CHANGES EN CANINE MYOCARDIAL BLOOD FLOW AND OXYGEN CONSUMPTION IN RESPONSE TO HALOTHANE

Transcription

1 Br. J. Anaesth. (1974), 46, 821 CHANGES EN CANINE MYOCARDIAL BLOOD FLOW AND OXYGEN CONSUMPTION IN RESPONSE TO HALOTHANE G. SMITH, J. P. VANCE, D. M. BROWN AND J. C MCMILLAN SUMMARY The effect of 0.5, 1 and 1.5 per cent inspired halothane concentrations on myocardial Wood flow has been studied using a xenon-133 clearance technique in 12 dogs anaesthetized with pentobarbitone 30 mg/kg body weight. Halothane was found to reduce cardiac output, mean systemic arterial pressure, myocardial blood flow and oxygen consumption in proportion to its inspired concentration. Witfi the higher concentrations of halothane, there was a small increase in myocardial vascular resistance associated with a small, significant reduction in coronary sinus Po 2 and oxygen content. It is well known that halothane can depress myocardial contractility leading to a reduction in cardiac output and mean arterial pressure in the intact animal (Hughes, 1973; Gil-Rodriguez, Hill and Lundberg, 1971). In the thoracotomized dog, halothane caused a reduction in coronary artery blood flow with no change in coronary vascular resistance (Weaver, Bailey and Preston, 1970), whilst in the isolated, mechanically perfused heart preparation it caused coronary vasoconstriction (Wolff et al., 1972). This study was designed to assess the effect of halothane on myocardial blood flow, vascular resistance and oxygen consumption in the intact dog. METHOD Anaesthesia was induced in 12 healthy adult mongrel dogs (weight range kg) with pentobarbitone 30 mg/kg administered intravenously. After endotracheal intubation, intermittent positive pressure ventilation was established and maintained with a Palmer pump, the stroke volume of which was adjusted to maintain an arterial Pco a at approximately 40 mm Hg; the ventilation rate was kept constant. Reflex movements were prevented by the intermittent, intramuscular administration of suxamethonium chloride 50 mg and anaesthesia was maintained with increments of sodium pentobarbitone (30-60 mg) administered at intervals of not G. SMITH,* B.SC., MH., F.F.A.RX.S.; J. P. VANCE,! M.B., CH.B., D.OBST.R.C.O.G., F.F.A.R.CS.J D. M. BROWN.j M.B., CH.B., D.OBST.R.C.O.C, F.F.A.R.OS.; J. C. McMlLLAN,* M.B., CH.B., D.OBST.R.C.O.G., F.F.A.R.C.S 1.; *University Department of Anaesthesia, Western Infirmary, Glasgow G12 8RZ; tdepartment of Anaesthesia, Royal Infirmary, Glasgow G4 OSF. less than 90 min. The inspired gas was a mixture of oxygen in nitrogen, the proportions being adjusted to maintain an arterial Po, at about 100 mm Hg. The preparation of each animal for measurement of mid-oesophageal temperature, aortic and right atrial pressure, cardiac output, arterial, right atrial and coronary sinus blood gases and ph has been described in previous publications (Vance, Brown and Smith, 1973; Smith, Vance and Brown, 1973; Vance, Parratt and Ledingham, 1971). Myocardial blood flow was measured by estimating, by external counting, the rate of clearance of radioactive xenon- 133 from the myocardium after its injection into the previously catheterized left coronary artery (Ledingham et al., 1970, 1971). The following data were derived: MOC=MBF X (Cao, - Ccs Oa ) MOA=Cao, X MBF X 0.01 MOE=(Cao, - Ccso 2 X100)/Cao 3 Vo 3 =Qt x (Ca 03 Craoj) X 0.01 Total O 3 = QtxCao 2 TOE= (Cao.-Crao,)/ Cao. X100 TPR=(MAP-RAP)/Qt MVR=(MAP-RAP)/MBF MOC=myocardial oxygen consumption (ml min" 1 loog 1 ) MBF = myocardial Wood flow (ml min- 1 loog 1 ) MOA=myocardial oxygen availability (ml min- 1 loog- 1 ) MOE=myocardial oxygen extraction (%)

2 822 BRITISH JOURNAL OF ANAESTHESIA Qt=cardiac output (litrc/min) Cao,=arterial oxygen content (ml/looml) Ccso,=coronary sinus oxygen content (ml/looml) Crao,=right atrial oxygen content (ml/100ml) Total 0,=total body oxygen availability (ml/min) TOE=total body oxygen extraction (%) TPR=total peripheral vascular resistance (units) MAP=mean arterial pressure (mm Hg) RAP=right atrial pressure (mm Hg) MVR=myocardial vascular resistance (units) After duplicate sets of measurements had been made during ventilation with O,/N 3 alone, halothane was introduced into the inspired gas from a Fluotec Mk II vaporizer (calibrated against a Riken Joburg refractometer) in concentrations of 0.5%, 1% or 1.5%. Following the introduction of halothane, a full set of measurements was made at and 30 min and halothane was then discontinued for a period of at least 30 min before new duplicate control measurements were made. The order of administration of the three different doses of halothane was randomized. A comparison has been made between the values of measurements obtained immediately before the introduction of halothane and those at and 30 min. Results have been analysed statistically using the Student's f-test for paired data. RESULTS At and 30 min mean systemic arterial pressure, myocardial blood flow, myocardial oxygen consumption, cardiac output and stroke volume were all reduced significantly with 0.5% inspired concentration of halothane (table I). The reduction in heart rate was not statistically significant. With halothane concentrations of 1% and 1.5%, there was a significant reduction of all these measurements (tables II and HI). Arterial oxygen tension and content remained constant during the halothane administration and the reduction in myocardial Wood flow was accompanied by a reduction in myocardial oxygen availability at all three dose levels. As a result of the reduction in myocardial oxygen consumption, the change in myocardial oxygen extraction from 51% to 56% with 1.5% halothane after 30 min was not significant. After 30 min of 1% and 1.5% halothane there was a proportionately greater reduction in myocardial blood flow than in coronary artery perfusion pressure during diastole as evidenced by a significant increase in myocardial vascular resistance (tables II and HI). Coronary sinus Po 3 decreased significantly with 1.5% halothane after 30 min although there were no significant changes in coronary sinus ph. The effects of halothane on mean arterial pressure, myocardial oxygen consumption, cardiac output and myocardial blood flow were a function of its concentration and the duration of exposure (figs. 1-4). TABLE I. Hatmoiynamic and blood gas data before and IS and 30 min after exposure of 12 dogs to 0.5% halothane (mean±sem). Halothane Heart rate (beats/min) Mean systemic blood pressure (mm Hg) Cardiac output (litre/min) Total peripheral resistance (units) Total body oxygen consumption (ml/min) Total body oxygen availability (ml/min) Total body oxygen extraction (%) Paot(mmHg) Pace* (mm Hg) Myocardial blood flow (ml miir 1 loog" 1 ) Myocardial vascular resistance (units) Myocardial oxygen availability (ml min" 1 loog" 1 ) Myocardial oxygen consumption (ml min" 1 loog" 1 ) Myocardial oxygen extraction (%) Coronary sinus Poi (mm Hg) Coronary sinus hydrogen ion concentration (g mol/litre) Control 175± ± ± ± ± ± ± ± ± ± ±5.2 24± ± ± ± X10-* ±7.51 x 10-" Significantly different from control values (P<0.05). min 173± ±5.6* 2.34 ±0.25* 58.9± ± ±63* 19.1 ±2.4* 109 ± ± ±4.5* 142± ±1.4* 10.7±1.5* 48.4± ± X10-* ±8.18 X10-" 30 min 171 ±6 118 ±5.4* 2.20 ±0.27* 60.3 ±5.7 96± ±84* 19.2±2.1* 108± ± ±3.9* 138± ±l.l* 10.6±1.2* 49.4 ± ± x10-* ±8.29 x lo" 10

3 HALOTHANE AND MYOCARDIAL BLOOD FLOW 823 TABLE II. Haemodynamc and blood gas data before and and 30 min after exposure of 12 dogs to 1% halothane (mean±sem). Halothane Control Heart rate (beats/min) 163 ±6.5 Mean systemic blood pressure (mm Hg) 132 ±7.2 Cardiac output Qkre/min) 2.69 ±0.25 Total peripheral resistance (units) 56.1 ±8.1 Total body oxygen consumption (ml/min) 114 ± 14.2 Total body oxygen availability (ml/min) 644±61 Total body oxygen extraction (%) 18.5 ±2.2 Pao,(mmHg) 107 ±2.9 Paco, (mm Hg) 40 ±0.8 Myocardial blood flow (ml min" 1 loogr 1 ) ±6.3 Myocardial vascular resistance (units) 134 ±6.5 Myocardial oxygen availability (ml mur 1 loog" 1 ) 24.2 ± 1.8 Myocardial oxygen consumption (ml mur 1 loog" 1 ) 12.7 ±1.5 Myocardial oxygen extraction (%) 51.1 ±4.2 Coronary sinus Poi (mm Hg) 29.3 ± 1.8 Coronary sinus hydrogen ion concentration (g mol/litre) 4.39 x 10~* ±1.08x10-* Significantly different from control values (P<0.05) min 30 min 170 ± ±6.5* 2.38 ±0.23* 53 ± ±.9 574±57* 19.9 ± ± ± ±6.5* 139 ± ±1.9» 10.8 ±1.6* 51.7 ±4.7 29± x 10-* ±1.13x10-* 5 ± ±7.0* 2.17 ±0.18* 49.1 ± ± ±45* 20.7 ± ±2.6 40± ±4.9* 4±8.3* 16.2±1.5* 8.9 ±1.2* 52.8 ± ± X10-* ±1.x10"* TABLE III. Haemodynamc and blood gas data before and and 30 min after exposure of 12 dogs to 1.5% halothane (mean±sem). Heart rate (beats/min) Mean systemic blood pressure (mm Hg) Cardiac output (lkre/min) Total peripheral resistance (units) Total body oxygen consumption (ml/min) Total body oxygen availability (ml/min) Total body oxygen extraction (%) Paoi (mm Hg) Pacoi (mm Hg) Myocardial blood flow (ml min- 1 loog" 1 ) Myocardial vascular resistance (units) Myocardial oxygen availability (ml min" 1 loogr 1 ) Myocardial oxygen consumption (ml min" 1 loog" 1 ) Myocardial oxygen extraction (%) Coronary sinus Po, (mm Hg) Coronary sinus hydrogen ion concentration (g mol/litre) Control 171 ± ± ± ± ± ± ± ±2.9 37± ± ± ± ± ± ± x 10~«±7.85 x 10-" Significantly different from control values (P<0.05) min 4±6.2* 90±5.3* 1.89 ±0.24* 56.4 ± ± ±61* 21.6±2.4* 113±2.3* 37± ±3.9* 149± ±1.1* 7.9±1.0* 52.8 ± ± X10"* ±1.42x10"* Halothane 30 min 140±7.5* 65±5.1* 1.43±0.12» 51.5±6.6* 76 ± ±31* 24.1 ±2.5* 114 ±2.7 37± ±3.3* 161±11.8* 9.9±1.0* 5.7 ±0.9* 55.7 ± ±1.8* 4.31 X10-* ±1.46x10-*

4 r 824 BRITISH JOURNAL OF ANAESTHESIA MinutM FIG. 1. Mean systemic blood pressure. MinutM FIG. 3. Cardiac output. Mmutel FIG. 2. Myocardial oxygen consumption. MJTUtB FIG. 4. Myocardial blood flow. FIGS. l^t. The effect of 0.5%, 1% and 1.5% inspired halothane concentrations on mean arterial blood pressure (fig. 1.), myocardial oxygen consumption (fig. 2), cardiac output (fig. 3) and myocardial blood flow (fig. 4). The results are shown as the mean and s.e.m. of measurements obtained and 30 min after the introduction of halothane and expressed as percentages of control measurements.

5 HALOTHANE AND MYOCARDIAL BLOOD FLOW 825 DISCUSSION It is well known that, in both animals and man, halothane causes arterial hypotension accompanied by bradycardia. These findings have been confirmed for the dog in the present study. The ganglionblocking properties of halothane (Biscoe and Millar, 1966; Price and Price, 1967; Hughes, 1973), the impaired response of peripheral vasculature to noradrenaline (Price and Price, 1966; Black and McArdle, 1962) and the direct relaxant effect of halothane on smooth muscle (Price and Dripps, 1970) are not thought to have important effects at low clinical concentrations of halothane (Hughes, 1973) where there is a considerable and dose-related direct myocardial depressant effect as suggested by measurements of a large number of indices of myocardial contractility (Hughes, 1973; Rusy, Moran and Fox, 1971; Weaver, Bailey and Preston, 1970; Prys-Roberts et al., 1972; Gersh et al., 1972). Furthermore, recent evidence suggests that 0.8% halothane has a direct effect on the myocardium which is not related to any change in responsiveness of the heart to the acetylcholine and noradrenaline released at the local nerve endings (Norman, 1973). However, it is known diat during prolonged anaesthesia in man the depressant effects of halothane on the cardiovascular system are considerably modified by autonomic activity (Eger et al., 1970) and much of the hypotension and bradycardia seen in the clinical situation is the result of autonomic imbalance and may respond to atropine (Farman, 1967). The direct myocardial depressant effect of halothane may account for the findings in the present study of a dose-related depression of myocardial oxygen consumption and cardiac output. Total peripheral vascular resistance in this study was seen to be reduced only after 30 min of ventilation with 1.5% halothane. These results are in agreement with those of Hughes (1973) who found no change in vascular resistance in dogs after min of ventilation with 1% halothane although there was a reduction with 2% and 4% of halothane. Despite the wealth of information on the direct myocardial and systemic haemodynamic effects of halothane, there have been relatively few studies of its action on the coronary circulation. In the openchest dog, using electromagnetic flow probes, it has been shown that halothane caused a reduction in coronary blood flow (Weaver, Bailey and Preston, 1970; Wolff, Graedel and Niederer, 1968) and in the closed-chest dog it has been shown by a radioisotope clearance technique that myocardial Hood flow was reduced (Merin, 1969). The present study confirms that halothane produces a reduction in myocardial Hood flow concomitantly with reductions in cardiac output and myocardial oxygen consumption. There appears to be less agreement on the effect of halothane on coronary vascular resistance. Weaver and his colleagues (1970) found, in the open-chest dog, no change in myocardial vascular resistance after min exposure to halothane in concentrations of up to 3% despite a reduction in systemic arterial pressure to 30% of control value (approximately 40 mm Hg). In a complex series of experiments using an open-chest preparation with mechanical perfusion of the left coronary artery, Wolff and his associates (1968, 1972) found that changing from ether to halothane was associated with an increase in coronary vascular resistance. The same workers found similar results in the empty, beating, mechanically perfused heart of dogs kept alive with cardiopulmonary bypass. The results of the present study using intact dogs showed that higher doses of halothane were associated with an increase in myocardial vascular resistance (table HI) with a reduction in myocardial blood flow which was of a proportionately greater degree than the reduction in myocardial oxygen consumption. This led to a small but not statistically significant increase in myocardial oxygen extraction. Weaver, Bailey and Preston (1970) found an increase in coronary sinus oxygen saturation with halothane and similar findings were obtained by Wolff et al. (1972). Bagwell (1965) and Merin (1969) found no change in coronary sinus excess lactate production and concluded that there was no evidence of myocardial hypoxaemia during halothane-induced depression of myocardial blood flow. Wolff et al. (1972) concluded that coronary vascular resistance increased "due to an autoregulating mechanism preventing unnecessary hyperperfusion" leading to only a small increase in coronary sinus oxygen saturation. The results of the present work lead to the hypothesis that halothane produces a reduction in myocardial blood flow secondary to the reduction in myocardial oxygen consumption and also in myocardial perfusion pressure. With higher doses of halothane, coronary artery vasoconstriction may occur, producing a proportionately greater reduction in myocardial oxygen availability than the

6 826 BRITISH JOURNAL OF ANAESTHESIA reduction in myocardial oxygen consumption. In the present study this was manifest by a significant reduction in coronary sinus Po, after 30 min of 1.5% halothane. However, the size of change was quite small and it is unlikely that the myocardium was in any jeopardy from the clinical doses of halothane used in this study. However, in clinical situations where impairment of myocardial perfusion exists, the use of halothane in myocardial depressant doses may be detrimental by causing further reductions in myocardial oxygen availability. ACKNOWLEDGEMENTS The authors are grateful to Dr I. McA. Ledingham of the Department of Surgery, Western Infirmary, Glasgow, for the use of equipment and facilities, to Messrs I. Douglas and K. Gorman for technical assistance, and to Mrs M. MacLeod for secretarial assistance. REFERENCES Bagwell, E. E. (1965). Effects of halothane on coronary flow and myocardial metabolism in dogs. Pharmacologist, 7, 177. Biscoe, T. J., and Millar, R. A. (1966). The effect of cyclopropane, halothane and ether on sympathetic ganglionic transmissions. Br. J. Anaesth., Black, G. W., and McArdle, L. (1962). The effect of halothane on the peripheral circulation in man. Br. J. Anaesth., 34, 2. Eger, E. I. n, Smith, N. T., Stocking, R. K., Cullen, D. J., Kadis, L. B., and Whitcher, C. E. (1970). Cardiovascular effect of halothane in man. Anesthesiology, 32, 396. Farman, J. V. (1967). Circulatory effects of atropine during halothane anaesthesia. Br. J. Anaesth., 39, 226. Gersh, B. J., Prys-Roberts, C, Reuben, S. R., and Schultz, D. L. (1972). The effect of halothane on the interactions between myocardial contractility, aortic impedance and left ventricular performance. II: Aortic input impedance and the distribution of energy during ventricular ejection. Br. J. Anaesth., 44, 767. Gil-Rodriguez, J. A., Hill, D. W., and Lundberg, S. (1971). The correlation between haemodynamic changes and arterial blood halothane concentrations during halothane-nitrous oxide anaesthesia in the dog. Br. J. Anaesth., 43, Hughes, R. (1973). The haemodynamic effects of halothane in dogs. Br. J. Anaesth., 45, 416. Ledingham, I. McA., McBride, T. I., Parratt, J. R-, and Vance, J. P. (1970). The effect of hypercapnia on myocardial blood flow and metabolism. J. Physiol. (Lond), 210, 87. Parratt, J. R-, Smith, G., and Vance, J. P. (1971). Haemodynamic and myocardial effects of hyperbaric oxygen in dogs subjected to haemorrhage. Cardiovasc. Res., 5, 277. Merin, R. G. (1969). Myocardial metabolism in the halothane-depressed canine heart. Anesthesiology, 31, 20. Norman, J. (1973). Halothane and the response of the heart to autonomic nerve stimulation. Br. J. Anaesth., AS, 422. Price, H. L., and Dripps, R. D. (1970). General anaesthetics; in The Pharmacological Basis of Therapeutics (eds. Goodman, L. S., and Gilman, A.), 4th edn, p. 85. New York: Macmillan. Price, M. L. (1966). Has halothane a predominant circulatory action? Anesthesiology, 27, 764. (1967). Relative ganglion blocking properties of cyclopropane, halothane and nitrous oxide and the interaction of nitrous oxide with halothane. Anesthesiology, 28, 349. Prys-Roberts, C, Gersh, B. J., Baker, A. B., and Reuben, S. R. (1972). The effects of halothane on the interaction between myocardial contractility, aortic impedance and left ventricular performance. I: Theoretical considerations and results. Br. J. Anaesth., 44, 634. Rusy, B. F., Moran, J. E., and Fox, S. (1971). The effects of halothane and cyclopropane on the ma-rimum acceleration of left ventricular ejection and the timetension index in dogs. Anesthesiology, 34, 139. Smith, G., Vance, J. P., and Brown, D. M. (1973). The effect of propanidid on myocardial blood flow and oxygen consumption in the dog. Br. J. Anaesth., 45, 691. Vance, J. P., Brown, D. M., and Smith, G. (1973). The effect of hypocapnia on myocardial blood flow and metabolism. Br. J. Anaesth., 45, 455. Parratt, J. R., and Ledingham, I. McA. (1971). The effects of hypoxia on myocardial blood flow and oxygen consumption: negative role of beta adreno-receptors. Clin. Sd., 41, 257. Weaver, P. C, Bailey, J. S., and Preston, T. D. (1970). Coronary artery blood flow in the halothane depressed canine heart. Br. J. Anaesth., 42, 678. Wolff, G., Claudi, M., Rist, M., Wardak, M. R., Niederer, W., and Graedel, E. (1972). Regulation of coronary blood flow during ether and halothane anaesthesia. Br. J. Anaesth., 44, Graedel, E., and Niederer, W. (1968). Changes of coronary arteriolar tone, mean coronary flow and aortic pressure under halothane and ether anaesthesia in the dog. Br. J. Anaesth., 40, 810.