Ann Thorac Surg 1995;59:1448-1455
© 1995 The Society of Thoracic Surgeons
Effects of Intracoronary Calcium Chloride on the Postischemic Heart in Pigs
Charles W. Buffington, MD,
Kenneth P. Rothfield, MD
Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Accepted for publication February 13, 1995.
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Abstract
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Whether calcium chloride (CaCl2) should be used to reverse myocardial dysfunction during cardiac operations remains a controversial issue. Calcium chloride may reduce, rather than increase, myocardial contractility and may produce exaggerated vasoconstriction in postischemic vessels in which the endothelium has been damaged. These possibilities were investigated in an open-chest porcine model that allowed control of systemic hemodynamics. Incremental doses of CaCl2 (1, 3, and 10 mg/min) were infused directly into a coronary artery before and after 10 or 15 minutes of ischemia followed by 15 minutes of reperfusion. Calcium chloride increased regional contraction, coronary blood flow, and oxygen consumption before ischemia, whereas oxygen and lactate extraction were unchanged. After ischemia and reperfusion, contraction was impaired and lactate extraction was reduced, but a similar response to CaCl2 was observed. Contraction returned to baseline values promptly after CaCl2. Thus, CaCl2 exerts a positive inotropic effect both in normal and in postischemic myocardium. Calcium chloride does not cause direct coronary constriction nor does it worsen myocardial stunning after a short period of normothermic myocardial ischemia.
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Introduction
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Controversy surrounds the administration of calcium salts (CaCl2) at the termination of cardiopulmonary bypass to patients undergoing cardiac operations. Although CaCl2 is an effective positive inotropic agent when given in the presence of hypocalcemia [1, 2], recent evidence suggests that it produces the opposite effect in normocalcemic animals [3]. Calcium chloride administration also may harm the myocardium by limiting coronary blood flow or by augmenting the calcium overload that occurs during reperfusion and is linked to postischemic myocardial dysfunction [4, 5]. We investigated these possibilities in a porcine model that permits direct intracoronary administration of CaCl2 and thus avoids confounding systemic effects on blood pressure, heart rate, and autonomic tone. The effects of CaCl2 were determined before and after a 10- or 15-minute period of normothermic myocardial ischemia followed by 15 minutes of reperfusion.
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Material and Methods
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General Preparation
Eighteen farm-bred pigs (20 to 25 kg) of either sex were studied. The pigs were given acetylsalicylic acid orally (25 mg/kg) the night before operation to decrease platelet activation by the external perfusion circuit (see below). Before the experiment, the pigs were premedicated with intramuscular ketamine (10 mg/kg) and then anesthetized with halothane (0.5% to 0.75% end-tidal; Datex, Helsinki, Finland). After tracheal intubation with a cuffed tube through a tracheotomy, the lungs were ventilated with a mixture of oxygen and air delivered by a positive-pressure respirator (Harvard, South Natick, MA) with 5 cm H2O positive end-expiratory pressure. The partial pressure of oxygen in arterial blood was kept above 200 mm Hg by controlling the inspired oxygen concentration. Tidal volume was fixed at 15 mL/kg, and respiratory rate was adjusted to keep the arterial carbon dioxide tension at 35 to 40 mm Hg. Blood gas tensions and pH were measured at intervals during the experiment (Radiometer, Copenhagen, NV, Denmark). Animals received humane care in compliance with the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication 85-23, revised 1985).
Arterial pressure was measured with a saline-filled transducer (Gould, Cleveland, OH) through a polyethylene catheter placed into the thoracic aorta via the right femoral artery. Left ventricular (LV) pressure was measured with a micromanometer (Millar, Houston, TX) inserted through a pursestring suture in the left atrial appendage. Left atrial pressure was measured with a saline-filled transducer. The heart was exposed with a left thoracotomy and suspended in a pericardial cradle. Several ribs were removed to improve access to the heart. Wires were sutured to the left atrium for pacing (Metronic 5880A; Medtronic Inc, Minneapolis, MN). The pericardium was left open. Halothane infusion was continued throughout the experiment, and end-tidal levels averaged 0.73% before and 0.64% after ischemia. Metocurine (4-mg initial intravenous bolus and subsequently 2-mg intravenous bolus doses as needed) was used for muscle relaxation.
Regional Wall Thickness
Regional myocardial contraction was measured in the area supplied by the left anterior descending coronary artery (LAD) with a pair of ultrasonic crystals and a sonomicrometer (Triton, San Diego, CA). A 1- to 2-mm diameter lensed piezoelectric crystal was inserted through a stab wound in the epicardium and tunneled tangentially to a position at the endocardial surface. A 2- to 3-mm diameter lensed crystal was sewn to the epicardium at the location that minimized the distance between the crystals. The pair of crystals measured wall thickness. Once the crystal pair was in place, a temporary occlusion of the LAD confirmed that the crystals were located in the ischemic area. At autopsy, the inner crystal was located by blunt dissection to confirm that it was within 3 mm of the subendocardium. The orientation of the crystals was checked to be certain that the pair was perpendicular to the epicardium.
Coronary Perfusion
The LAD was dissected free from the epicardium distal to the first diagonal branch. Intravenous lidocaine (30 mg) and heparin (750 U/kg bolus plus 250 U • kg-1 • h-1) were given, and a 4-mm long, thin-walled, 14- or 16-gauge Teflon tube was inserted into the LAD and tied into place. Blood from the left carotid artery was supplied to this cannula by a shunt. After cannulation, the shunt was clamped for 10 seconds, and release of the clamp elicited a brisk reactive hyperemia with peak flow of 1.5 to 2.0 times resting flow in all animals. The shunt was made of thick-walled silicone tubing (3.0 mm inner diameter; Dow Corning, Midland, MI) and incorporated an electromagnetic flow probe and a mixing chamber. The inside of the shunt was coated with a silicone compound (Prosil-28; PCR, Gainesville, FL) and dried before use. A flowmeter (Zepeda SWF-4RD, Seattle, WA) was used to measure LAD flow. The flowmeter was calibrated with the pig's blood by timed collection after each experiment. Pressure in the circuit was measured just proximal to the coronary cannula. The pressure gradient from the measuring site to the tip of the cannula was determined in bench experiments with the animals' blood. The gradient did not exceed 4 mm Hg, even at the highest flow rates used in the experiment. Reported coronary pressures were corrected for this gradient.
Blood Pressure Control
A 1-L capacity pressurized blood reservoir was connected to a femoral artery. Blood flowed from the animal into the reservoir if arterial pressure exceeded reservoir pressure, and vice versa. Saline solution (0.9%, 150 mL) was given to expand the blood volume.
Regional Metabolism
A 22-gauge catheter was inserted retrograde into a small vein in the territory supplied by the LAD. Small samples (0.5 to 0.6 mL) of blood were slowly withdrawn over 20 to 30 seconds from this catheter, and an arterial sample of blood was obtained simultaneously. The samples were stored on ice for 10 to 15 minutes until measurement of oxyhemoglobin saturation and hemoglobin concentrations (OSM3 Hemoximeter, Copenhagen, Denmark), oxygen tension (PO2), and lactate concentration (YSI, Yellow Springs, OH).
Transmural Flow Measurements
Regional myocardial blood flow was measured in a subset of six animals with radioactive microspheres (15 ± 1 µm in diameter) labeled with niobium 95, strontium 85, chromium 51, or cerium 141 injected into the tubing that supplied blood to the LAD. Approximately 105 microspheres were injected over a 30- to 45-second period. The injection site was upstream from a small mixing chamber. After the experiment, 2 to 3 mL of crystal violet dye was infused in the cannula, staining the perfused area. The stained area was weighed, and the central region containing the crystals was subdivided into four transmural sections that were in turn divided into inner, middle, and outer layers. Epicardial fat and vessels and endocardium were trimmed from the sections before the final division. Each resulting piece was weighed, then the radioactivity in these sections from the central core and all of the surrounding dyed tissue was counted in a well-type scintillation counter. The spectrum from 0.01 to 1.0 MeV was divided into four regions corresponding to the major peaks of the isotopes used. After correction for background counts and Compton scatter from higher energy isotopes by a matrix inversion technique, the counts for each isotope were summed, and flow to individual sections was calculated as the ratio of section counts to total counts times total flow measured with the electromagnetic flowmeter. Section flows were divided by tissue weight and averaged for endocardial, midwall, and epicardial layers. The inner-to-outer blood flow ratio (I:O) was calculated by dividing the flow per gram in the inner layer of each section by the flow per gram in the outer layer and averaging the values for all four sections. Tissue samples containing less than 400 microspheres were excluded from analysis.
Drug Preparation
CaCl2 (500 mg; Sigma) was added to 0.9% saline solution to achieve a concentration of 10 mg/mL. The drug was infused into the tubing supplying blood to the LAD in doses of 1, 3, and 10 mg/min. Samples of coronary arterial blood were obtained from the perfusion circuit downstream from the mixing chamber, and the concentration of ionized calcium was determined (Stat Profile-9, Nova Biomedical, Waltham, MA). The concentration of CaCl2 in the blood varied depending on coronary flow and the weight of perfused tissue (30.3 ± 7.8 g (mean ± standard deviation); range, 20 to 46 g).
Experimental Protocol
The heart rate was stabilized at 120 beats/min by atrial pacing. Arterial blood pressure was controlled at 60 mm Hg with the pressurized blood reservoir. Measurements were obtained of hemodynamic variables, regional wall thickness, coronary flow, and arterial and coronary venous lactate and oxygen content. Then CaCl2 was infused in incremental doses of 1, 3, and then 10 mg/min for 4 to 5 minutes each. Measurements were repeated at the end of each dose increment and 5 minutes after CaCl2 infusion was stopped. To produce myocardial stunning, flow to the LAD was stopped for 10 minutes (5 pigs) or 15 minutes (8 pigs), and then the area was reperfused for 15 minutes. Different lengths of occlusion were used to produce a range of myocardial dysfunction. During reperfusion, coronary flow peaked and then gradually returned to or below baseline. Regional contraction initially increased and then decreased to a stable value. Measurements before, during, and after calcium infusion were repeated when hemodynamics and flow values were stable, 15 minutes after the start of reperfusion. Transmural coronary flow distribution was measured by microsphere injection in 6 animals, all of which underwent a 15-minute period of ischemia. Four measurements were made in each animal: during control and during the 3-mg/min CaCl2 dose both before and after ischemia. After the final measurement, the animal was killed by infusion of KCl (1 mL/kg) while deeply anesthetized. Postmortem inspection revealed that the sonomicrometer crystals were located within the central area of the perfused zone in all animals.
Intravenous CaCl2 Experiments
In a subset of 4 animals, an intravenous bolus of CaCl2 (8 mg/kg) was given before ischemia, and the peak response was recorded approximately 90 seconds later. Blood pressure was held as nearly constant as possible during this period with the aid of the pressurized blood reservoir.
Data Collection and Analysis
Aortic pressure, LV pressure, and regional wall thickness were recorded on a polygraph (Gould, Cleveland, OH). The first derivative of LV pressure with respect to time (LV dP/dt) was obtained with an analog circuit (model 13-4615-71; Gould, Cleveland, OH). To allow accurate timing of the start and end of systole, a paper speed of 100 mm/s was used. The beginning of systole was taken as the time when LV dP/dt first left the baseline before peak-positive LV dP/dt. The end of systole was assumed to occur 25 ms before peak-negative LV dP/dt. The absolute change in wall thickness (
) during systole was calculated as maximum wall thickness during systole minus end-diastolic wall thickness. Systolic thickening was calculated as thickness during systole divided by end-diastolic thickness and expressed as a percentage. Coronary perfusion pressure was calculated as mean proximal coronary pressure minus left atrial pressure.
Statistical Analysis
A standard statistical package (SPSS/PC version 1.1) was used to analyze the data. Measurements made before CaCl2 infusion were compared by paired t test with those made approximately 5 minutes after the infusion was stopped. No significant differences in the important dependent variables were found (Table 1
). Thus, these values were averaged in each animal to obtain a baseline value (indicated as 0.0 dose of CaCl2 in the Tables). The process was repeated for data obtained after ischemia and reperfusion.
Two-way analysis of variance was used to test the hypotheses that CaCl2 dose or ischemia and reperfusion affected the measured variables. The independent variable representing calcium infusion was coded 0, 1, 2, 3 to correspond to infusion rates of 0, 1, 3, and 10 mg/min. Thus, a significant treatment effect of calcium in the analysis of variance model implies a dose--response relation. Multiple regression analysis using measured blood ionized calcium concentrations and a ``dummy variable'' for stunning produced very similar results (not shown). A dummy variable coded for the duration of ischemia (10 or 15 minutes) was not a significant predictor in any of the regression models. Hence, the data from subgroups with different periods of ischemia were combined for presentation. Data in text and tables are presented as the mean and standard deviation; data in figures as the mean and standard error.
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Results
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Four pigs died as a result of technical problems cannulating the coronary artery. Ventricular fibrillation occurred during occlusion or shortly after reperfusion in 7 pigs. The heart was defibrillated successfully with direct current (10 to 20 mA, 1 to 3 shocks) in 6 of the 7 pigs. Successful experiments were completed in 13 pigs.
The results of two-way analysis of variance testing the significance of ischemia and reperfusion and CaCl2 effects are given in Table 2. Arterial blood pressure was slightly lower (p < 0.001), and heart rate was higher (p < 0.001) after ischemia and reperfusion (Table 3). Heart rate was held at 120 beats/min in most animals during the experiment by pacing, although several animals had an increase in rate to 130 to 150 beats/min after ischemia. Left ventricular dP/dt increased with increasing CaCl2 dose (p < 0.001), as did regional contraction in the test zone (p < 0.005). Systolic thickening was decreased after ischemia and reperfusion to about 40% of baseline values (range, 11% to 90%, p < 0.001). The interaction term of the two-way analysis of variance of systolic thickening was nonsignificant, indicating that the response to CaCl2 was similar before and after ischemia and reperfusion (Fig 1).
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Fig 1. . Systolic thickening increased with increasing Ca2+ concentration in the blood perfusing the myocardium (p < 0.005), demonstrating a positive inotropic effect. Thickening during systole was reduced by 10 or 15 minutes of normothermic ischemia and 15 minutes of reperfusion (open circles, dashed line, p < 0.001) compared with preischemic values (closed circles, solid line). The relations are roughly parallel, demonstrating equal sensitivity of normal and postischemic myocardium to inotropic stimulation by Ca2+. Data are means ± 1 standard error of the mean in 13 pigs.
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Coronary flow increased above baseline during early reperfusion (data not shown) but was not different from control after 15 minutes. Flow increased with increasing CaCl2 dose (p < 0.01, Table 4). The PO2 of blood draining from the test area increased (p < 0.001) with ischemia and reperfusion but was unaffected by CaCl2. Myocardial lactate extraction was decreased by ischemia and reperfusion (p < 0.001) but was not affected by CaCl2 infusion.
Myocardial oxygen consumption was reduced about 20% after ischemia (p < 0.001) and increased with CaCl2 administration (p < 0.05). A moderate correlation between oxygen consumption and systolic thickening (r = 0.68, p < 0.0001) was found (Fig 2), although differences in sonomicrometer crystal placement produced considerable variability among animals in the absolute value of thickening at baseline.
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Fig 2. . Oxygen consumption of the perfused region (expressed in mL • 100 g-1 • min-1) increased with increases in systolic thickening during CaCl2 infusion during both control (filled circles) and postischemic (open circles) conditions. The relation (y = 26 + 6.56x) was moderately strong (r = 0.68, p < 0.001), indicating that the positive inotropic effect of CaCl2 produced an appropriate increase in oxygen use. Both regional contraction and oxygen consumption were reduced after ischemia. Data are from 13 pigs.
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An intravenous bolus of CaCl2 increased both LV dP/dt and systolic thickening about 35% in the 4 pigs that received it (Table 5).
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Comment
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The results indicate that CaCl2 increases myocardial contraction in both normal and postischemic myocardium without adversely affecting coronary blood flow or myocardial lactate metabolism.
Assumptions
The strength of any conclusions derived from these data depends on several assumptions. Calcium chloride dose was altered incrementally rather than randomly, and we assumed no carry-over effect between doses and no effect of time, per se, on the measurements. Regional contraction and coronary flow returned promptly to baseline when the CaCl2 infusion was stopped, and the post-CaCl2 values were similar to pre-CaCl2 values. We averaged these control values for each condition to take into account any time effect in individual animals. This issue is a special concern after ischemia because both regional contraction and coronary flow initially increase and then decline during reperfusion. We started measurements 15 minutes after the start of reperfusion, when regional contraction and coronary flow were stable. However, flow may not have returned completely to baseline because coronary venous blood PO2 values were higher than those observed before ischemia, consistent with residual vasodilation. Similarly, postischemic measurements were always made second. This is an unavoidable design constraint because regional contraction takes hours or days to reach preischemic levels [6].
We assumed that 10 to 15 minutes of normothermic ischemia produced reversible injury rather than myocardial cell death. Because pigs have very low collateral flow, this duration represents a more serious insult than it would in dogs. We did not use histology or a vital stain to determine whether irreversible injury had occurred.
We assumed that ischemia and reperfusion caused vascular damage but have no direct evidence of endothelial injury, such as increased vascular permeability or diminished response to an endothelium-dependent vasodilator (eg, acetylcholine). Altered vascular control has been demonstrated in similar models of short-term ischemia (see below), and may have occurred in this animal model.
We assumed that the majority of blood collected from the vein accompanying the LAD was derived from the LAD zone. Stowe and colleagues [7] have investigated this issue in pigs with a dye technique. They found that 98% of venous blood draining from the LAD zone originated from the LAD in 6 pigs, and 67%, in 1 pig. These numbers are similar to those found in dogs and provide assurance that our regional metabolism measurements are accurate.
Critique of the Model
The model used a 10- or 15-minute normothermic occlusion to obtain mild to moderate stunning, the degree of mechanical impairment frequently seen after longer periods of protected, hypothermic ischemia during cardiac operation. Calcium chloride was administered 15 minutes after the start of reperfusion, because this is the shortest interval between reperfusion of the heart and discontinuation of cardiopulmonary bypass that is likely to occur during cardiac operations. Timing is an important issue because calcium causes clear injury at the onset of reperfusion [4], whereas a previous study by Yokoyama and co-workers [1] demonstrated the benefit of postischemic Ca2+ repletion after 60 minutes of reperfusion.
The effects of ischemia and reperfusion in this study are similar to those previously reported [6]. Regional contraction was decreased but not abolished. Myocardial lactate extraction was decreased after ischemia, but no animal demonstrated production 15 minutes after reperfusion. Myocardial lactate extraction resumes after an initial washout phase after ischemia but does not reach preischemia levels for 1 hour [8]. The reason for reduced lactate uptake is unknown. Myocardial oxygen consumption was reduced about 20% after ischemia in the present experiment and correlated reasonably well with regional contraction (Fig 2
). Other investigators have found ``normal'' oxygen consumption despite severe hypokinesis after ischemia [9]. Why our results differ is not readily apparent.
Interpretation
A goal of this experiment was to model the clinical situation of cardiac operation involving deliberate myocardial ischemia. If cardiac function does not recover after reperfusion, inotropic support commonly is used to allow separation from cardiopulmonary bypass. Postischemic myocardial dysfunction results from reduced sensitivity of myofibrils to intracellular Ca2+ [10]. Thus, it makes sense that augmenting extracellular Ca2+ might overcome this defect, but whether CaCl2 is an effective and safe remedy in this setting remains a matter of controversy [1, 11]. On one hand, plasma Ca2+ level exerts a strong influence on myocardial contractility [12], and dilutional hypocalcemia commonly occurs during cardiopulmonary bypass [11]. Administration of CaCl2 in this setting seems reasonable and likely to improve contractility [1, 2]. On the other hand, increasing CaCl2 levels above normal has little positive inotropic effect [2] and may even reduce contractility [3]. Calcium affects vascular smooth muscle as well as cardiac muscle and may increase systemic vascular resistance, often an undesired effect [13]. Calcium is thought to constrict coronary arteries [14], and has been associated with coronary spasm in rare cases [15]. Finally, administration of CaCl2 early during reperfusion might contribute to the intracellular calcium overload that is thought to play a central role in stunning and more serious forms of myocardial injury [4, 5, 16].
Our results are relevant to many of these issues. Calcium chloride, when administered directly into the coronary artery, definitely improved contraction of both normal and postischemic myocardium. The effect was similar to that produced by intracoronary Au: OK?isoproterenol (0.03 to 0.3 µg) in 3 pigs (Fig 3). Intravenous administration of CaCl2 in a dose of 8 mg/kg also increased regional contraction and LV dP/dt. The results are consistent with those from isolated heart preparations and previous studies in normal animals and humans [1, 2, 17]. The results conflict with those of Mathru and colleagues [3], who demonstrated a 50% decrease in myocardial contractility (estimated by end-systolic elastance) when CaCl2 was given to normocalcemic dogs. The present data suggest that the results of Mathru and colleagues are not attributable to the direct effect of CaCl2 on the heart or coronary arteries.
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Fig 3. . The effect of CaCl2 (1, 3, and 10 mg/min, intracoronary) on regional contraction (circles) is compared with the effect of isoproternol (0.03, 0.1, and 0.3 µg/min, intracoronary, triangles) in 3 separate pigs not subjected to ischemia and reperfusion. Roughly parallel dose-response curves were obtained, suggesting that CaCl2 is an effective positive inotropic agent. Data are means ± 1 standard error of the mean.
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We found essentially parallel increases in regional contraction during CaCl2 infusion before and after ischemia and reperfusion. These results are very similar to those of Carrozza and co-workers [16]. In contrast, Ito and colleagues [18] found a steeper response to CaCl2 in postischemic myocardium. The shape of these curves is of relevance to theories of the mechanism of myocardial stunning but of small practical importance. The Ca2+ concentrations produced in these studies are unlikely to occur in clinical practice, thus the lower end of the CaCl2 dose--response curve is the important zone for discussion.
We found no evidence that CaCl2 causes coronary constriction. Coronary blood flow increased during CaCl2 in tandem with myocardial oxygen consumption. Coronary venous PO2 was unchanged by CaCl2, providing solid evidence that the balance between oxygen supply and demand was unchanged. A previous study by Sialer and co-workers [14] concluded (in error) that CaCl2 causes coronary constriction. This conclusion was based on the observation that coronary blood flow decreased 17% when CaCl2 was given to anesthetized dogs. However, CaCl2 decreased heart rate 30% and increased mean arterial pressure only 4%. Thus, reduced myocardial oxygen demand caused reduced coronary flow. Coronary venous oxygen content was unchanged, indicating that CaCl2 had no direct effect on coronary tone in this study.
The vascular response to CaCl2 might be affected by ischemia and reperfusion. Previous studies demonstrate altered vascular control after even a short period of ischemia [19–22]. Increased protein leak through damaged endothelium after 15 minutes of ischemia in dogs has been demonstrated [20]. The response to endothelium-dependent vasodilators was reduced, whereas the response to constrictors such as thromboxane was enhanced [21, 22]. Thus, it seems reasonable to predict a different response to CaCl2 in the postischemic state than in the normal state, especially given case reports of coronary spasm associated with CaCl2 administration after coronary artery bypass grafting [15]. However, our data contradict this idea; coronary flow increased and coronary venous blood PO2 was unchanged by CaCl2 after ischemia. Regional myocardial flow data determined by microspheres demonstrate stable I:O flow ratios that were unaffected either by ischemia and reperfusion or by CaCl2. Lactate extraction was unchanged by CaCl2, arguing against myocardial ischemia. Ito and colleagues [18] also have demonstrated an appropriate increase in coronary flow as regional contraction was stimulated by intracoronary CaCl2 in the postischemic state, although they did not sample venous blood for oxygen or lactate content. We did not study the effect of CaCl2 on large epicardial coronary arteries and cannot comment on the influence of ischemia on the sensitivity of these vessels to CaCl2 or interactions of Ca2+ with various constrictor mechanisms.
We found reasonable evidence that inotropic stimulation with CaCl2 did not harm the myocardium during reperfusion. Regional contraction, coronary venous PO2, and lactate extraction returned to postischemic baseline after discontinuation of CaCl2. If CaCl2 had contributed to ``calcium overload,'' function might have deteriorated. A similar lack of deterioration after inotropic stimulation of stunned myocardium with epinephrine has been noted by others [23]. Viable cells regain control of cytoplasmic Ca2+ fairly quickly after ischemia [16]. Cytoplasmic Ca2+ levels are elevated at the start of reperfusion [24], but Ca2+ is taken up by the sarcoplasmic reticulum once high-energy phosphate compounds are available to fuel the process. Then Ca2+ is slowly transferred across the sarcolemma by the sodium--calcium exchange [25]. Intracellular Ca2+ levels return to baseline after 20 minutes of reperfusion [16]. Recovery is not rapid in lethally injured myocytes, and increased extracellular Ca2+ levels could exacerbate damage in this situation.
Limitations of the Study
This study was done in pigs with normal coronary arteries, and therefore extrapolation of the results to humans with diseased coronary arteries must be done cautiously. Atherosclerosis accentuates the response to vasoconstrictor agents such as norepinephrine, and even small degrees of constriction are magnified by the geometry of eccentric stenoses.
We gave a lot of calcium to a small region of the heart, and it is unlikely that clinical levels would ever get this high unless a bolus dose of CaCl2 was administered into a central vein during the low flow state that accompanies cardiac arrest.
We used a simple measure of regional contraction, the change in wall thickness during systole, to decide if CaCl2 was a positive inotrope. Although this is a reasonable approach in the absence of large changes in preload and afterload, more sophisticated measures of contractility such as preload-recruitable segment work might yield somewhat different answers.
We used direct intracoronary infusion of CaCl2 to avoid systemic effects from intravenous infusion. Thus, the application of our results to humans undergoing cardiac operations is uncertain. The response of such patients to intravenous CaCl2 will likely depend on the underlying status of the heart and systemic circulation.
Summary and Conclusions
Intracoronary CaCl2 has a positive inotropic effect on postischemic as well as normal porcine myocardium. Calcium chloride does not affect coronary arteriolar tone directly nor does it adversely affect the metabolic and functional state of postischemic myocardium.
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Acknowledgments
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This work was supported in part by a grant from the National Institutes of Health (GM 43074), Bethesda, Maryland. Doctor David Amory provided the initial stimulus for the project. Doctor Mark Banoub provided helpful comments. The project could not have been done without the expert technical assistance of Marc Wallace and Susan Dase. We thank Carolyn Cuba for expert secretarial assistance and Lisa Cohn for editorial comments.
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Footnotes
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Address reprint requests to Dr Buffington, Department of Anesthesiology, University of Pittsburgh, Suite 910, 3471 Fifth Ave, Pittsburgh, PA 15213.
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Br. J. Anaesth.,
January 1, 2002;
88(1):
78 - 86.
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Abstract
Introduction
