EFFECTS OF ENFLURANE ON MYOCARDIAL ISCHAEMIA IN THE DOG

Br.J. Anaesth. (1985), 57, 497-504

EFFECTS OF ENFLURANE ON MYOCARDIAL ISCHAEMIA IN THE DOG K. VAN ACKERN, H. O. VETTER, U. B. BRUCKNER, C. MADLER, U. MITTMAN AND K. PETER

MATERIALS AND METHODS Investigations were undertaken on 14 mongrel dogs of either sex with a mean weight of 17.8 ± 5.1 kg. Nine dogs received enflurane in a concentration of 2.2 vol.% (1 MAC; enflurane group; EG) in air. Five animals received no enflurane and served as controls (control group; CG). K. VAN ACKERN, M.D.; C. MADLER, M.D.; K . PETER, M.D.;

Institut fur Anaesthesiologie, LM-Universitat Munchen, Nufibaumstr. 20, D-8000 Munchen FRG. H. O. VETTER, M.D.; U.

B.

BRUCKNER,

M.D.;

U.

MITTAN,

M.D.;

SUMMARY The effects of experimentally induced, severe coronary artery stenosis on regional changes in myocardial blood supply, cardiac function, and metabolism were studied in 14 dogs. The anterior interventricular branch of the left coronary artery (LAD) was constricted such that arterial inflow was reduced by 80%. Nine dogs were given enflurane in a concentration of 2.2 vol. % (1 MAC) in air, and five animals received no enflurane (controls). Regional myocardial blood supply was measured by the tracer microspheres technique, using 8-fim microspheres labelled with five different radioisotopes. Regional cardiac function (enddiastolic length of the muscle fibres = EDL; segmental shortening during systole = AL) was estimated with the aid of two ultrasonic crystals which were placed in the subendocardial layer of the myocardium supplied by the LAD. Regional myocardial metabolism (oxygen consumption; lactate extraction) was evaluated from arterial and coronary venous blood samples. The latter were collected selectively from the region supplied by the LAD via the great cardiac vein. The results showed that, during severe coronary artery stenosis comparable to clinical conditions, apart from the known actions on systemic haemodynamics and contractility, enflurane had beneficial effects on regional myocardial variables. This was indicated by reduced regional contraction, measured as EDL and AL; unchanged subendocardial blood flow without any redistribution; and improved lactate extraction in the ischaemic region.

Abteilung

Experimentelle Chirurgie, Chirurgisches Zentrum, Universitat Heidelberg, Im Neuenheimer Feld 347, D-6900 Heidelberg 1, FRG. Correspondence to K. v. A.

Anaesthesia The dogs were premedicated with morphine 0.4 mg/kg body-weight) and propiolyl-promazine

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In patients with coronary artery disease, cardiac function is governed by the oxygen consumption of the myocardium and the oxygen available to the myocardium. The major determinants of cardiac oxygen demand are: heart rate, wall tension, and contractility: an increase in any or all of these increases the requirement for oxygen. Inevitably, this means that the risks of anaesthesia and surgery are increased in patients with coronary artery disease (Tarhan et al., 1972; Topkins and Artusio, 1964). However, under clinical conditions it is difficult to evaluate precisely the effects of anaesthetic agents on myocardial ischaemia—for two main reasons: the extent of ischaemia varies greatly between individual patients, and it is impossible to delineate clearly regional changes in myocardial performance. We have developed a model of myocardial ischaemia comparable to that obtained clinically, and have investigated the effects of enflurane on regional myocardial blood supply, regional myocardial function and regional myocardial metabolism during severe coronary stenosis.

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BRITISH JOURNAL OF ANAESTHESIA

Surgical preparation

A large polyethylene (PE) catheter was placed in the femoral vein to allow infusions and injections i.v. Another PE catheter, for continuous pressure measurements (Statham P23Db) was passed into the aortic arch via a femoral artery. Cardiac output was measured by the thermodilution method, the appropriate injection catheter being placed in the right atrium via the external jugular vein. The thermistor was passed into the aortic arch via a small branch of the femoral artery. A thoracotomy was performed (fifth left intercostal space), the pericardium opened and the anterior interventricular branch of the left coronary artery (LAD) exposed immediately distal to its origin. Care was taken not to damage the closely adjacent coronary vein or the major descending arterial branches. An electromagnetic flowmeter (Statham SP2202) was fixed at this site, and a mechanical coronary constrictor with a micrometer screw gauge (Vetter and Mittmann, 1981) sited distal to the flowmeter. A flexible PE catheter was inserted, via the coronary sinus, to the great cardiac vein for selective collection of coronary venous blood from the LAD region (Obeid et al., 1972). A surgical snare was used to compress the vein during blood sampling, and p r vent any backflow from the coronary sinus (fig. 1 A microtip manometer (Millar PC35O) was plaa transmurally into the left ventricle to measure t) left ventricular pressure (LVP) and its first deriv tive (dp/di). A silicone catheter was tied into the k

auricle for the injection of radioactive microspheres. The shortening of the regional muscle fibres was estimated with the aid of two ultrasonic crystals which were placed in the subendocardial layer of the area of myocardium supplied by the LAD (fig. 1). Haemodynamics

The following variables were recorded continuously on an eight-channel recorder (Brush Mk481): Lead II electrocardiogram (ECG) using needle electrodes, LVP, dpldt, left ventricular end-diastolic pressure (LVEDP), aortic pressure, coronary flow in the LAD (CFLAD)> and shortening of the regional muscle fibres in the area supplied by the LAD (AL). Coronary perfusion pressure (CPP) was calculated as diastolic pressure minus the LVEDP. Cardiac contractility was estimated as the so-called Krayenbuehl contractility index (KI) and was calculated using the following formula (Krayenbuehl, 1967, 1969):

IP

where IP = instantaneously developed pressure. Regional myocardial function

One pair of ultrasonic transducers (Parks Electronics, Beaverton, U.S.A.) was placed in the sub-

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LAD-Flow (Combelen) 0.2 mg kg'1 i.m. Anaesthesia was induced with pentobarbitone sodium 15 mg kg"1 , Microspheres injection i.v., and after tracheal intubation, the lungs were LAD-Constrictor > w ventilated with 67% nitrous oxide in oxygen using a Drager Narkosespiromat at a rate of 12 b.p.m. Nitrous oxide was administered during the surgical preTemporary paration only. The dogs were then ventilated with an occlusion oxygen-air mixture (Flo2 = 0.33) during the measurements. The arterial oxygen tension did not exceed 16 kPa and the mean carbon dioxide tension was 5.1 ± 0.27 kPa. Ventilation was monitored by Coronary venous blood-gas analysis (Eschweiler D33) at regular intercatheter vals. Any metabolic acidosis was corrected by administration of 8.4% sodium bicarbonate. AnaesLVP, dp/df thesia was maintained by hourly doses of pentobarbitone 3 mg kg"1. Core temperature was maintained at 37 ± 1 °Cby Crystals means of a heating pad. Fluid requirements during operation were supplied by lactated Ringer's solu- FIG. 1. Diagram of the experimental procedure. LAD = left descending coronary artery; Ao = aorta; PA = pulmotion i.v. Alcuronium was given before the anterior nary artery; LVP = left-ventricular pressure; dp/dt = first thoracotomy. derivative of LVP.

ENFLURANE AND EXPERIMENTAL MYCOCARDIAL ISCHAEMIA

. EDL • 10 EDL c o r r =——

c n

. , (mm)

E'-L' -L
The extent of the segmental shortening during systole (AL) was calculated as the difference between EDL and ESL divided by EDL. AL was expressed in percent of the EDL. The standardization was carried out in accordance with the above formula. Regional myocardial blood flow Myocardial blood flow (MBF) was determined with the aid of tracer microspheres (Rudolph and Heymann, 1967). Microspheres (3M Company) with a mean diameter of 8 urn and labelled with five different radioisotopes (iodine-125, cerium-58, chromium-51, strontium-85, scandium-46) were injected to the left atrium at the measuring times. During the injection of the microspheres, a reference blood sample was drawn through a catheter in the carotid artery the tip of which rested in the arch of the aorta (Domenech et al., 1969). When all measurements were completed, the LAD was ligated and the pressure was measured distal to the occlusion ("retro-pressure")- The ratio of the retro-pressure and mean aortic pressure (MAP) served as a measure of the collateral blood supply of the area supplied by the LAD. This ratio was invariably less than 0.3, that is there was no extensive collateral supply. At the end of the experiment, the occluded LAD was injected with 20 ml of a saturated potassium chloride solution mixed with lissamine green. The green-stained part of the myocardial tissue represented the area supplied by the LAD. The heart was divided into several samples (Wirth et al., 1979). Each sample was subdivided into three layers, subendocardium, myocardial third, and sub-

epicardium and the MBF in each sample was determined by measurement of the radioactivity in relation to the reference blood sample. Myocardial metabolism In order to assess the metabolic processes in the ischaemic area of the myocardium, coronary venous blood was selectively sampled via the great cardiac vein from the region supplied by the LAD. The following variables were estimated in samples of arterial and coronary venous blood: the concentrations of potassium, sodium, lactate, pyruvate, CK-MB (Boehringer) and haemoglobin, the haematocrit, pH, PCO2, PO2, and oxygen content (Lexington Instruments, Waltham, U.S.A.). Experimental procedure The individual sections of the experimental procedure are shown in table I. MBF was determined (tracer microspheres) at points 2 , 4 , 6 , 8 and 10. The control group (CG) received no enflurane at stages 5 and 6. Statistics The results are presented as means ± standard error of the mean (SEM). Differences between the mean values were evaluated for statistical significance by Student's paired and unpaired t tests, and were considered significant at P values ^ 0.05. RESULTS

Haemodynamic variables (table II) The coronary stenosis had no effect on the mean aortic pressure (MAP) or the left ventricular pressure (LVP). The only reaction to the acute ischaemia TABLE I. Outline of the experimental design

Episode

Time (min)

1 2

0 10

3 4

20 30

5 6

40 50 60 70

9 10

80 90

Experimental procedure Basal Basal Coronary stenosis (CS) (20% of basal flow) 10 min after CS 20 min after CS Administration of enflurane 2.2 Vol% 30 min after CS( 10 min after enflurane) 40 min after CS (20 min after enflurane) End of enflurane 50 min after CS 60 min after CS Release of coronary stenosis 10 min after opening of CS 20 min after opening of CS

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endocardial layer at right angles to the axis of the heart (Franklin et al., 1973; Hagl et al., 1977). The site was selected so that both crystals were placed in the area of the myocardium supplied by the LAD. By measuring continuously the ultrasound transit times between both crystals, it was possible to trace regional wall movement of the left ventricle quantitatively and qualitatively. The end-diastolic length (EDL) and the length at the end of the ventricular systole (ESL) were measured. As the distances between the crystals differed in the various experiments, these were standardized to a baseline segmental length of 10 mm by means of the following formula (Theroux et al., 1976):

499

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TABLE II. Haemodynamic variables. E = enflurane group (n=9); C = control animals (n=5). MAP = mean aortic pressure; LVEDP = left ventricular end-diastolic pressure; CO = cardiac output; TSR = total peripheral resistance; dp/dx^JIP = (Krayenbuehl index; see Methods); CFLAD = inflow of the left anterior descending coronar artery; CPP = coronary perfusion pressure. *P<0.05; **P<0.01, enflurane group compared with the control dogs for the same time. fP<0.05 compared with the preconstriction basal value Basal Omin

10 min

20 min

Heart rate E (beat min"1) C

165±12 168116

166±11 165±17

173 + 31 183+8

MAP (mm Hg)

E C

112±5 95±5

115 + 5 96±5

LVEDP (mm Hg)

E C

4.8±0.7 3.2±0.8

CO (ml"' kg min"')

E

137±13

123±8 C E 4372±427 TSR (dyne s"1 cm"5)C 3307+348

Coronary stenosis (Flow 20% of basal value) •* Enflurane > 40 min 30 min 50 min 60 min

Basal 70 min

80 min

90 min

15319** 195+6

15919** 19916

15519* 190+7

153110* 19017

103+6 94+4

10715 94+4

10816 95±5

5.9±1.0 4.2+1.2

10515 97±4 5.3±0.9 3.3+1.0

4.910.7 2.410.8

5.4+0.6 2.410.8

118113

124+11

118111

124+12

126110

11415

172134 18718

165112 19217

153111* 19418

111+6 95+6

113+6 93±7

10218 94±6

9817f 95±5

4.7±0.6 3.4±0.8

7.211.2 4.6+1.0

7.811.5 4.6±1.0

7.211.4 4.2+1.0

7.411.5 4.0+1.0

136±11

12618

126114

121110

120+9

117111

11118

114110

51281464 35651364

4436150 If 35921423

121+8 4272+426 3334+405

11518

47101432 35481475

11018 44361435 37151408

116+10

43541356 34091378

4816+504 36301424

46191425 3538+339

45971467 3628+421

26.8+2.5 25.111.2

26.811.4+ 25.711.3+

25.0+1.6 25.211.3

25.2+1.4 25.511.5

25.8 + 1.7 26.6+1.6

25.711.5 26.8+1.5

27.8+1.7 29.011.5

29.2+1.6 28.811.1

11 + lt 6ilf

1111 7+1

911 7+1

10±l 711

10+1 6+1

1212 711

51+6 51 + 11

4616 42+10

9615 79+5

9716 7615

8614 7716

81±5f 7816

88+6 78+5

9216 8316

9315 80+5

92+4 79+6

(dp/dO/IP (s-1) CFLAD (ml min"1)

E C E C

31.8+1.5 29.4±0.4

31.312.3 30.2+0.8

39±2 33±3

3813 34+3

CPP (mm Hg)

E C

99±5 81±4

10015 8115

ENFLURANE AND EXPERIMENTAL MYOCARDIAL ISCHAEMIA

LVEDP. Cardiac output tended to decrease after enflurane in isolated experiments, but the mean reduction was not significant. Regional function (fig. 2)

A substantial increase in the end-diastolic length (EDL) was recorded 10 min after the stenosis. This was more pronounced in the enflurane group (27%; P < 0.001) than in the control group (18%; P < 0.001). Segmental shortening (AL), as a function of time, decreased significantly following stenosis in both groups (P < 0.05). Enflurane caused no decrease in AL. Discontinuation of enflurane was followed by an increase which did not occur in the control group at this time. Myocardial blood flow

Regional myocardial bloodflowdecreased following the stenosis, especially in the inner layers of the ischaemic area—20% of the baseline value in the CG and 26% in the EG. Although the constriction was 200 • m

Enflurane Control

150-

U-i

Ischaemic area

• Enflurane 100 GO

£ 10-

50 0-1 Basal

CS

CS+E

CS

Basal

CS

Basal

150-,

6-

Non-ischaemic area 5--S

4

100-

c a

fe 5o^

i

I

£ 0J

0-

Basal 0

-2-

Enflurane 0

10 I

20 30 40 50 60 70 80 90 Myocardial ischaemia I Time (min) FlG. 2. Regional myocardial function in the ischaemic area. Under enflurane a decrease of the end-diastolic muscle length (EDL) was observed in contrast to the segmental shortening of the muscle fibres (AL). Mean values ± SEM.

10

CS

CS+E

2 0 3 0 4 0 5 0

60

7 0 8 0 9 0

I—Myocardial i s c h a e n i a — ' Time (min)

FIG. 3. Myocardial blood flow in the subendocardial layers (MBF endo ). Changes in percent of basal flow in the ischaemic area of the left anterior coronary artery (LAD) and in the nonischaemic region of the circumflex coronary artery (CCA). CS = coronary stenosis. CS+E = coronary stenosis + enflurane administration.

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was a slight, non-significant increase in the heart rate. LVEDP increased slightly in the enflurane group (EG) and in the control group (CG). Contractility (dp/dr^/IP) decreased significantly in both groups (EG by 14%: CG by 17%, P < 0.05). Cardiac output was unaffected, and total peripheral resistance (TSR) was unchanged. Coronary perfusion pressure (CPP) decreased slightly in the enflurane group following the stenosis. The administration of enflurane 2.2 vol.% 20 min after the stenosis (episodes 5 and 6) was followed by effects similar to those described in the literature (Horan et al., 1977; Merin, Kumazawa and Luka, 1976). MAP decreased from 113 ±6 mm Hg by 10% 10 min after enflurane to 102 ± 8 mm Hg, and at episode 6 by 13% to 98 ± 7 mm Hg (P < 0.05). Enflurane decreased CPP from 97 ± 6 to 81 ± 5 mm Hg (P < 0.05). Heart rate was reduced by a maximum of 11%. The TSR decreased by 14% (P < 0.05) during the administration of enflurane. All these values began to increase again after the withdrawal of the enflurane, showing that the effects were reversible. Enflurane had no detectable effects on the

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BRITISH JOURNAL OF ANAESTHESIA

502 TABLE III. Regional myocardial blood flow (+SEM); ratio of flow in subendocardial layer to that in subepicardial layer. CS = coronary stenosis. CS+ E = coronary stenosis + enflurane administration

Area

Basal

CS

CS + E

CS

Basal

lOmin

30min

50min

70min

90min

0.92 ±0.06 1.05 ±0.02

0.42 ±0.08 0.29 ±0.03

0.41 ±0.07 0.56 ±0.16

0.53 ±0.05 0.64 ±0.15

1.38 ±0.24 1.14 ±0.09

1.05 ±0.04 1.17 ±0.08

1.05 ±0.06 1.08 ±0.07

1.09 ±0.05 1.09 ±0.07

1.09 ±0.07 1.16 ±0.08

1.13 ±0.08 1.13 ±0.07

Ischaemic

E C

C

maintained at the same pressure, myocardial blood flow increased in all layers in the course of the experiment, especially in the subendocardial layers (endo), so that at experimental stage 8 (= 60 min after stenosis and 20 min after termination of the enflurane administration), MBFendo in the LAD distribution was only 45% of the baseline value in the CG and 41% in the EG (fig. 3). There was, however, no significant difference between the subendocardial blood flows (MBFendo) m the two groups. The endo/epi ratio was unchanged during the ischaemic period in the LAD distribution, nor was it affected by enflurane (table III). The coronary vasoconstriction itself had no effect on the endo/epi ratio of the non-stenosed myocardium, that is, the region supplied by the circumflex coronary artery (CCA): there were no significant differences from baseline values.

10 I

20

30

40

50

60

70

Myocardial ischaemia Time (min)

'

80

90

FIG. 4. Regional myocardial lactate extraction in control dogs (o) and in the enflurane group (•). After the onset of the coronary stenosis lactate was produced in both groups. Enflurane reduced this lactate production, whereas a marked lactate output from the ischaemic area continued in the control group. Mean values ± SEM.

DISCUSSION

In this study, the effects of enflurane on regional myocardial variables were investigated in dogs in which the heart had been rendered acutely ischaemic. In both groups, the administration of pentobarbitone 15 mg kg caused the well-known increase in heart rate. However, there were no significant differences between the control animals and the enflurane group before exposure to the volatile agent. Following the coronary stenosis, a further but insignificant increase in heart rate occurred (no further increments of pentobarbitone were given during the period of myocardial ischaemia). The heart rate decreased to basal values during Myocardial metabolism (fig. 4) enflurane administration. In contrast, this variable After the onset of coronary stenosis, the normal remained increased in the control group. On the myocardial lactate extraction was turned into lactate other hand, enflurane is known to reduce the total production in both groups. This lactate production peripheral vascular resistance (Horan et al., 1977; decreased significantly after the administration of van Ackern et al., 1979). The global contractility, enflurane (P < 0.01). In contrast, in the control expressed as dp/drmax of the non-constricted left vengroup a further discernible increase in lactate pro- tricle, was diminished as much in response to duction was seen. After the withdrawal of enflurane, enflurane as in the ischaemic area, measured as lactate extraction did not change, but remained regional change in contractility, AL. This means nearly constant. The values in both groups returned that, under the influence of enflurane, the nonaffected area as well as the ischaemic region conto baseline values on release of the stenosis. There were no changes in any given direction in tracts with reduced inotropism against a smaller other metabolic values, for example pyruvate, afterload. These reductions in contractility and wall tension must result inevitably in a decrease of the sodium and potassium concentrations.

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Non-ischaemic E

-200 J

ENFLURANE AND EXPERIMENTAL MYOCARDIAL ISCHAEMIA

in the study by Behrenbeck and associates (1980) who carried out a canine study with coronary artery stenosis of approximately 80%. They reported that the administration of 0.5-1.5 MAC of halothane resulted in a significant decrease in the systolic change in wall thickness in the ischaemic area, as an expression of an increase in ischaemia. They attributed the increase in ischaemia to peripheral circulatory effects and to the global depression induced by halothane. Verrier and colleagues (1980), who also designed a study with coronary stenosis, reported that the administration of halothane 0.8 vol.% to dogs with a low mean aortic pressure of 89 or 84 mm Hg was followed by a reduction in myocardial oxygen consumption and an increase in coronary reserves, but these advantages of halothane were lost when the heart rate was maintained constant by electrical pacing. In our study, however, enflurane did not cause a significant decrease in the heart rate and so a decrease in heart rate was not responsible for the beneficial effects of enflurane. In conclusion, our study in dogs showed that enflurane may be advantageous during severe myocardial ischaemia. This is indicated by the reduced regional contraction, measured as EDL and AL, the unchanged subendocardial blood flow, and the improved lactate extraction in the ischaemic area.

ACKNOWLEDGEMENTS

We gratefully acknowledge the skilful technical assistance of Mrs I. Fottner, Miss B. Kiirschner, Miss G. Rothkegel and Dipl.Ing. H. Victor during the course of these studies. We also thank Dr E. O. Wiethoff, Deutsche Abbott GmbH for the generous supply of enflurane used in these investigations.

REFERENCES

van Ackern, K., Franke, N . , Peter, K., and Schmucker, P. (1979). Enflurane in patients with coronary artery disease. Acia Anaesthesiol. Scand. (Suppl.), 71, 71. Behrenbeck, T., Nugent, M., Quasha, A., Hoffman, E., Ritman, E., and Trinker, J. (1980). Halothane and ischemic regional myocardial wall dynamics. Anesthesiology, 53, 140. Domenech, R. J., Hoffman, J. I. E., Noble,M. I. M., Saunders, K. B., Henson, J. R., and Subijanto, S. (1969). Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ. Res., 25,581. Franklin, D., Kemper, W. S., Patrick, T., and McKown, D. (1973). Technique for continuous measurement of regional myocardial segment dimensions in chronic animal preparations. Fed. Proc, 32, 343.

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myocardial oxygen consumption unless the myocardial depression is so severe that it causes a compensatory increase in LVEDP. The fact that this did not occur is indicated by the behaviour of the EDL in the ischaemic area, and of the LVEDP in the entire ventricle. The endocardial flow rates during ischaemia were virtually the same in the two groups, with 21 ml min-'/lOO g (EG) and 23 ml mur'/lOO g (CG). The perfusion pressure during ischaemia was slightly higher in the enflurane group—but before the actual administration of enflurane—than in the control animals. The perfusion pressure decreased by 16% approximately in the course of the administration of enflurane. There was no change in this variable in the control group. At the end of the enflurane administration, perfusion pressure was 81 mm Hg, being 78 mm Hg in the control group at the same time. There was no difference between the two groups. Enflurane not only prevented a further increase in lactate production, but it led to a decrease in lactate output. As lactate production did not increase at the end of ischaemia and after withdrawal of enflurane in spite of an increase in MBF, the difference between both groups could not be explained by intracellular or interstitial lactate retention. It is very difficult to compare the results obtained in different experimental models and under different experimental conditions. Furthermore, authors differ in their interpretations of the term "critical coronary stenosis". Lowenstein and colleagues (1981) found that halo thane (between 0.5 and 2.0 vol.%) produced no change in regional myocardial ischaemia. A comparison of the two experimental models shows that Lowenstein and colleagues, according to their own definition of the changes in the regional contraction patterns, used a model of mild ischaemia, whereas our own experiments involved more severe ischaemia. They administered a basal anaesthetic of halothane 0.5 vol.% to their animals, but there was no reference to control values without halothane. Hickey and co-workers (1980), who like us measured the myocardial blood flow and lactate extraction, found that the administration of halothane at 1.2-2.1 ,MAC to dogs with 75% coronary stenosis resulted in severe reductions in endocardial blood flow and lactate production. However, the low diastolic aortic pressure of 42 mm Hg these authors reported would probably prevent a beneficial effect. This may also be the case

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504

Obeid, A., Smulyan, H., Gilbert, R., and Eich, R. (1972). Regional metabolic changes in the myocardium following coronary artery ligation in dogs. Am. Heart J., 83, 189. Rudolph, H. M., and Heymann, M. A. (1967). The circulation of the fetus in utero. Circ. Res., 21, 163. Tarhan, S., Moffitt, E. A., Taylor, W. F., and Giuliani, A. R. (1972). Myocardial infarction after general anesthesia. J.A.M.A., 220, 1451. Theroux, P., Ross, J., Franklin, D., Kemper, W. S., and Sasayama, S. (1976). Regional myocardial function in the conscious dog during acute coronary occlusion and responses to morphine, propranolol, nitroglycerin, and lidocaine. Circulation, 53, 302. Topkins, M. J., and Artusio, J. F. (1964). Myocardial infarction and surgery: A five year study. Anesth. Analg., 43, 716. Verrier, E. D., Edelist, G., Consigny, P. M., Robinson, S., and Hoffman, J. I. E. (1980). Greater coronary vascular reserve in dogs anesthetized with halothane. Anesthesiology, 53,445. Vetter, H. O., and Mittmann, U. (1981). Standardisierte Coronarstenosierung im Tierexperiment. Reduktion von Durchmesser und Querschnittsflache bei exzentrischer Einengung. Res. Exp. Med., 179, 113. Wirth, R. H., Bruckner, U. B., Keller, H. E., Rothenberger, W., Schmier, J., and Mittmann, U. (1979). Effects of moderate coronary stenosis on myocardial flow reserve in man and in the dog. Basic Res. Cardiol., 74, 351.

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Hagl, S., Heimisch, W., Meisner, H., Erben, R., Baum, M., and Mendler, N . (1977). The effect of hemodilution on regional myocardial function in the presence of coronary stenosis. Basic Res. Cadiol., 72, 344. Hickey, R. F . , Verrier, E. D . , Baer, R. W., Vlahakes, G. J., and Hoffman, J. I . E . (1980). Does deliberate hypotension produce myocardial ischemia when the coronary artery is stenotic? Aneslhesiology, 53, 89. Horan, B. F . , Prys-Roberts, C , Hamilton, W. K., and Roberts, J. G. (1977). Haemodynamic responses to enflurane anaesthesia and hypovolaemia in the dog, and their modification by propranolol. Br. J. Anaesth., 49, 1189. Krayenbuehl, H. P. (1967). Kraft-Geschwindigkeits-Beziehung wahrend der isovolumetrischen Phase der linksventrikularen Systole beim Hund (Ganztier). Helv. Physiol. Ada, 25, 200. (1969). Die Dynamik und Kontraktilitat des linken Ventrikels. Bibl. Cardiol., 23, 46. Lowenstein, E., Foex, P., Francis, C M . , Davies, W. L., Yusuf, S., and Ryder, W. A. (1981). Regional ischemic ventricular dysfunction in myocardium supplied by a narrowed coronary artery with increasing halothane concentration in the dog. Anesthesiology, 55, 349. Merin, R. G., Kumazawa, T., and Luka, N. L. (1976). Enflurane depresses myocardial function, perfusion, and metabolism in the dog. Anesthesiology, 45, 501.

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