1Department of Anesthesiology, Chonnam National University Medical School, 8 Hak-dong, Kwangju 501-746, Korea. 2Chonnam University Research Institute of Medical Sciences, 5 Hak-dong, Kwangju 501-746, Korea*Corresponding author
Accepted for publication: August 3, 2001
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Regional myocardial oxygen consumption (MV·O2), mechanical function and coronary blood flow (CBF) in response to calcium chloride (0.10, 0.25, 0.50 and 0.75 mg ml1 of CBF) directly infused into the left anterior descending (LAD) artery were determined before (normal) and 30 min after a 15-min-period of LAD occlusion (stunned) in an open-chest canine model. Percentage segment shortening (%SS) and percentage postsystolic shortening (%PSS) in the LAD territory were determined using ultrasonic crystals and CBF using a Doppler transducer. Myocardial extraction of oxygen (EO2) and lactate (Elac) was calculated.
Results. The infusion of calcium chloride resulted in dose-dependent increases in %SS and MV·O2 but did not affect %PSS in normal myocardium. These changes were accompanied by parallel increases in CBF, resulting in no change in EO2. In stunned myocardium, the responses to calcium chloride were not significantly altered, with the exception of a reduction in %PSS. However, ischaemia and reperfusion itself significantly reduced %SS and Elac and increased %PSS.
Conclusions. These data suggest that calcium chloride improves regional systolic and diastolic function both in normal and stunned myocardium. Calcium chloride is unlikely to cause direct coronary vasoconstriction or to deteriorate regional mechanical function in postischaemic myocardium.
Br J Anaesth 2002; 88: 7886
Keywords: heart, coronary circulation; ions, calcium; drugs, inotropic; dog
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Clinically, calcium is frequently used as an initial therapeutic agent to reverse acute postischaemic ventricular dysfunction during separation from cardiopulmonary bypass.6 However, calcium has been observed to reduce coronary blood flow (CBF) in an isolated beating heart.7 A recent in vivo study also demonstrated that intracoronary calcium chloride caused direct coronary vasoconstriction, in addition to its inotropic action, in normal canine heart.8
On the other hand, the stunned myocardium is associated with decreased coronary flow reserve and vasodilator responsiveness.9 10 Furthermore, it shows normal oxygen consumption (MV·O2), despite depressed contractile function, i.e. increased oxygen cost of contractility.11 It is speculated that calcium may exaggerate the vasoconstrictor response and hence impair myocardial oxygen balance in the stunned myocardium. Indeed, it has been demonstrated that mechanical function is not as tightly coupled as CBF and MV·O2, and thus oxygen extraction (EO2) increased during inotropic stimulation with dobutamine in postischaemic canine myocardium.5
In addition, intracellular Ca2+ overloading during ischaemia and reperfusion has been implicated in the pathogenesis of myocardial stunning.12 In an isolated rat heart, postischaemic myocardium was susceptible to Ca2+ influx and subsequent injury.13 Administration of calcium may therefore deteriorate rather than improve regional function, by augmenting calcium overload in postischaemic myocardium. The seeming paradox of the clinical use and known pathophysiological effects of calcium remains to be explained. In the present work we studied the effects of calcium chloride on regional oxygen balance and mechanical function in the stunned myocardium.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A left thoracotomy was performed via the fifth intercostal space and the heart was suspended in a pericardial cradle. Instruments were implanted in and around the heart as shown in Fig. 1. A Doppler transit time flow probe (Transonic Systems, Ithaca, NY, USA) was placed around the main pulmonary artery to measure cardiac output, and another flow probe was placed around the left anterior descending coronary artery (LAD) distal to the first diagonal branch for continuous blood flow measurement. A rubber band was placed around the LAD immediately distal to the flow probe to serve as an occluder. For the infusion of drugs, a 24-gauge catheter was inserted into the proximal LAD. A pair of ultrasonic dimension transducers (Medical Research Technology, Gaithersburg, MD, USA) were implanted approximately 10 mm apart in the subendocardium of a region of anterior wall that demonstrated myocardial cyanosis during a brief test occlusion of the LAD. A catheter-tipped micromanometer (SPR-524; Millar Instruments, Houston, TX, USA) was inserted directly into the left ventricle via an apical incision for the measurement of left ventricular pressure (LVP). The first derivative of LVP (+dP/dtmax and dP/dtmin) was obtained by electronic differentiation. The right femoral artery was cannulated for measurement of aortic pressure with a catheter-tipped micromanometer and for blood sampling to measure arterial oxygen and lactate contents. An 18-gauge catheter was inserted into the left atrium for the measurement of luminal pressure (Datex, Helsinki, Finland) and a 24-gauge catheter into the anterior interventricular vein at the same level as the LAD occluder for measurement of coronary venous oxygen and lactate concentrations.14
|
After a stabilization period of 60 min, pre-infusion mechanical and haemodynamic data were collected in one group of 16 dogs (series 1). Simultaneous measurements were obtained of arterial and coronary venous oxygen and lactate concentrations (metabolic data). The animals then received intracoronary infusions of calcium chloride with a syringe pump (STC 524; Terumo, Japan). Calcium chloride was infused in incremental concentrations of 0.10, 0.25, 0.50 and 0.75 mg ml1 LAD flow for 35 min, each administered 810 min apart. The infusion rate was calculated by multiplying the desired concentration by LAD blood flow, resulting in a rate between 0.3 and 2.0 ml min1. All measurements except metabolic data at 0.50 mg ml1 were repeated at the end of each dose and 5 min after calcium chloride infusion was stopped. Because mechanical and CBF responses to calcium chloride at 0.50 mg ml1 did not differ significantly from those at 0.75 mg ml1 and myocardial oxygen balance was well maintained, metabolic data at 0.50 mg ml1 were not obtained. After one series of experiments in normal myocardium, all dogs were subjected to a 15-min LAD occlusion and subsequent reperfusion to stun the myocardium. Approximately 30 min after the onset of reperfusion, when haemodynamic and flow values were stable, the same calcium chloride infusion protocol was repeated.
In eight dogs (series 2), experiments were performed to evaluate whether preischaemic administration of calcium chloride altered postischaemic contractile responsiveness (preconditioning against postischaemic contractile dysfunction) and whether volatile anaesthetics affected postischaemic myocardial responsiveness. To address the first issue, calcium chloride was infused only in the postischaemic myocardium. To address the second issue, fentanylmidazolam instead of enflurane was used to maintain anaesthesia. The responses to intracoronary infusions of calcium chloride (0.10, 0.25, 0.50 and 0.75 mg ml1 of LAD flow) were assessed using a protocol similar to that used for series 1.
Data acquisition and analysis
Blood flow (main pulmonary artery and LAD), the segmental dimension of the anterior wall and pressures (LVP and mean aortic pressure) were monitored continuously and recorded on a polygraph (TA 5000; Gould, Cleveland, OH, USA). End-systolic segment length (ESL) was determined approximately 20 ms before peak dP/dtmin and end-diastolic segment length (EDL) was determined at the onset of left ventricular isovolumetric contraction.15 Steady beat data were obtained from three to five cardiac cycles. Regional myocardial contractility was determined using percentage segment shortening (%SS), calculated from the equation %SS=[(EDLESL)/EDL]x100. Percentage postsystolic shortening (%PSS), as a regional diastolic function, was calculated from the equation %PSS=[(ESLLminD)/(LmaxLminD)]x100, where LminD and Lmax are minimum length during diastole and maximum length in an overall contraction, respectively. Coronary perfusion pressure was calculated as aortic diastolic pressure minus left atrial pressure.
At the end of the experiment, the heart was stopped by intra-atrial injection of concentrated potassium chloride solution. The area supplied by the LAD artery was defined by injection of Evans blue into the vessel at the site of the flow transducer. Weighing of the stained muscle allowed calculation of mean flow in ml min1 per 100 g of muscle. The LAD perfusion territory was 24.3 (5.6)% of the total left ventricular mass.
Statistical analysis
All data are presented as mean (SD). They were analysed using StatView software version 4.0 (Abacus Concepts, Berkeley, CA, USA) on a Macintosh computer. Statistical analysis of the calcium chloride responses in normal and stunned myocardium was performed by two-way analysis of variance for repeated measures followed by Dunnetts t test. Comparisons between the pre-infusion values of normal and stunned myocardium were made with the paired Students t-test. Enflurane- and fentanylmidazolam-anaesthetized groups were compared using the MannWhitney U-test. Linear regression analysis was used to examine the relationship between CBF and MV·O2 at all doses of calcium chloride in series 1. Significance was assumed when P<0.05.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Table 1 shows systemic haemodynamics in normal and stunned myocardium in enflurane-anaesthetized dogs. Calcium chloride was without significant effects on these variables in normal myocardium. However, there was a dose-dependent increase in +dP/dtmax. LAD occlusion produced a small increase in heart rate and left atrial pressure and decreased mean aortic pressure, +dP/dtmax, dP/dtmin and cardiac index. They quickly returned towards baseline values at the onset of reperfusion, with the exception of +dP/dtmax and dP/dtmin, which remained lower than their baseline values. In stunned myocardium, the effects of calcium chloride were similar to those in normal myocardium.
|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Vascular dysfunction may occur even after a short period of ischaemia.9 10 The vascular response to endothelium-dependent dilators (e.g. acetylcholine) was reduced, whereas that to constrictors (e.g. the thromboxane mimic U46619) was enhanced after 15 min of regional ischaemia in canine hearts in situ.10 Therefore, the vascular response to calcium chloride may differ between normal and stunned myocardium. However, the response to calcium chloride, increased CBF with no significant changes in coronary venous oxygen tension and EO2, did not differ significantly between normal and stunned myocardium (Table 3). Similarly, Buffington and Rothfield4 observed an appropriate increase in CBF when regional contractility was stimulated by calcium chloride in stunned porcine myocardium. These findings suggest that, in stunned myocardium, calcium chloride does not interfere with normal metabolic vasoregulation but maintains CBF in proportion to the myocardial oxygen demand.
In contrast, Crystal and colleagues8 demonstrated that intracoronary calcium chloride produced direct vasoconstriction and impaired coupling of CBF to the augmented myocardial oxygen demand in normal myocardium of dogs anaesthetized with fentanylmidazolam. The discrepancy between these studies is not readily explained. It has been shown that volatile anaesthetics decrease Ca2+ sensitivity in rat aortic vascular smooth muscle in vitro19 and produce coronary vasodilation directly in in situ canine hearts.20 However, the vascular responses to calcium chloride were similar in fentanylmidazolam- and enflurane anaesthetized dogs in the present study (Fig. 4). It is unlikely that anaesthetics are responsible for the discrepancy between these studies. Another possible explanation may include different experimental methods. Crystal and colleagues8 used an extracorporeal perfusion system with a pressurized reservoir to keep coronary perfusion pressure constant, whereas we administered calcium chloride directly into the LAD. However, the coronary perfusion pressure was not affected by calcium chloride in either study.
The markedly reduced contractile function has been associated with an unaltered MV·O2 in stunned myocardium.11 If contractile function increases at a higher energy cost in stunned myocardium, an elevated CBF would be expected for a given level of function (assuming unchanged EO2). However, the CBF response in relation to segment shortening was similar in normal and stunned myocardium in the present study. Chiu and colleagues21 have demonstrated that regional inotropic stimulation with isoproterenol restores synchrony and regional work in stunned myocardium without greatly affecting MV·O2 in dogs. They speculated that myocardial stunning produced asynchrony between force development and segment shortening, thereby decreasing systolic regional work (but not total work) to a greater extent than MV·O2. It is likely that inotropic drugs, including calcium chloride, do not increase total mechanical work but restore the synchrony, resulting in no greater increases in CBF relative to regional mechanical work in stunned myocardium.
Although systolic function associated with the use of inotropic drugs has been studied extensively in stunned myocardium, the diastolic function has been overlooked. In the present study, calcium chloride did not affect peak dP/dtmin but produced a progressive reduction in %PSS (Table 2). Similarly, Schlack and colleagues22 observed that intracoronary norepinephrine did not affect peak dP/dtmin but reduced postejection wall thickening in an open-chest canine model. It is also likely that calcium chloride improves early diastolic function. On the other hand, peak dP/dtmin has been demonstrated to reflect changes in contractility (i.e. peak ventricular pressure) rather than relaxation in regionally ischaemic canine hearts.23 The unaltered aortic pressure during the infusion of calcium chloride in the present study may be related to the unaltered peak dP/dtmin. There has been debate about whether calcium chloride increases chamber stiffness (late diastolic dysfunction) in postischaemic myocardium. Gao and colleagues24 observed that, in response to supraphysiological increases in [Ca2+]o, diastolic [Ca2+]i and tone increased in stunned trabeculae, with frequent occurrence of aftercontractions in the isolated rat heart. They speculated that increased susceptibility to Ca2+ results in increased diastolic tone under conditions that favour cellular Ca2+ accumulation. DeHert and colleagues25 also found an increase in ventricular stiffness when calcium chloride was given early after cardiopulmonary bypass, suggesting temporary diastolic dysfunction. In contrast, Eberli and colleagues26 observed that increased [Ca2+]i was not causally related to the increase in diastolic chamber stiffness in isolated rat hearts.
The effect of calcium chloride on myocardial function is transient, despite persistent elevation of the plasma concentration of ionized calcium, whereas the effect on systemic vascular resistance is more prolonged.27 We therefore chose to infuse calcium chloride continuously rather than use a single bolus injection to produce steady-state changes in myocardial contractility (and hence myocardial oxygen demand), as shown previously by Crystal and colleagues.8 In general, calcium chloride at doses of 515 mg kg1 body weight is given i.v. to improve haemodynamics while the patient is weaned from cardiopulmonary bypass.28 An i.v. bolus administration of calcium chloride at a dose of 15 mg kg1 caused a maximal increase of approximately 0.8 mmol litre1.29 Therefore, our data with the lowest rate of calcium chloride (0.1 mg ml1=0.9 mmol litre1) appears to be clinically relevant.
Lactate production has been a reliable sign of a mismatch between myocardial oxygen demand and supply.30 In the present study, a progressive reduction in lactate extraction was observed during the infusion of calcium chloride in stunned myocardium, albeit statistically insignificant. Moreover, lactate was produced in four of 13 animals anaesthetized with enflurane during calcium chloride infusion at 0.75 mg ml1 in stunned myocardium (Fig. 3). Stahl and colleagues31 observed increased heterogeneity of oxygen extraction with very low venous oxygen saturation in stunned myocardium despite patent microvasculature and normal perfusion, implying either focally impaired perfusion or increased metabolic activity. Calcium chloride would have induced focal microcirculatory changes with localized areas of tissue hypoxia and anaerobic metabolism, leading to lactate production, despite unaltered coronary venous oxygen tension. In addition, increased susceptibility to Ca2+ load in stunned myocardium has been demonstrated in isolated rat hearts.13 24 Indeed, functional deterioration has been reported after intense inotropic stimulation with high-dose dobutamine in many reperfused segments that respond positively to low-dose dobutamine infusion, probably because of impaired intracellular Ca2+ handling.32 Likewise, calcium chloride may have a deleterious long-lasting effect that differs from an immediate functional and metabolic effect, as in the present study. Therefore, caution should be exercised in extrapolating our results, showing that the postischaemic dysfunction was effectively improved by calcium chloride without impairing myocardial oxygen balance, to the clinical situation.
The present study has several limitations. First, enflurane was used to maintain anaesthesia. Volatile anaesthetics have been shown to enhance recovery of postischaemic myocardium33 and to produce coronary vasodilation directly in vivo.20 Enflurane may have protected the myocardium against ischaemia and reperfusion injury, altering the response to calcium chloride. However, we observed that responses to calcium chloride in postischaemic myocardium were similar in enflurane- and fentanylmidazolam-anaesthetized groups (Fig. 4). Secondly, it has been demonstrated that calcium chloride has a preconditioning effect against postischaemic contractile dysfunction.34 However, the responses to calcium chloride in the stunned myocardium were similar in series 1 and series 2 (Fig. 4). It is unlikely that a preconditioning effect was exerted in our experimental protocol. Thirdly, the present study did not evaluate the time course of recovery of postischaemic, reperfused myocardium during the period corresponding to drug infusion (3070 min of reperfusion). However, an open-chest canine model has shown constant regional contractile function (%SS) between 30 and 90 min of reperfusion.35 Furthermore, %SS returned to the pre-infusion values after cessation of calcium chloride infusion. Finally, changes in heart rate and systemic blood pressure during calcium chloride infusion may result in increases in MV·O2 and CBF. However, calcium chloride did not affect aortic pressure, heart rate or coronary perfusion pressure at any time during the study.
In summary, calcium chloride improved regional systolic and diastolic functions both in normal and stunned myocardium. However, the metabolic control of CBF is unlikely to be impaired in stunned myocardium, as shown by an enhanced regional function in association with proportional increases in CBF. In addition, calcium chloride is unlikely to deteriorate regional mechanical function in postischaemic myocardium.
![]() |
Acknowledgement |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2
Patel B, Kloner RA, Przyklenk K, Braunwald E. Postischemic myocardial stunning: a clinically relevant phenomenon. Ann Intern Med 1988; 108: 6268
3
Ito BR, Tate H, Kobayashi M, Schaper W. Reversibly injured, postischemic canine myocardium retains normal contractile reserve. Circ Res 1987; 61: 83446
4
Buffington CW, Rothfield KP. Effects of intracoronary calcium chloride on the postischemic heart in pigs. Ann Thorac Surg 1995; 59: 144855
5
Hashimoto T, Buxton DB, Krivokapich J, Hansen HW, Phelps ME, Schelbert HR. Responses of blood flow, oxygen consumption, and contractile function to inotropic stimulation in stunned canine myocardium. Am Heart J 1994; 127: 125062
6
Royster RL, Butterworth JF IV, Prielipp RC, et al. A randomized, blinded, placebo-controlled evaluation of calcium chloride and epinephrine for inotropic support after emergence from cardiopulmonary bypass. Anesth Analg 1992; 74: 313
7
Gruber CM, Roberts SJ. The effect of adrenaline upon the coronary circulation. Am J Physiol 1926; 76: 50824
8
Crystal GJ, Zhou X, Salem MR. Is calcium a coronary vasoconstrictor in vivo? Anesthesiology 1998; 88: 73543
9
Dauber IM, Van Benthuysen KM, McMurtry IF. Functional coronary microvascular injury evident as increased permeability due to brief ischemia and reperfusion. Circ Res 1990; 66: 98698
10
Kim YD, Fomsgaard JS, Heim KF, et al. Brief ischemiareperfusion induces stunning of endothelium in canine coronary artery. Circulation 1992; 85: 147382
11
Ohgoshi Y, Goto Y, Futaki S, Yaku H, Kawaguchi O, Suga H. Increased oxygen cost of contractility in stunned myocardium of dog. Circ Res 1991; 69: 97588
12
Kusuoka H, Porterfield JK, Weisman HF, Weisfeldt ML, Marban E. Pathophysiology and pathogenesis of stunned myocardium: depressed Ca2+ activation of contraction as a consequence of reperfusion induced cellular calcium overload in ferret hearts. J Clin Invest 1987; 79: 95061
13
Abbott A Jr, Hill R, Shears L, Beamer K, Gustafson R, Murray G. Effects of calcium chloride administration on the postischemic isolated rat heart. Ann Thorac Surg 1991; 51: 70510
14
Vinten-Johannsen J, Johnston WE, Crystal GJ, Mills SA, Santamore WP, Cordell AT. Validation of local venous sampling within the at risk left anterior vascular bed in the canine left ventricle. Cardiovasc Res 1987; 21: 64651
15
Theroux P, Ross J Jr, Franklin D, Covell JW, Bloor CW, Sasayama S. Regional myocardial function and dimensions early and late after myocardial infarction in the unanesthetized dog. Circ Res 1977; 40: 15865
16
Hoffmeister HM, Ströbele M, Beyer ME, et al. Inotropic response of stunned hypertrophied myocardium: responsiveness of hypertrophied and normal postischemic isolated rat hearts to calcium and dopamine stimulation. Cardiovasc Res 1998; 38: 14957
17
Heusch G, Rose J, Skyschally A, et al. Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart: inotropic responses to postextrasystolic potentiation and intra-coronary calcium. Circulation 1996; 93: 155666
18
Carrozza JP Jr, Bentivegna LA, Williams CP, Kuntz RE, Grossman W, Morgan JP. Decreased myofilament responsiveness in myocardial stunning follows transient calcium overload during ischemia and reperfusion. Circ Res 1992; 71: 133440
19
Kakuyama M, Nakamura K, Mori K. Halothane decreases calcium sensitivity of rat aortic smooth muscle. Can J Anaesth 1999; 46: 116471
20
Gurevicius J, Holmes CB, Salem MR, et al. The direct effects of enflurane on coronary blood flow, myocardial oxygen consumption, and myocardial segmental shortening in in situ canine hearts. Anesth Analg 1996; 83: 6874
21
Chiu WC, Kedem J, Scholz PM, Weiss HR. Regional asynchrony of segmental contraction may explain the oxygen consumption paradox in stunned myocardium. Basic Res Cardiol 1994; 89: 14962
22
Schlack W, Ebel D, Thämer V. Effect of inotropic stimulation on the synchrony of left ventricular wall motion in a dog model of myocardial stunning. Acta Anaesthesiol Scand 1996; 40: 62130
23
Dalmas S, Marsch SCU, Philbin DM, et al. Effects and interactions of myocardial ischaemia and alterations in circulating blood volume on canine left ventricular diastolic function. Br J Anaesth 1996; 76: 41927
24
Gao WD, Atar D, Backx PH, et al. Relationship between intracellular calcium and contractile force in stunned myocardium: direct evidence for decreased myofilament Ca2+ responsiveness and altered diastolic function in intact ventricular muscle. Circ Res 1995; 76: 103648
25
DeHert SG, Ten Broecke PW, De Mulder PA, et al. Effects of calcium on left ventricular function early after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997; 11: 8649
26
Eberli FR, Strömer H, Ferrell MA, et al. Lack of direct role for calcium in ischaemic diastolic dysfunction in isolated hearts. Circulation 2000; 102: 26439
27
Shapira N, Schaff HV, White RD, Pluth JR. Hemodynamic effects of calcium chloride injection following cardiopulmonary bypass: response to bolus injection and continuous infusion. Ann Thorac Surg 1984; 37: 13340
28
Drop LJ. Ionized calcium, the heart, and hemodynamic function. Anesth Anal 1985; 64: 43251
29
Eriksen C, Sorensen MB, Bille-Braha NE, Skovsted P, Lunding M. Hemodynamic effects of calcium chloride administered intravenously to patients with and without cardiac disease during neurolept anaesthesia. Acta Anaesthesiol Scand 1983; 27: 137
30
Gertz EW, Wisneski JA, Neese R, Houser A, Korte R, Bristow JD. Myocardial lactate extraction: multidetermined metabolic function. Circulation 1980; 61: 25661
31
Stahl LD, Weiss HR, Becker LC. Myocardial oxygen consumption, oxygen supply/demand heterogeneity, and microvascular patency in regionally stunned myocardium. Circulation 1988; 77: 86572
32
Smart SC, Sawada S, Ryan T, et al. Low-dose dobutamine echocardiography detects reversible dysfunction after thrombolytic therapy of acute myocardial infarction. Circulation 1993; 88: 40515
33
Warltier DC, Al-Wathiqui MH, Kampine JP, Schmeling WT. Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane. Anesthesiology 1988; 69: 55265
34
Cain BS, Meldrum DR, Meng X, Shames BD, Banerjee A, Harken AH. Calcium preconditioning in human myocardium. Ann Thorac Surg 1998; 65: 106570
35
Belo SE, Mazer CD. Effects of halothane and isoflurane on postischemic stunned myocardium in the dog. Anesthesiology 1990; 73: 12435