Diltiazem and regional left ventricular function during graded coronary constriction and propofol anesthesia in the dog

Diltiazem

and Regional Left Ventricular Constriction and Propofol

Function Anesthesia

During Graded in the Dog

Coronary

Alan H. Goldberg, MD, PhD, Johan Diedericks, BA, MMed (Anes), FFA (SA), John W. Sear, MA, BSc, MB, BS, PhD, FRCA, Margaret B. Hopwood,

MA, RN,

and Pierre Fog,, DM, DPhil, FRCA, FANZCA Although calcium channel blockers may preserve function in ischemic myocardium, they may also produce myocardial depression and dysfunction in the presence of decreased coronary flow. This study was designed to examine the issue of possible protection afforded by diltiazem against ischemiainduced myocardial dysfunction during propofol anesthesia. In eight anesthetized and ventilated dogs, regional myocardial (ultrasonic crystals in both left anterior descending [LAD] and left circumflex [LC] perfusion areas) and global ventricular function were evaluated during progressively severe degrees of myocardial ischemia (LAD constriction) before and after intravenous diltiazem (150 pg/kg). As coronary flow decreased, heart rate increased, and arterial and coronary perfusion pressures, left ventricular dP/dt, and cardiac output decreased. Systemic vascular resistance was unaffected. Diltiazem without coronary constriction increased heart rate, and decreased diastolic arterial pressures, left ventricular (LV) end-diastolic, coronary perfusion pressures, LV dP/dt max. LAD coronary blood flow, stroke volume, and cardiac output. At all levels of coronary constriction follow-

T

he cellular damage that occurs during myocardial ischemia may be mediated by intracellular calcium overload with reductions in ATP and other high-energy phosphate compounds.‘-“ This is associated with decreased global and regional myocardial function in ischemic tissue.5 Calcium channel blockers may, therefore, be expected to reduce the severity of ischemia-related dysfunction, possibly by a direct effect on ischemic myocardium, or by a combination of increased collateral coronary flow and decreased heart rate and contractility.5 Diltiazem has been shown to increase ATP concentrations and to improve myocardial function in ischemic dog6s7 and rabbit8 myocardium. Diltiazem may also decrease myocardial oxygen demand by decreasing contractility9J0 and afterload,*lJ* and may increase myocardial oxygen supply by relieving coronary artery vasospasm13,14 and improving collateral flow.lsJ6 However, diltiazem also causes selective depression and dysfunction of myocardium with critically compromised blood supply (defined as absence of postocclusive reactive hyperemia),17 and the results of clinical trials of calcium channel blockers in acute myocardial infarction have not been encouraging.lx Because of conflicting information regarding the properties of the drug, the present study was designed to address the issue of whether diltiazem provides any protection from ischemiainduced myocardial dysfunction over the whole range of coronary flow reduction, during anesthesia with a recently introduced intravenous anesthetic agent agent, propofol. METHODS The methods used in this study conform to the Animals (Scientific Procedures) Act of 1986 (UK) and to the position of the American Heart Association on research animal use. Ten beagles were initially studied, but two were excluded because of arrhythmias that precluded accurate measurements. The weights of the 8

Journalof

Cardiothoracic

and

Vascular Anesthesia,Vol7,

No 6

ing diltiazem, there were decreases in systolic and diastolic arterial pressures, stroke volume, cardiac output, LV dP/dt, and coronary perfusion pressure. Heart rate increased at critical coronary constriction, and then remained constant relative to the prediltiazem state. The regional muscle effects of the reductions in coronary flow in the LAD perfusion territory included decreased systolic shortening and increased postsystolic shortening before and after diltiazem. Diltiazem did not alter the magnitude of the alterations in systolic or postsystolic shortening brought about by coronary constriction. No changes occurred in the LC area. In conclusion, diltiazem depressed global ventricular performance in the presence of propofol anesthesia, but did not worsen or protect regional myocardial function of the compromised LAD segment. Copyright o 1993 by W. 6. Saunders Company KEY WORDS: regionalmyocardialischemia, dial dysfunction, diltiazem, propofol

regionalmyocar-

that were included ranged from 11.8 to 18.0 kg. All were premedicated with morphine sulfate (1 mg/kg, IM) and anesthesia was induced with intravenous thiopental (15.0 to 32.5 mg/kg). The trachea was then intubated and intermittent positive pressure was instituted with 40% o.xygen in nitrogen at 12 breaths/min. Minute volume was adjusted to maintain end-tidal CO2 between 4.5% and 5.5% as determined by infrared analysis. Anesthesia was maintained with 1.25% to 1.5% inspired halothane (initial concentrations) and end-tidal concentrations were measured by ultraviolet analysis (Halothane Meter, Penlon, Oxford, UK). ECG lead II was monitored throughout the experiment and used for calculation of heart rate. A heating element incorporated in the operating table maintained esophageal temperature between 37” and 38°C. Physiologic maintenance solution (Hartmann’s) was infused at 5 ml/kg/h via a catheter threaded into the inferior vena cava. A rigid 8F (2.76 mm external diameter) polyethylene catheter was advanced through the exposed left internal carotid artery to within 2 cm of the aortic valve for blood sampling and measurement of systemic arterial pressure with a pressure transducer (Statham, Statham-Gould, Hato Ray, Puerto Rico). Via a left thoracotomy, the fifth and sixth ribs were removed and

From the Medical College of Wisconsin; the Department of Anaesthesiology, University qf the Orange Free State, Bloemfontein, South Africa; Nuffield Department OfAnaesthetics, University of Oxford, UK Supported by grant nos. G8002204 SA and G8306850 SA porn the Medical Research Council of Great Britain, London and ICI Pharmaceuticals, UK and Criticare Systems, Inc, Milwaukee, WI. Dr Goldberg was supported by the Medical College of Wisconsin. Dr Diedeticks was suppotied by the Zoutendyk Scholarship Trust and the University of the Orange Free State, Bloemfontein, South Africa. Previously published in abstract form in Anesthesiology 73:A637, 1990. Address reprint requests to Alan H. Goldberg, MD, Medical College of Wisconsin, Box 150, 8700 W Wisconsin Ave, Milwaukee, WI 53226. Copyright 0 1993 by W B. Saunders Company 1053-0770/93/0706-0012$03.0010

(December), 1993: pp 705-710

705

706

the heart was exposed and suspended

in a pericardial cradle. After the aortic root was dissected from its fat pad, an appropriately sized electromagnetic flow probe (Transflow 601, Skalar Medical, Delft, Holland) was placed around the aortic root and connected to an electromagnetic flowmeter (S.E.M. 230, S.E. Laboratories, Feltham, UK). A second stiff 8F cannula was inserted into the left ventricle via a stab wound in the apical dimple and connected to a pressure transducer (Statham, Statham-Gould, Hato Ray, Puerto Rico) for measurement of left ventricular pressure. A flexible polyvinyl catheter was placed into the pulmonary artery via the right ventricular outflow tract for determination of cardiac output by dye dilution. A small length of the left anterior descending artery (LAD) was dissected free distal to its second diagonal branch, and an appropriately sized electromagnetic flow probe (Transflow 601, Skalar Medical, Delft, Holland) was placed around the vessel and connected to an electromagnetic flowmeter (S.E.M. 230, SE. Laboratories). Distal to the flow probe, an occluding snare and a 3.0 woven dacron suture were placed around the LAD. Fine adjustment (kO.25 mm) of the degree of LAD constriction produced by the occluding snare was achieved with the aid of a micrometer-controlled spring-suspended mechanism. The second loop was used for brief abrupt manual occlusions for determination of zero flow reference points. Regional myocardial function was assessed by obtaining continuous measurements of segment lengths between pairs of crystals based on the measurement of ultrasonic transit time.” For this purpose, two pairs of piezo-electric crystals (5 MHz, 1.5 mm diameter) were placed in the subendocardium of the left ventricle via 3 mm wide incisions through the epicardium. The components of each were approximately 1 cm apart and oriented parallel to the short axis of the heart, One pair was placed in the apical region within the perfusion territory distal to the isolated LAD arterial segment. The second was placed within the area supplied by the left circumflex artery (LC) at the base of the left ventricle. Placement of the crystals at the subendocardium, including parallel orientation and equality of depth, were confirmed visually at necropsy. Aortic and LAD blood flows and aortic and left ventricular pressures were recorded. The maximum left ventricular rate of pressure development (dP/dt,,,) was obtained by on-line differentiation of the left ventricular pressure tracing and taken as the maximum positive deflection of its first derivative. Stroke volume was determined from the integrated aortic flow signal and was calibrated in vivo by simultaneous determination of cardiac output with indocyanine green dye dilution. All data (except dye dilution) were recorded on an eight channel recorder (Mingograf 81, Elema Schonander, Stockholm, Sweden) at a paper speed of 250 mm/s. After the surgical preparations were completed, halothane was discontinued and replaced with propofol (5 mgikg intravenous bolus over 2 minutes followed by a continuous intravenous infusion of 200 ugikgimin). During this time (approximately 1 hour) the instruments were calibrated and any acid-base abnormalities were corrected with intravenous sodium bicarbonate to maintain arterial pH within the range 7.35 to 7.45 and base excess less than 5.0 mmol/L. Also, dextran (average molecular weight 70,000 d) was administered intravenously for preload maintenance. At the end of this period, control data were obtained. During the next 30 minutes, the LAD snare was gradually tightened to produce four progressively severe degrees of myocardial ischemia. Each degree of ischemia was determined by its effect on regional myocardial function, as assessed by alterations in LV pressuresegment length loops observed on an oscilloscope. The first stage of ischemia, critical constriction (CC), was achieved when there was neither postocclusive reactive hyperemia nor regional myocardial

GOLDBERG ET AL

dysfunction (eg, postsystolic shortening). This coincided with a noticeable diminution in pulsatility of the LAD flow curve with no alteration in wall motion. The snare was then further tightened to the point when postsystolic shortening (PSS) first appeared with no (or only slight) decrease in systolic shortening. This was termed ischemia 1 (11). Further tightening of the snare resulted in the onset of an obvious decrease in systolic shortening (hypokinesia), in addition to the PSS. This was considered ischemia 2 (12). The snare was then further tightened until total occlusion (TO) of the LAD was produced and the coronary blood flow tracing fell to zero. Systolic bulging (dyskinesia) was apparent at this stage. Recordings were obtained as soon as each stage was achieved, and zero coronary blood flow (except during TO) was determined to allow for the measurement of mean coronary blood flow. Following a l-hour period of recovery, a bolus of diltiazem (150 kg/kg IV over 2 minutes) was given and the four stages of coronary ischemia were repeated. At the end of the experiment and after the animals had been killed by an overdose of halothanc. the left anterior descending coronary artery was cannulated and 5 mL aliquots of blood were injected manually. The area of the mean flow signal, obtained planimetrically, was used to calibrate the coronary flow transducer-. Immediately after this calibration, 10 mL of Evans blue was injected through the same cannula and the stained areas of the ventricle were dissected and weighed. This allowed coronary flow to be determined in mL/min/lOOg. Data were obtained prior to (Control) and during each of the four stages of coronary ischemia. both before and after the administration of diltiazem. End-systole was defined as the point when aortic blood flow velocity returned to zero. End-diastole was defined as the point of initial upslope of LV dP/dt. Systolic shortening (SS) was calculated as the difference between the maximum and minimum muscle lengths during ejection. and, to normalize for changes in preload. was computed as percent ot end-diastolic length. Postsystolic shortening was calculated as the difference between the end-systolic length and the minimum length during diastole, and, to normalize for changes in inotropy. was computed as percent of total shortening. Total shortening was taken as the difference between the greater of the end-systolic length or the maximum length during diastole, and the lesser of the minimum length during either ejection or diastole. Global hemodynamic values were calculated according to conventional formulae. Coronary perfusion pressure was calculated as aortic diastolic minus left ventricular end-diastolic pressures. Separate two-way repeated measureb of analyses of variance over levels of ischemia and diltiazem were performed on all variables. Comparisons of pairs of means were also performed within the analyses of variance using Tukey’s HSD. The associations of LAD flow with systolic and postsystolic shortening, pre-diltiazem and post-diltiazem, were tested using simple regres-sion analyses. A P value of O.OS was taken to indicate coincidence of the lines. RESULTS As expected,

coronary

in the degree

blood

flow

decreased

with

each

of coronary constriction (Table 1). The administration of diltiazem was associated with a 24.2% decrease in the control blood flow prior to coronary constriction. Otherwise, diltiazem had no effect on the absolute or relative coronary blood flows at any level of coronary constriction. The gradual reductions in LAD flow increase

DILTIAZEM AND MYOCARDIAL ISCHEMIA

707

Table 1. Global Hemodynamics

During Graded lschemia and Diltiazem (means 2 SD) Total

Critical Parameter

Control

Constriction

107.8 -t 28.3

lschemia 2

Occlusion

115.9 * 22.9’

117.6 r 22.6*

125.1 f 22.7*

lschemia

1

Heart rate (beatslmin)

*

103.8 + 24.6

§

120.4 ‘- 17.8t

122.3 + 18.7t

124.0 + 18.9

124.8 + 16.9

128.4 -f 16.2*

Systolic arterial pressure (mmHg)

*

128.6 2 14.3

121.5 -f 11.4

116.0 ? 9.7*

114.8 + 7.7’

105.1 * 12.2’

0

97.9 * 12.6t

92.63 ‘- 10.8t

93.63 + 11.2t

89.38 * 13.2t

86.0 -t 11.0t

Diastolic arterial pressure (mmHg)

*

98.6 + 8.1

95.2 2 9.9

89.5 ? 10.0

89.9%

§

69.5 + 16.2t

63.1 ‘- 14.5t

66.1 + 15.6t

62.0 2 13.7t

LV dP/dt,,,

(mmHg/sec)

11.3

79.6 ? 13.7* 60.6 ? 12.8t

*

1696.3 t 457

1618.8 + 396

1432.5 * 279*

1413.8 2 295*

1291 ? 278*

§

1206.3 + 228t

1205.0 t 319t

1180.0 or 209t

1086.3 + 230t

1025 * 205t

Systemic vascular resistance (mmHg/L/min)

*

71.8 + 35.9

76.1 ? 34.8

78.8 2 47.5

74.6 2 28.6

70.7 k 27.4

§

68.4 2 22.2

67.8 -t 18.8

73.9 ? 24.4

74.1 * 22.9

75.1 ? 20.8

Stroke volume (mL)

*

17.7 + 6.9

15.3 t 6.4

13.5 + 6.1

12.7 2 4.1

11.2 ? 3.6*

§

10.5 + 3.4t

Cardiac output (mL/min)

LAD coronary blood flow (mL/min/lOO

*

g)

2480?

184

9.6 + 3.3t

9.1 f 3.3*t

8.5 f 3.2*t

7.8 r 2.7*t

2330 r 165

2189 f 157

2073 2 148*

1897 2 137+ 1533 ? 98t

§

1777 ‘- 123t

1808 -t 113t

1807 ? 109t

1788% 104t

*

120.2 2 42.4

86.2 -c 30.1*

68.3 2 23.0,

50.0 2 18.7*

0 * o*

5

90.7 ‘- 38.4t

65.6 * 21.2*

56.6 ? 22.1*

41.8 ? 18.8’

0 r o*

LAD coronary blood flow (% of Control)

*

100 * 0

76.6 + 32.4*

61.0 + 24.1+

47.6 2 27.3’

0 f 0’

§

100 + 0

76.5 + 14.1*

65.6 + 17.8*

47.4 + 11.51

0 2 o*

LV end-diastolic pressure (mmHg)

*

8.3 r 2.4

6.3 t 1.8

5.8 2 2.0

8.5 + 4.4

9.6 ? 4.0

5

4.8 + 2.0t

4.4 f 1.6

4.6 2 1.7

Coronary perfusion pressure (mmlig)

*

90.4 f 7.56

89.0 ? 10.3

83.8 -t 10.1

81.4?

§

64.8 & 16.2t

58.8 ? 14.5t

61.6 * 15.4t

56.7 ? 13.2t

5.3 * 1.4 12.2

9.0 ? 3.2* 70.0 f 13.6* 51.6 ? *t

?? P < 0.05 v Control. tP < 0.05 prediltiazem v postdiltiazem. SPrediltiazem. IPostdiltiazem.

produced by tightening the occluding snare were similar at the four stages of regional ischemia before and after diltiazem, averaging 23%, 37%, 52%, and 100% of control (Table 1). Prior to diltiazem and coincident with the externally imposed decreases in LAD flow, increases in heart rate and reductions in systolic arterial pressure and LV dP/dt,, at 11, 12, and TO occurred. Cardiac output decreased at 12 and TO. Diastolic arterial and coronary perfusion pressures and stroke volume decreased only at TO. There were no statistically significant changes in systemic vascular resistance. Following diltiazem and prior to coronary constriction, heart rate increased and systolic and diastolic arterial pressures, LV end-diastolic and coronary perfusion presLAD coronary blood flow, stroke sures, LV dP/dt,,, volume, and cardiac output all decreased. At all levels of coronary constriction following diltiazem, there were decreases in systolic and diastolic arterial pressures, stroke volume, cardiac output, LV dP/dt,,, and coronary perfusion pressure. Heart rate increased at CC, and then remained constant relative to the prediltiazem state. The regional muscle effects of the reductions in coronary flow in the LAD perfusion territory (Table 2) included decreased systolic shortening and increased postsystolic shortening at 11, 12, and TO. Diltiazem did not alter the

magnitude of the changes in systolic or postsystolic shortening brought about by coronary constriction (Figs 1, 2). End-diastolic length increased at TO before and after diltiazem. In the LC perfusion territory (Table 2), changes occurred only in end-diastolic length. With LAD coronary constriction prior to diltiazem, there were small ( - 3%) decreases at CC and Il. Similarly, small reductions occurred with diltiazem prior to and during LAD coronary constriction at all levels of ischemia. DISCUSSION

The global effects of &hernia consisted of significant reductions in systolic and diastolic arterial pressures, as well as coronary perfusion pressure, LV dP/dt,,, stroke volume, and cardiac output, and an increase in heart rate. The administration of diltiazem resulted in a mild to moderate depression of global left ventricular function similar to those caused by ischemia alone. When ischemia was induced in the presence of diltiazem, heart rate again increased, and stroke volume and diastolic and coronary perfusion pressures decreased. Also, there were further reductions, compared to prediltiazem, in systolic and diastolic arterial pressures, LV dP/dt,,, stroke volume, cardiac output, and coronary perfusion pressure. There were no changes in systemic vascular resistance, with or without

GOLDBERG ET AL

708

Table 2. Regional Muscle Function During Graded lschemia and Dikiazem (means + SD) Critical

Perfusion Territory

Control

Parameter

TOtal

Constriction

10.85 + 2.74

Ischemn

lschemia

2

Occlusion

LAD

End-diastolic length (mm)

*

LAD

Systolic shortening (% EDL)

*

22.61 + 5.8

23.04 t 7.9

5

19.56 2 10.0

18.55 2 9.7

LAD

Postsystolic shortening 1% TS)

*

5.29 t 6.33

4.85 k 7.25

36.26 t 19.35*

74.85 i 20.69*

100.0 t o*

0

11.50 k 12.49

11.33 + 12.89

31.11 i 19.31

63.73 t 32.9*

100.0 + o*

LC

End-diastolic length (mm)

*

11.28 k 1.79

10.93 k 1.66X

10.93 t 1.61*

11.14 i 1.54

11.25 + 1.68

9

10.64 + 1.56t

10.54 2 1.54t

10.52 i

10.63 c 1.73t

10.95 t 1.65*t

LC

Systolic shortening 1% EDL)

*

17.28 t 3.41

15.93 2 3.29

16.11 2 6.11

17.99 + 5.69

19.29 + 6.35

§

15.54 -t 5.23

15.69 + 4.97

14.88 + 4.94

16.64 z 5.97

16.95 + 6.47

LC

Postsystolic shortening (% TS)

*

9.53 -+ 10.98

7.89 + 15.89

7.04 +- 17.5

0.66 c 1.87

0.6 + 1.70

5

6.59 2 9.21

6.74 + 9.98

4.91 i 9.54

3.96 2 8.82

4.16 2 11.77

§

10.46 + 2.76

1

9.86 + 2.46t

9.71 t- 2.46

10.56 + 2.74

11.41 -e 3.27

11.73 -t 3.12*

9.93 + 2.59

10.45 + 3.06t

11.15 2 2.93x

7.63 k 3.6”

4.01 i 2.7*

15.78 k 5.5* 15.24 k 6.9

8.43 -c 4.9*

1.57t

2.18 + 2.0*

Abbreviations: LAD, left anterior descending: LC, left circumflex; EDL, end-diastolic length; TS, total shortening. *P < 0.05 v Control. tf

< 0.05 Prediltiazem v postdiltiazem

ZPrediltiazem. §Postdiltiazem.

&hernia or diltiazem. This is in contrast to the increases in systemic vascular resistances, which have been described at normal coronary flows with verapamil and halothane21,22 or isoflurane,23 or with critically reduced flows with verapamil and fentanyl.24Js The regional effects of graded ischemia, before and after diltiazem, were similar to those previously reported, ie, a reduction in systolic shortening associated with increased postsystolic shortening.17.26 However, systolic shortening did not increase in the LC segment even in the face of LAD ischemia. This is most likely related to the fact that ischemia was produced in only 34.5% * 3.2 (SD) of the wall of the left ventricle, an amount that would not be expected to induce compensatory LC changes. The regional muscle changes during interactions between calcium channel blockers and anesthetic agents can

*

01

p <0.05

VS.

also be compared with previous reports at two stages of this study: normal coronary blood flow and critical constriction. In the presence of halothane21,Z2 or isoflurane2” aneTtheria . . and with normal coronary blood flow, verapamil decreased systolic shortening and increased postsystolic shortening. By contrast, with intravenous fentanyl anesthesia,2s verapamil had no effect on systolic shortening, whereas postsystolic shortening increased, but only into a range that is probably physiologically unimportant (9.5% of total shortening). In the present study at normal coronary blood flow, the association of diltiazem-propofol produced only small insignificant changes in regional muscle function. However, propofo1,27,28 like halothane and isoflurane,29 has been reported to reduce calcium fluxes into the myocardium, and, therefore, may be expected to have interacted with diltiazem.

CONTROL *

I

I

100

75

LAD FLOW

50

25

0

(% OF CONTROL)

Fig 1. Effects of diltiazem and graded ischemia on systolic shortening (means f SE). Abbreviations: EDL, end-diastolic muscle length; LAD, left anterior descending coronary artery.

100

7’5

LAD FLOW

5’0

2’5

d

(X OF CONTROL)

Fig 2. Effects of diltiazem and graded ischemia on postsystolic shortening (means f SE). TS, total muscle shortening; LAD, left anterior descending coronary artery.

DILTIAZEM AND MYOCARDIAL ISCHEMIA

709

In the presence of critical coronary constriction, Diedericks et alz4 reported a reduction in systolic shortening and an increase in postsystolic shortening (to approximately 24% of total shortening) when verapamil was administered during fentanyl anesthesia. A change in postsystolic shortening of this magnitude may well interfere with synchronization of myocardial contraction to a degree that is of physiologic importance. In contrast to the relatively minor interaction between fentanyl and verapamil, Ramsay et a121described a considerably greater increase in postsystolic shortening when verapamil was added to halothane anesthesia. Leone et all7 reported the only previous comparable study with diltiazem. Their primary anesthetic was halothane/N20 with a basal fentanyl infusion, and coronary blood flow was critically reduced. Under these conditions, diltiazem produced a considerable decrease in systolic shortening and increase in postsystolic shortening, the latter to 70% of total shortening. In the present study, at the stage of critical constriction of the LAD, the association of diltiazem-propofol did not cause major changes in regional function of the compromised segment. The difference between this study and that of Leone et alI7 is the basal anesthetic: halothane versus propofol. This suggests that, at the infusion rate used in this study, propofol may not exert a major effect on calcium fluxes, and, therefore, probably does not appreciably potentiate the myocardial effects of diltiazem. The absence of an effect of diltiazem on regional muscle function may be seen in plots of normalized values of systolic or postsystolic shortening versus normalized coronary flow in the presence or absence of diltiazem (Figs 3,4). In both cases, the linear regressions are statistically significant for both pre-diltiazem and post-diltiazem data. For each analysis, the graphs are essentially superimposed and the slopes are not significantly different from one another. This confirms that diltiazem does not have any pharmacologic effect on regional function of compromised myocar-

25P z

20-

E a, p&

p=O.808 indicates coincidence of the lines

15-

PRE-DILTIAZEM

::: -

0

lo-

2 k 5;

5-

O”,

0

I

I

I

I

I

I

I

20

40

60

80

100

120

140

LAD FLOW (mL/min/lOOg) Fig 3. Regression analysis of systolic shortening versus LAD coronary blood flow (means + SE). The slope of each regression line is significantly different from zero (prediltiazem P = 0.026, postdiltiazem P = 0.010). while also being coincident with the other (P = 0.606). Abbreviations: EDL, end-diastolic muscle length; LAD, left anterior descending coronary artery.

p=O.348 indicates coincidence of the

PRE-DILTIAZEM

0

I 0

I 20

I 40

I 60

1 80

I 100

I 120

0

I 140

LAD FLOW (mL/min/lOOg) Fig 4. Regression analysis of postsystolic shortening versus LAD coronary blood flow (means f SE). The slope of each regression line is significantly different from zero (prediltiazem P = 0.016, postdiltiazem P = 0.012). while also being coincident with the other (P = 0.346). Abbreviations: EDL, end-diastolic muscle length; LAD, left anterior descending coronary artery.

dium. Therefore, when diltiazem is added to propofol anesthesia, it has neither a beneficial nor a deleterious effect on regional myocardial function at any level of coronary blood flow. In a dog model similar to the present one, the development of postsystolic shortening was considered an early marker of myocardial ischemia,17,30J1 and it has recently been shown to correlate with lactate production.32 In the present study, because physiologically important postsystolic shortening did not develop at critical constriction with a 24% reduction in coronary blood flow, it is reasonable to conclude that there was no ischemia at this time. With further decreases in coronary blood flow, postsystolic shortening increased pari passu. However, diltiazem provided no protection against this progressive, ischemia-induced, increase in postsystolic shortening. Because postsystolic shortening was neither prevented nor exaggerated by diltiazem over the whole range of coronary flow reduction, this is consistent with the observation that diltiazem does not appear to provide any protection to the ischemic myocardium in terms of muscle function, but neither does it cause any additional untoward effects. In conclusion, diltiazem depressed global performance in the presence of a propofol infusion, but did not worsen or protect regional muscle function of the compromised segment. This lack of effect is at variance with the reported worsening of regional function by diltiazem or verapamil in the presence of halothane and critical coronary constriction, and suggests that the detrimental effects of calcium channel blockers may be smaller or even eliminated when given in the presence of intravenous anesthetic agents (ie, fentanyl, propofol) in contrast to inhalation anesthetic agents (ie, halothane, N20). ACKNOWLEDGMENT

The authors wish to thank technical assistance.

Mr W.A.

Ryder

for his excellent

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