Effects of calcium on left ventricular function early after cardiopulmonary bypass

Effects of Calcium on Left Ventricular Function Early After Cardiopulmonary Bypass Stefan G. DeHert, MD, PhD, Pieter W. Ten Broecke, MD, Peter A. De Mulder, MD, Inez E. Rodrigus, MD, Luc R. Haenen, MD, Christiane J. Boeckxstaens, MD, Karel M. Vermeyen, Thierry C. Gillebert, MD, and Adriaan C. Moulijn, MD Objectives: Evaluation of the effects of intravenous CaCI2 on systolic and diastolic function early after separation from cardiopulmonary bypass (CPB) Design: Prospective study Setting: University hospital Participants: Twenty patients scheduled for elective coronary artery surgery Interventions: Left ventricular (LV) pressures were measured with fluid-filled catheters. Data were digitally recorded during~pressure elevation induced by tilt-up of the legs. Trans~gastric short-axis echocardiographic views of the LV were simultaneously recorded on videotape. Measurements were obta,ned before the start of CPB, 10 minutes after termifiation of CPB, after intravenous administration of CaCI2, 5 mg/kg, and 10 minutes later. Measurements and Main Results: Systolic function was

evaluated with the slope (Ees, mmHg/mL) of the systolic pressure-volume relation. Diastolic function was evaluated with the chamber stiffness constant (Kc, mmHg/mL) of the diastolic pressure-volume relation. CaCI2 increased Ees from 2.62 _+ 0.46to 5.58 -+ 0.61 (mean _+ SD), but induced diastolic dysfunction with an increase in Kc from 0.01i +- 0.006 to 0.019 _+ 0.007. These changes were transient and had disappeared within 10 minutes after administration of CaCI2'. Conclusions: CaCI2 early after CPB transiently improved systolic function at the expense of an increase in ventricular stiffness, suggesting temporary diastolic dysfunction.

ALCIUM plays a key role in the maintenance and regulation of normal cardiac function. Myocardial force of contraction may be altered by modifying Ca---- fluxes, levels of Ca ++ at storage sites, or Ca ++ sensitivity of contractile proteins. 1 All Currently used positive inotropic drugs ultimately increase myocardial intrace]lular calcium concentrations by modulation of calcium homeostasis at one or more of these different levels. Among the positive inotropic agents used in the course of cardiac surgery, calcium salts are frequently used to treat transient decreases in myocardial contractility such as myocardial depression early after termination of cardiopuimonary bypass (CPB). 2 Bolus doses in the range of 5 to 10 mg/kg have been shown to produce moderate improvemen t in myocardial contractility and performance, which usually persists for 10 to 20 minutes. 3-5 Despite these reports, the use of calcium salts as inotropic support remains controversial. Reasons for this include uncertainty regarding the role of peripheral versus cardiac effects of the drug, concerns regarding possible effects on coronary spasm, and lack of clinical data on the potential importance and clinical implications of the reported changes in myofibrillar caicium responsiveness in the postischemic stunne d myocardium. To further document this last issue, the present study evaluated the effects of intravenous calcium administration early after separation from CPB on left ventricular (LV) function. Clinical studies on effects of calcium frequently reported only traditional intraoperative measurements of ventricular function, such as cardiac output, which are dependent on changes in loading conditions of the ventricle. Therefore, LV systolic and diastolic function were assessed in the present

study using end-systolic and end-diastolic pressure-volume relationships. These pressure-volume relationships were shown to be useful as a relatively load-independent index in the assessment of ventricular function in different clinical settings, 6,7 including in patients undergoing cardiac surgery, s

C

From the Departments of Anesthesiology and Cardiac Surgery, University Hospital Antwerp, University of Antwerp, Belgium. Address reprint requests to Stefan G. De Hert, MD, PhD, Department of Anesthesiology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium. Copyright © 1997 by W.B. Saunders Company 1053-0770/97/1107-001153.00/0

864

Copyright © 1997 by W.B. Saunders Company KEY WORDS: coronary surgery; systolic function, diastolic function, cardiopulmonary bypass, calcium

METHODS

The study was performed in 20 patients scheduled for elective coronary bypass surgery. The study was approved by the Institutional Ethical Committee and informed consent was obtained in all patients. Patients with an ejection fraction of more than 35% or with an LV end-diastolic pressure of less than 15 mmHg on preoperative hemodynamic evaluation were considered. Patients undergoing repeat coronary surgery, unstable angina, concurrent valve repair, or aneurysm resection were excluded. A description of anesthetic and surgical management has previously been published. 9,I° Briefly, all patients received routine monitoring, including 5-lead electrocardiogram, radial and pulmonary artery pressure, pulse oximetry, capnography, and blood and urine temperature monitoring. Anesthesia was induced with fentanyl, 20 #g/kg, diazepam, 0.1 mg/kg, and pancuronium bromide, 0.1 mg/kg. An additional dose of 30 ~ag/kgof fentanyl was administered before sternotomy. Patients were ventilated with an FIO2 of 0.5; when necessary, isoflurane, 0.2% to 0.4%, was added to the air-oxygen mixture. All patients received 2 g of methylprednisolone after induction of anesthesia and 2 × 106 kallikrein inhibitory units (KIU) of aprotinin in the priming fluid of the extracorporeal circuit. Echocardiographic data were acquired using a biplane 5-MHz esophageal ultrasound probe (Aloka UST-5233-S) connected to an SSD-830 Aloka echocardiographic unit (Aloka, Tokyo, Japan). Shortaxis transgastric incidences were selected for analysis. The midpapillary muscle level was taken as an anatomic landmark, and the probe was positioned to obtain the image with the most circular overall geometry with uniform wall thickness. This plane was selected because this procedure was acceptable during surgery and because earlier studies have shown that this cross-sectional area allowed fair estimation of LV volume. ]1-14 After sternotomy and pericardiotomy, the aorta was cannulated and epicardial pacemaker wires were attached to the right atrium and right ventricle. Then a fluid-filled catheter with a broad internal lumen and a rigid wall (Cavafix, Braun Melsungen AG, Melsungen, Germany; 18-G,

Journal of Cardiothoracic and Vascular Anesthesia, Vol 11, No 7 (December), 1997: pp 864-869

CALCIUM A N D LEFT VENTRICULAR FUNCTION

865

length, 45 cm) was positioned in the LV cavity through the apical dimple in order to record LV pressure. The catheter was connected through 120 cm of high-pressure tubing (Jiggo Spectrament, Swinston, UK) to a pressure transducer (M1006A, Hewlett Packard, Denmark). All transducers were zeroed to the air at the beginning of the protocol. Zeroes were checked before each set of measurements. Dynamic response (natural frequency and damping coefficient) of the cathete> transducer system was evaluated by means of the flush method described by Gardner, 15 before and after each experiment. For the LV pressure measurement system, mean frequency response was 32 Hz, with a mean damping coefficient of 0.41. All individual measurements were within the adequate range of dynamic response requirements for direct pressure measurements. Electrocardiographic data and LV pressure data were converted on-line into digital data (Codas, DataQ, Akron, Ohio) at 5-msec intervals. Venous drainage during CPB was obtained with a two-stage venous cannula inserted into the right atrium. A ventricular sump was inserted into the left ventricle through the right Superior pulmonary vein. Peffusion flow on CPB was 2.4 L/m2/min. Patients were cooled to a bladder temperature of 28°C. In all patients, the left internal thoracic artery was used in addition to one or more saphenous vein grafts. After the surgical procedure, reperfusion of the heart (repeffusion time was at least 50% of the aortic cross-clamp time in all patients), and rewarming to a bladder temperature of 35°C, patients were separated from CPB.

Experimental Protocol The heart was paced for the duration of the protocol at a fixed rate of 90 beats/rain in atrioventricular sequential mode with an atrioventricular interval of 150 msec. No vasoactive or inotropic drugs were allowed during the period of the study. Measurements were obtained with the ventilation suspended at end-expiration. Measurements consisted of high-speed recordings of digitized electrocardiographic and LV pressure tracings, and echocardiographic images on videotape. These data were recorded during a progressive increase of systolic and diastolic LV pressures obtained bY tilting the caudal part of the surgical table by 45 ° , resulting in elevation of the legs. Measurements of pressure and dimension data were synchronized by sending a synchronized electronic signal at the beginning and at the end of the recording. Care was taken to have at least 15 consecutive beats for analysis. After recording, the surgical table was returned to the horizontal position. Measurements were obtained before the start of CPB (baseline), 10

minutes after separation from CPB (post-CPB), after intravenous administration of CaCl2, 5 mg/kg, (CALCIUM), and 10 minutes after CaCI2 administration (time 10). The period of i0 minutes after the end of CPB was allowed because of the earlier observations that demonstrated a progressive improvement of systolic and diastolic LV function within the first 10 minutes after separation from CPB with a stabilization thereafter. 9 Protamine was not administered until the end of the measurements. Bladder temperature at the different times of measurement after separation from CPB ranged between 35 ° and 37°C.

Data Analysis End-diastolic pressure was timed at the peak of the R wave on ECG. The first derivative of LV pressure (dP/dt) was calculated on digitized data with a seven-point smoothing algorithm. Echocardiographic data were recorded on VHS videotape (Panasonic AG-7330, Matsashute, Japan) and analyzed off-line, blinded from the LV pressure data by an independent observer. End-diastole was measured at the point of maximal LV cavity area, whereas end-systole was measured at the point of minimal LV cavity area. If this was not readily available, end-diastole and end-systole were measured when the ECG-gated freeze-frame analysis of echocardiographic images con'esponded to the peak of the R wave and of the end of the T wave, respectively. Care was taken that timing of end-diastole arid endTsystole was obtained in the same way in the consecutive measurements of a given patient. Endocardial borders were manually outlined from the video screen with a trackball, images were evaluated according to the position and quality scores proposed by London et a156 Only patients with a position score of 1 (optimal short-axis orientation) and a quality score of 3 (good endocardial and epicardial resolution) were included for echocardiographic analysis. The papillary muscles were excluded when the endocardial border was traced. LV dimensions were measured and calculated using a computer program (Echo-corn, PPG Hellige GmbH, Germany). The measured cross-sectional area corresponded to v - r 2. Assuming a spheric model, ventricular cavity Volume (V) was calculated with the formula V = (4v/3) • r 3. The measured cross-sectional cavity areas were reported in Table 1, and derived cavity volumes were used for the computation of ventricular systolic elastance and diastolic stiffness. Regional wall motion abnormalities may influence the accuracy of calculating ventricular volumes based on a spherical model using radius calculated from cross-sectional

Table 1. Hemodynamic Data at Baseline, Post-CPB, after Administration of Calcium Chloride, 5 mg/kg (CALCIUM), and 10 Minutes Later Baseline

Post-CPB

CALCIUM

Time 10

EDP ( m m H g )

11 +_ 4

12 + 5

15 +- 4 *

13 -+ 5

Peak LVP ( m m H g )

92 ± 8

93 ± 9

100 +- 10"

94 +- 7

dP/dt m a x (mmHg/s)

942 + 152

805 + 121

996 -- 101"

822 ± 125

dP/dt min (mmHg/s)

681 -+ 92

652 +- 102

788 +- 96*

644 ± 112

End-diastolic area (cm 2)

22 ± 5

22 -+ 6

End-systolicarea (cm 2)

12 + 5

12 ± 3

9 -+ 4*

11 ± 4

Area ejection fraction (%)

40 +. 9

39 ± 9

52 +- 14"

43 + 9

Strokearea (cm 2)

21 _+ 5

22 ÷ 6

11 ± 3

11 ± 4

12 +- 3

11 ÷ 4

Ees ( m m H g / m L )

2.71 _+ 0.32

2.62 + 0.46

5.58 +, 0.61

2.87 -+ 0.54

Kc ( m m H g / m L )

0.013 _+ 0.006

0.011 -+ 0.006

0.019 + 0.007*

0.013 +- 0.007

MAP ( m m H g )

71 + 8

72 ± 9

83 +- 8*

73 -+ 7

Stroke v o l u m e (mL)

64 + 12

61 -- 7

62 -- 8

1,038 +, 165

1,014 + 196

1,185 -- 72*

0.97 + 0.11

0.92 +- 0.13

SVR (dynes/sec/cm -~) Blood ionized calcium (mmol/L)

1.01 -+ 0.09

62 -+ 10 1,194 :_- 112 0.96 ÷ 0.12

NOTE. Data are means +- SD. Abbreviations: EDP, end-diastolic pressure; LVP, left ventricular pressure; MAP, mean arterial pressure; SVR, systemic vascular resistance. * = statistical significance w i t h respect to value at post-CPB.

866

DEHERT ET AL

areas measured by echocardiography. In the present study population, none of the patients exhibited severe wall motion abnormalities such as dyskinetic Or akinetic segments. All patients exhibiting akinetic or dyskinetic regional wall segment behavior also had ejection fractions less than 35%, and were already excluded from the present protocol for this reason. Ten to 15 consecutive beats were taken for LV pressure and dimension analysis. End-diastolic pressure-dimension relationships were constructed for each set of measurements. Passive properties of the ventricle were described by fitting an exponential equation through these points using the three-constant equation that allows LV pressure to decay to a natural asymptote.~7 P = A • ekc'v + B in which P and V represent the corresponding end-diastolic pressure and volume, kc corresponds to the stiffness constant, and A and B are empirical constants. Systolic performance was assessed by evaluation of the end-systolic pressure-volume relationship. End-systolic volume was taken as minimal systolic area, and end-systolic pressure was defined as pressure at dP/dtmin. The corresponding systolic pressure and volume data were fit by lineai"least squares analysis to the following equation: P = Ees(V - V0) in which P = LV pressure, Ees = the slope of the systolic pressure volume relation, V = LV systolic volume and V0 = the volume intercept of the systolic pressure - volume relationship. Sample correlation coefficient of both the end-diastolic and the end-systolic pressure-volume relationship yielded values of r > 0.91 in all patients. Additional measurements included mean arterial pressure (MAP), central venous pressure (CVP) and cardiac output (CO) by thermodilution technique. These variables were used to calculate systemic vascular resistance (SVR) using the equation: SVR - (MAP - CVP) . 80/CO At each moment of measurement blood ionized calcium ion concentrations were determined using a Radiometer ABL electrode system 620 (Radionix, Copenhagen, Denmark). Statistics Data were analyzed using analysis of variance for repeated measurements. Posttest hypothesis used the Scheff6 F-test where appropriate. Data were reported means _+ 1 SD. Statistical significance was accepted forp < 0.01. RESULTS

Demographic and intraoperative data of the patients enrolled in this study are summarized in Table 2. Seven patients had a previous myocardial infarctionl and two patients had diabetes. All patients were on a combination of different medications, including 13-blocking agents, calcium channel blocking agents, nitrateS, and other drugs such as platelet-inhibiting agents. Hemodynamic data of the 20 patients at the different times of measurement are Summarized in Table 1. After CPB, hemodynamic data were similar to BASELINE, except for dP/dtmax, which remained lower. Administration of CaC12 increased EDE peak LVR M A P dP/dtma×, and dP/dtrnin. End-diastolic area was not altered, but end-systolic area decreased. Ejection fraction increased, but stroke area was not altered. Stroke volume, calculated from thermodilution cardiac output measurements, also remained the same. SVR increased with calcium. All these

Table 2. Demographic and Intraoperative Data Male/female Age (years) Length (cm) Weight (kg) BSA (m 2) No. of grafts Aortic cross-clamp time (rain) CPB time (min) Previous myocardial infarction Diabetes Medication 13-blocking agents Calcium channel blocking agents N it rates Others

13/7 62 _+ 11 167 _+ 16 74 _+ 11 1.70 _+ 0.38 4 (range 2-5) 42 _+ 18 95 -- 21 7 2 17 8 18 20

NOTE. Data are means + SD. Abbreviations: BSA, body surface area; CPB, cardiopulmonary bypass.

changes were transient within 10 minutes after CaCla administration. A representative example of the effects of calcium on systolic (ESPVR) and diastolic pressure-volume (EDPVR) data of patient 6 is shown in Fig 1. Compared with post-CPB, administration of calcium resulted in a steeper slope of the systolic pressure-volume relation, but also caused an upward shift of the diastolic pressure-volume relation. Group data on Ees and Kc were included in Table 1. Systolic function improved with an increase in Ees, but diastolic function was impaired after calcium with an increase of Kc, indicating an increased ventricular stiffness. This means that when calcium was administered 10 minutes after CPB, the expected positive inotropic effect was observed, but with a concomitant transient increase in ventricular stiffness. Figure 2 illustrates the effects of tilt-up of the legs on end-diastolic volume and stroke volume (calculated from echocardiographic data). For each individual patient, the corresponding increases in end-diastolic volume and stroke volume with leg tilt-up were shown before and after calcium administration. In both conditions, a linear relationship was found between the increase in end-diastolic volume and the increase in stroke volume (r = 0.91 [p < 0.001] for the measurements post-CPB; and r = 0.93 [p < 0.001] for the measurements after calcium). As obvious from Fig 2, the effects on stroke volume of increasing end-diastolic volume by leg tilt-up were similar before and after calcium (p = 0.57). Table 1 also summarizes the blood ionized calcium ion concentrations at the different times of measurement. All measurements were obtained with blood ionized calcium ion concentrations within normal ranges. Administration of 5 mg/kg of CaC12 did not significantly alter blood ionized calcium concentrations. DISCUSSION

The chemical basis of cardiac mechanics is cross-bridge interaction, associated with my0fibrillar adenosine triphosphatase (ATPase) activity. Calcium acts as a cofactor for this myofibrillar ATPase and is, therefore, considered as an important regulator of ventricular contractile function. 18 Several

CALCIUM AND LEFT VENTRICULAR FUNCTION

867

8° ESPVR

~ 401EDPVR

/

0 la.i

,o

ta.i

20

2o

"

10

J O

//

/

o postCPB • calcium

/

2'0

4'0

6'0

ESV (ml)

~

• cahYmm 20

4'0

EDV

6'0

8'0

1O0

(ml)

Fig 1, Illustration of a representative set of end-systolic (ESPVR) and end-diastolic pressure-volume data (EDPVR) (patient 6) obtained during tilt-up of the legs at post-CPB and after administration of CaCIz (CALCIUM). Compared with post-CPB (open squares), administration of CaCI2 resulted in a steeper slope of the systolic pressure-volume relation, but also caused an upward shift of the diastolic pressure-volume relation. Abbreviations: ESV, end-systolic volume; ESP, end-systolic pressure; EDV, end-diastolic volume; EDP, end-diastolic pressure.

studies have focused on the inotropic effects of calcium in the clinical situation. Intravenous administration of calcium has been reported to increase left ventricular stroke volume and dP/dt together with a decrease in heart rate. These hemodynamic effects were limited in the presence of normocalcemia, but appeared more pronounced in the presence of hypocalcemia. 19 Conflicting data exist on the hemodynamic effects of CaC12 in the course of cardiac surgery. Whereas several authors have reported a moderate improvement in myocardial contractility and performance, 3-5 others found CaC12 to affect mean arterial pressure, but not cardiac index. 2° In addition, it was reported that effects of CaC12 were less than with other inotropic agents) 1 In the present study, it was found administration of CaC12 20 minutes after weaning from CPB improved systolic function significantly. These observations were made in the presence of normocalcemia, as determined in biochemical 30

E m

>O

20 •

OD / /

O t~

. ~

10

<3 0

10

A

•o st.CPB .opoc,um 20

end-diastolic

30

40

volume

Fig 2. Effects of leg raising on end-diastolic volume and stroke volume (as calculated from echocardiographic data). For each individual patient, the corresponding increase in end-diastolic volume and stroke volume with leg raising was shown post-CPB and after CaCI2 (CALCIUM) administration, The effects on stroke volume of increasing end-diastolic volume by leg tilt-up was similar before and after calcium (p = 0,57),

analysis. The positive inotropic effect of CaC12 was not reflected in an increase in SV or stroke area. This is probably because of the concomitant observed increase in SVR. A similar phenomenon was reported by Hysing et al in other experimental conditions.22 In conscious dogs, they found that increasing blood ionized calcium concentration produced a mixed positive inotropic and peripheral vascular effect, with no change in either cardiac output or stroke volume. Another interesting phenomenon was the observation that CaC12 did not alter the effects of increases in end-diastolic volume (by leg elevation) on stroke volume (Fig 2). This suggested that preload recruitable effects on stroke volume were not altered with CaC12 early after CPB. Whereas effects of calcium salts on systolic function were extensively described, less information is available about their effects on diastolic function. In 1883, Ringer already mentioned that CaC12 might delay diastolic dilation. 23 This was the first suggestion that calcium also affected diastolic myocardial performance. In isolated cardiac muscle, the resting lengthtension relation was reported to remain unchanged,24 but relaxation time increased with higher calcium concentrations.25 Observations in open chest dogs indicated that increased extracellular calcium did not alter ventricular relaxation rate and chamber stiffness. 26 Similar observations were reported by Pagel et al27 They found that CaC12 did not alter diastolic function in conscious dogs, but it did reverse halothane- and isoflurane-inducednegative lusitropic actions, a7Recently, Dazai et al reported that oral calcium supplementation during 1 week in patients with essential hypertension improved LV diastolic function and systemic arterial compliance.% In the present study, CaC12 transiently impaired diastolic function. The mechanisms for these different observations on diastolic function are not unequivocally clear. The normal fall of the calcium ion concentration in the cytosol at the start of diastole is mainly by uptake into the sarcoplasmic reticulum. In the stunned myocardium, however, calcium reuptake in the sarcoplasmic reticulum appears to be reduced. 29,3° This decrease in rate of calcium uptake in the sarcoplasmic reticulum could influence rate of relaxation, and it was suggested that changes in calcium uptake may be manifested most strikingly in impaired relaxation and

868

DEHERT ET AL

diastolic function, rather than in the decrease of systolic force production. 31,32Although diastolic stiffness of stunned myocardium appears to be unaltered in normal ventricles, 33-35this is not true in hypertrophic ventricles, where the effect of being stunned increases myocardial stiffness. 35 The present observations were made early after CPB for coronary surgery. This specific clinical situation probably accounted for the different observations compared with the effects of calcium in normal hearts. It can be expected that early after CPB, normal intracellular calcium-regulating processes are still impaired, resulting in modified effects on relaxation and diastolic function. Because of the specific methodology with fluid-filled catheters in the present study, reliable evaluation of timing intervals and relaxation constants was not possible. The authors, therefore, cannot comment on changes in relaxation rate with CaC12 and its possible effects on diastolic dysfunction. Further studies will have to elucidate these issues. CaC12 has been incriminated in precipitating coronary artery spasm after CPB. 36 Coronary artery spasm may be responsible in the pathogenesis of myocardial ischemia after CPB. 3v Although it cannot be unequivocally excluded that this phenomenon was involved in these observations, the absence of electrocardiographic ST-segment changes, the absence of changes in regional wall movement on echocardiography, and the hemodynamic stability of the patients after administration of CaC12 make the hypothesis of coronary artery spasm unlikely.

Limitations of the Study A first limitation of the present study is the use of a single two-dimensional plane to describe changes in overall left ventricular volume. The accuracy of calculating ventricular

volumes based on a spherical model using radius calculated from cross-sectional areas measured by echocardiography may be impaired in the presence of regional wall motion abnormalities. However, none of the patients evaluated in the present study had dyskinetic or akinetic segments on echocardiographic examination; consequently, this phenomenon did not influence the data. In the present study, fluid-filled catheters were used to measure left ventricular pressures. All individual measurements conformed to the dynamic responses required for fluid-filled pressure transducer systems. This means that pressure and dP/dt measurements were reliable. The only drawback is that measurement of time intervals might be delayed with respect to measurements by micromanometers. Therefore, the analysis of time intervals was omitted in this report. Loading conditions were altered with leg elevation to construct pressure-dimension relations. This implies that the present data cannot simply be compared quantitaively with data obtained by other means of altering loading conditions, because the type of constructing pressure-dimension relations (altering preload or afterload) influences the data obtained.

CONCLUSION

In conclusion, intravenous administration of CaCl2 early after cardiopulmonary bypass improved systolic function, but impaired diastolic function. Although the mechanisms of this phenomenon remain to be established, it might be suggested to be cautious with the use of CaC19 early after cardiopulmonary bypass, especially when preexisting impairment of diastolic function can be expected.

REFERENCES

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CALCIUM AND LEFT VENTRICULAR FUNCTION

17. Mirsky I: Assessment of diastolic function: Suggested methods and future directions. Circulation 69:836-841, 1984 18. Parmley WW, Wikman-Coffelt J: Myocardial hypertrophy, failure, and ischernia, in Parmley WW, Chatterjee K (eds): Cardiology, Vol l. Philadelphia, PA, Lippincott, 1994, chap 4, pp 1-26 19. Drop LJ, Geffin GA, O'Keefe DD, et al: Relation between ionized calcium concentration and ventricular pump performance in the dog under hemodynamically controlled conditions. Am J Cardiol 47:1041-1051, 1981 20. Royster RL, Butterworth JF, Prielipp RC, et al: A randomized, blinded, placebo-controlled evaluation of calcium chloride and epinephrine for inotropic support after emergence from cardiopulrnonary bypass. Anesth Analg 74:3-13, 1992 21. Johnston WE, Robertie PG, Butterworth JE et al: Is calcium or ephedrine superior to placebo for emergence from cardiopulmonary bypass? J Cardiothorac Vasc Anesth 6:528-534, 1992 22. Hysing ES, Chelly JE, Jacobson L, et al: Cardiovascular effects of acute changes in extracellular ionized calcium concentration induced by citrate and CaC12 infusions in chronically instrumented dogs, conscious and during enflurane, halotbane, and isoflurane anesthesia. Anesthesiology 72:100-104, 1990 23. Ringer S: A third contribution regarding the influence of the inorgamc constituents of the blood on the ventricular contraction. J Physiol (London) 4:222-225, 1883 24. Sonnenblick EH: Force-velocity relations in mammalian heart muscle. Am J Physio1202:931-937, 1962 25. Parmley WW, Sonnenblick EH: Relation between mechanics of contraction and relaxation in mammalian cardiac muscle. Am J Physiol 216:1084-1091, 1969 26. Mosca SM, Borelli RR, Cingolani HE, Gelpi RJ: Effects of calcium on left ventricular diastolic function in anesthetized dogs. Acta Pbysiol Pharrnacol Ther Latinoam 41:325-336, 1991

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27. Pagel S, Kampine JR Schmeling WT, Warltier DC: Reversal of volatile anesthetic-induced depression of myocardial contractility by extracellular calcium also enhances left ventricular diastolic function. Anesthesiology 78:141-154, 1993 28. Dazai Y, Kohara K, Iwata T, et al: Cardiovascular effect of oral calcium supplementation: Echocardiographic study in patients with essential hypertension. Angiology 47:273-280, 1996 29. Krause S, Jacobus WE, Becker LC: Alterations in cardiac sarcoplasrnatic reticulum calcium transport in the postischemic stunned myocardium. Circ Res 65:526-530, 1989 30. Lirnbruno U, Zucchi R, Ronca-Testoni S, et al: Sarcoplasmic reticulurn function in the "stunned" myocardiurn. J Mol Cell Cardiol 21:163-172, 1989 31. Przyklenk K, Patel B, Kloner RA: Diastolic abnormalities of postischemic stunned rnyocardiurn. Am J Cardio160:1211 - 1213, 1987 32. Kusuoka H, Marban E: Cellular mechanisms of myocardial stunning. Ann Rev Physio154:243-256, 1992 33. Aksnes G, Kirkeb0en KA, Christensen G, Ilebekk A: Characteristics and development of myocardial stunning in the pig. Am J Physiol 263:H544-551, 1992 34. Miyazaki S, Goto Y, Nonogi H, et al: Impaired early and intact late diastolic function in stunned myocardium induced by demand ischemia. Am J Physio1264:H739-746, 1993 35. Mochizuki T, Eberli FR, Ngoy S, et al: Effects of brief repetitive ischernia on contractility, relaxation and coronary flow. Exaggerated postischemic diastolic dysfunction in pressure-overload hypertrophy. Circ Res 73:550-558, 1993 36. Boulanger M, Maille JG, Pelletier GB, Michalk S: Vasospastic angina after calcium injection. Anesth Analg 63:1124-1126, 1984 37. Buxton AE, Goldberg S, Harken A, et al: Coronary-artery spasm immediately after myocardial revascularization: Recognition and management. N Engl J Med 304:1249-1253, 1981