at six hours. The serum CK-MB activity curve for 48 hours in the nicardipine group was significantly lower than that in the control group ( p < 0.01 by analysis of variance). For quantitative evaluation of myocardial leakage of CK-MB, the average peak CK-MB activity in individual patients and total CK-MB releases were calculated (Table 4). The total CK-MB release in the nicardipine group was significantly less than that of the control group ( p < 0.05), indicating less myocardial damage during cardioplegic arrest.
'-
Comment
-
In the last few years, numerous investigations of myocardial protection during cardiac operations have focused on
r--I--- --I ---------1 Control
P<0.05
Table 4. Quantitative Evaluation of Creatine Kinase M B Fraction Release"
c-4Nicardipine
Mean ? lSEM 3
6
12
24 HR
After Bypass
Fig 3. Mean and standard error (SEM) of sequential pulmonary capillay wedge pressure (PCWP) measurements in the postoperative period. Pulmona y capillary wedge pressures in the nicardipine group were lower than those in the control group during the postoperative 24 hours (p < 0.01 by analysis of variance). (*p < 0.05 versus the nicardipine group [by t test].)
Variable Peak CK-MB (IU/L) Total CK-MB release (IU/L)
Control Group
Nicardipine Group
140 2 90 272 ? 183
88 -+ 51 126 -+ 80b
*
Data are shown as the mean standard deviation. compared with the control group.
a
CK-MB = MB isoenzyme of creatine kinase.
p < 0.05 as
416
MORIETAL NICARDIPINE CARDIOPLEGIA IN CHILDREN
calcium metabolism during ischemia and reperfusion. In 1972, Shen and Jennings [8] first proposed the hypothesis that intracellular calcium influx was the critical event in the transition from reversible to irreversible tissue damage of ischemic and reperfused myocardium. The intracellular calcium overloading produces a deterioration of mitochondrial function, which can be quantitated in terms of a reduced oxidative phosphorylating activity and an impaired adenosine triphosphate-generating capacity [9]. In the ischemic myocardium, decrease in the tissue stores of adenosine triphosphate occurs through depressed aerobic glycolysis and impairs the integrity of cell membrane and the maintenance of intracellular calcium homeostasis [101. The excessive calcium influx leads to ischemic contracture, the ”stone heart” syndrome, which is a life-threatening event. Calcium is an essential element in the myocardial cell. It is required for integrity of cell membranes and the enzyme system and for activation of the contraction apparatus. Four pathways exist for calcium ions to enter the cell: passive diffusion, exchange with sodium, voltageactivated transport, and possibly also exchange with potassium. The calcium ions carried by these pathways to the interior of the myocardial cell generally serve as a chemical and electrical messenger. Calcium antagonists mainly inhibit entry of calcium ions during the plateau phase of the action potential and thereby exert a negative inotropic effect on the heart and cause vasodilatation in the vascular vessels [ll]. The elements necessary for effective myocardial protection during cardioplegic arrest play an important role: energy sparing by rapid induction of electromechanical cardiac arrest, slowing down of energy consumption during ischemia by hypothermia, and combating of harmful changes caused by ischemia and reperfusion with protective agents. Inadequate protection may have resulted from heterogeneous cardioplegic delivery, incomplete electrical and mechanical arrest, or loss of highenergy phosphates during ischemia. In view of these considerations, calcium antagonists may offer substantial advantages in myocardial protection during surgically induced arrest. The possible role of calcium antagonist cardioplegia appears to be that of ensuring homogeneous delivery of cardioplegic solution, profound electromechanical cardiac arrest, and preservation of high-energy phosphates through inhibition of intracellular calcium overload. Calcium antagonists are potent coronary vasodilators and have been reported to improve cardioplegic delivery in an animal model of limited coronary flow [12]. Persistent microfibrillatory electrical activity and resultant mechanical activity were reported despite apparently adequate hypothermic potassium cardioplegic arrest [13]. Calcium antagonists may augment the electrical and mechanical arrest achieved with hypothermia and potassium [l, 41. Preventing intracellular calcium accumulation reduces adenosine triphosphate hydrolysis, improves oxidative phosphorylation during reperfusion, and promotes adenosine triphosphate restoration [lo, 141. Experimental studies [4, 5, 151 have shown that calcium antagonists preserve high-energy phosphate stores after cardioplegic arrest.
Ann Thorac Surg
1990;49:41%3
The most widely used calcium antagonists (nifedipine, verapamil, and diltiazem) have been studied to evaluate their protective effects on myocardial ischemia and reperfusion in animals. Nicardipine is a dihydropyridine calcium antagonist similar to nifedipine and is as potent a coronary vasodilator as nifedipine. Hashimoto and associates [16] showed that nicardipine limited myocardial infarct size in baboons and dogs. Possible mechanisms of beneficial effects on the ischemic myocardium reported were an increase in myocardial oxygen tension, which is caused mainly by increased regional blood flow, and some direct protective effects on ischemic myocardial cells [17]. Nicardipine has much less effect on atrioventricular conduction and myocardial contractility than do verapamil and diltiazem [16]. With regard to myocardial protection during open heart operations, many investigators [l, 3-5, 12, 151 have reported additional protective effects of calcium antagonists as adjuncts to potassium cardioplegia in anesthetized animals and isolated perfused hearts of several species. In some studies, however, calcium antagonists did not significantly ameliorate protection by hypothermic potassium cardioplegia. Most of the negative studies were done by Hearse and colleagues [6], who reported a temperature dependency for the effectiveness of calcium antagonists and merely a redundant effect of the agent under conditions of hypothermia. On the other hand, Nayler [3] showed that the protective effects of hypothermia and nifedipine are additive, and the protective effect of nifedipine was more demonstrable in an extended period of ischemia. Boe and co-workers [18] reported that nifedipine in combination with hypothermic potassium cardioplegia effectively controlled myocardial calcium sequestration during ischemia and reperfusion. Few clinical trials of calcium antagonists added to a cardioplegic solution have been published. Clark and associates reported the first clinical experience with nifedipine cardioplegia [2] and later reported that nifedipine and cold potassium cardioplegia improved cardiac performance immediately after operation and reduced the incidence of acute low cardiac output death in a group of high-risk patients [19]. Hicks and colleagues [20] reported that verapamil in cold potassium cardioplegia and nifedipine instituted postoperatively resulted in a reduction in postoperative creatine kinase release and fatal arrhythmias. Grondin and colleagues [21] reported excellent protective effects of diltiazem as the sole arresting agent in cold crystalloid cardioplegia in patients undergoing coronary artery bypass grafting. The potential benefits of calcium antagonist cardioplegia must be balanced by the potential risks. Christakis and colleagues [22] documented that diltiazem cardioplegia may not be beneficial for patients with poor ventricular function because diltiazem was a potent negative inotrope and produced prolonged electromechanical arrest. In the present study using nicardipine cardioplegia, however, there was no deterioration in ventricular function or atrioventricular conduction in the perioperative and postoperative periods. Age-related differences appear to exist with respect to myocardial calcium metabolism. These differences include affinity of the sarcoplasmic reticulum for calcium ion, the
Ann Thorac Surg 1990;49:41>8
calcium regulatory function of the sarcolemma, the relative inotropic response to exogenous calcium, and the effect of hypoxia on calcium influx and resulting depression of contractile function [23, 241. Boucek and associates [25] found a greater sensitivity to calcium antagonists in the immature heart. Lupinetti and co-workers [15] showed that addition of verapamil to a potassium cardioplegic solution enhanced myocardial protection in the immature canine heart after normothermic global ischemia. In our clinical trial, addition of nicardipine to a cold potassium cardioplegic solution improved immediate postoperative cardiac performance and lessened myocardial CK-MB release in children undergoing surgical repair of congenital heart diseases. A dose of 0.25 mg of nicardipine in 1 L of cardioplegic solution did not produce the disadvantageous sequelae of calcium antagonists clinically. These results suggest the usefulness of nicardipine as an adjunct to potassium cardioplegia for cardiac surgery in children.
References 1. Magovern GJ, Dixon CM, Burkholder JA. Improved myocardial protection with nifedipine and potassium-based cardioplegia. J Thorac Cardiovasc Surg 1981;82:23944. 2. Clark RE, Christlieb IY, Ferguson TB, et al. The first American clinical trial of nifedipine in cardioplegia. A report of the first 12-month experience. J Thorac Cardiovasc Surg 1981;82: 848-59. 3. Nayler WG. Protection of the myocardium against postischemic reperfusion damage. The combined effect of hypothermia and nifedipine. J Thorac Cardiovasc Surg 1982;84: 897-905. 4. Standeven JW, Jellinek M, Menz LJ, Kolata RJ, Barner HB. Cold blood potassium diltiazem cardioplegia. J Thorac Cardiovasc Surg 1984;87:201-12. 5. Balderman SC, Chan AK, Gage AA. Verapamil cardioplegia: improved myocardial preservation during global ischemia. J Thorac Cardiovasc Surg 1984;88:5746. 6. Hearse DJ, Yamamoto F, Shattock MJ. Calcium antagonists and hypothermia: the temperature dependency of the negative inotropic and anti-ischemic properties of verapamil in the isolated rat heart. Circulation 1984;7O(Suppl 1):54-64. 7. Shell WE, Sobel BE. Biochemical markers of ischemic injury. Circulation 1976;53(Suppl 1):98-106. 8. Shen AC, Jennings RB. Kinetics of calcium accumulation in acute myocardial ischemic injury. Am J Pathol 1972;67: 441-52. 9. Murphy JG, Marsh JD, Smith TW. The role of calcium in ischemic myocardial injury. Circulation 1987;75(Suppl 5): 15-24. 10. Nayler WG, Ferrari R, Williams A. The protective effect of pretreatment with verapamil, nifedipine and propranolol on mitochondria1 function in the ischemic and reperfused myocardium. Am J Cardiol 1980;46:242-8.
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11. Katz AM, Pappano AJ, Messineo FC, Smilowitz H, NashAdler P. Calcium channel blocking drugs. In: Fozzard HA, Haber E, Jenning RB, Katz AM, Morgan HE, eds. The heart and cardiovascular system. New York: Raven Press, 1986: 1597-611. 12. Guyton RA, Dorsey LM, Colgan TK, Hatcher CR. Calciumchannel blockade as an adjunct to heterogenous delivery of cardioplegia. Ann Thorac Surg 1983;35:62&32. 13. Tchervenkov CI, Wynands JE, Symes JF, Malcolm ID, Dobell ARC, Morin JE. Electrical behavior of the heart following high-potassium cardioplegia. Ann Thorac Surg 1983;36: 314-9. 14. Jolly SR, Mehahan LA, Gross GJ. Diltiazem in myocardial recovery from global ischemia and reperfusion. J Mol Cell Cardiol 1981;13:359-72. 15. Lupinetti FM, Hammon JW, Huddleston CB, Boucek RJ, Bender HW. Global ischemia in the immature canine ventricle. Enhanced protective effect of verapamil and potassium. J Thorac Cardiovasc Surg 1984;87:213-9. 16. Endo T, Nejima J, Fujita S, et al. Comparative effects of nicardipine, a new calcium antagonist, on size of myocardial infarction after coronary artery occlusion in dogs. Circulation 1986;74:42@-30. 17. Hashimoto H, Asano M, Takiguchi Y, Katoh H, Nakashima M. Effects of nicardipine, a dihydropyridine calcium antagonist, on regional myocardial blood flow, myocardial oxygen tension, and electrical abnormalities during acute coronary artery occlusion in dogs. J Cardiovasc Pharmacol 1985;7: 613-21. 18. Boe SL, Dixon CM, Sakert TA, Magovern GJ. The control of myocardial Ca++ sequestration with nifedipine cardioplegia. J Thorac Cardiovasc Surg 1982;84:678-84. 19. Clark RE, Magovern GJ, Christlieb IY, Boe SL. Nifedipine cardioplegia experience: results of a 3-year co-operative clinical study. Ann Thorac Surg 1983;36:65+63. 20. Hicks GL Jr, Salley RK, DeWeese JA. Calcium channel blockers: an intraoperative and postoperative trial in women. Ann Thorac Surg 1984;37:319-23. 21. Grondin CM, Poman JL, Vouhe PR, Hebert Y. Cold cardioplegia with diltiazem, a calcium channel blocker, during coronary revascularization [Abstract]. J Cardiovasc Surg 1983;24:291. 22. Christakis GT, Fremes SE, Weisel RD, et al. Diltiazem cardioplegia: a balance of risk and benefit. J Thorac Cardiovasc Surg 1986;91:647-61. 23. Nishioka K, Nakanishi T, George BL, Jarmakani JM. The effect of calcium on the inotropy of catecholamine and paired electrical stimulation in the newborn and adult myocardium. J Mol Cell Cardiol 1981;13:511-20. 24. Nakanishi T, Young HH, Shimiza T, Nishioka K, Jarmakani JM. Effects of hypoxia and reoxygenation(re-0,) on creatine kinase (CK) release and tissue Ca uptake in the newborn myocardium [Abstract]. Pediatr Res 1981;15:468. 25. Boucek RJ Jr, Shelton M, Artman M, Musklin PS, Starnes VA, Olson RD. Comparative effects of verapamil, nifedipine and diltiazem on contractile function in the isolated immature and adult rabbit heart. Pediatr Res 1984;18:948-52.
INVITED COMMENTARY In this article Mori and colleagues examined the effectiveness of nicardipine as an additive to cardioplegic arrest in pediatric cardiac surgery. It was concluded that nicardipine offers additional protection for the myocardium. This conclusion was based on the observations that (1)
indices of mechanical function were improved by nicardipine three to 24 hours after reperfusion and (2) reperfusion-induced elevation of serum CK-MB level was reduced by nicardipine. Is this conclusion justified? In my view it is not.
418
MORIETAL NICARDIPINE CARDIOPLEGIA IN CHILDREN
48h Time aiter reperfusion
48h
Time aHer reperfusion
Fig I . Hypothetical relationship between recovery of cardiac function (eg, cardiac output or slope of the Frank-Starling curve) and time after reperfusion. Filled circles are controls and open circles represent an intervention group. In (A) the intervention is shown providing sustained improvement of function. In ( B ) the intervention is shown providing transient protection representing an action best described as a hastening of recovey from stunning. Note that comparative assessment of function at least two days after reperfusion (sufficient to allow a stable level of function to be reached) is necessay to allow distinction between these alternative effcts [31. Part (A) defines a type-A intervention as one providing additional protection to that resulting from recovey from stunning. Part (B)defines a type-B intervention as one that merely hastens recovery from stunning.
There are two pieces of information pertaining to Mori and colleagues’ data that must be emphasized. First, hemodynamic status was monitored for only 24 hours during reperfusion. Second, “all patients are alive and well after hospital discharge.” It is unquestionably the case that survival and good health are ultimate arbiters of the adequacy of myocardial protection. Therefore the present study indicates that although laboratory indices of myocardial function were improved by nicardipine in the short term, the ability of the myocardium to function effectively in the long term was de facto unmodified. In view of this apparent paradox a degree of circumspection is appropriate in the interpretation of the data. A factor not considered by Mori and colleagues but that may have considerable relevance to the present study is myocardial stunning [11. Recovery of myocardial function during reperfusion often requires several days for completion [2]. Bolli and associates (3, 41 have shown that even when ischemia-induced mechanical dysfunction is 100% reversible it takes at least 48 hours of reperfusion for systolic and diastolic function to recover maximally from
Ann Thorac Surg 1990;49:413-8
stunning. Mechanical function was monitored only during the first 24 hours of reperfusion in the present study. This does not permit an assessment of whether the hemodynamic improvement provided by nicardipine was sustained or whether the effect of nicardipine merely reflected a hastening of recovery from stunning. In Figure 1 I have defined a type-A intervention as one that provides additional protection to that resulting from recovery from stunning and a type-B intervention as one that merely hastens recovery from stunning. If we accept that equivalent patient survival and recovery of health both with and without nicardipine is indicative of equivalent recovery of myocardial function, then it could be argued from the data of Mori and associates that nicardipine is more likely to be a type-B intervention than a type-A. However, in reality it is not possible to draw any definite conclusion from the present data because cardiac function was not assessed after 24 hours. If it were the case that ultimate recovery from stunning in the drug-free control patients was 100% then the present protocol could be criticized on the grounds that it offered no scope for distinguishing between type-A and type-B activity, because demonstration of type-A activity requires a recovery of function in controls of less than 100%. Finally, if we consider the obvious improvement in laboratory variables (hemodynamic status and CK-MB release) afforded by nicardipine during the first 24 hours of reperfusion in relation to the final clinical outcome then two factors arise. First, it would appear that the laboratory variables have no prognostic significance in the present setting, and second, it would seem clear that the protocol of cardioplegia presently employed is perfectly adequate and without the need for any additives.
Michael 1. Curtis, PhD Cardiovascular Research Laboratories Department of Pharmacology Division of Biomedical Sciences King‘s College London Manresa Rd London SW3 6 L X , United Kingdom
References 1. Heyndrickx GR, Millard RW, McRitchie RJ, Maroko PR, Vatner SF. Regional myocardial function and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest 1975;56:978-85. 2. Braunwald E, Kloner RA. The stunned myocardium: prolonged postischemic ventricular dysfunction. Circulation 1982;66:1146-9. 3. Bolli R, Zhu WX, Thornby JI, ONeill PG, Roberts R. Timecourse and determinants of recovery of function after reversible ischemia in conscious dogs. Am J Physiol 1988;254: H102-14. 4. Bolli R, Jeroudi MO, Patel BS, et al. Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial “stunning” is a manifestation of reperfusion injury. Circ Res 1989;65:607-22.