THE HAEMODYNAMIC EFFECTS OF SHORT-ACTING BARBITURATES

Transcription

1 Brit. J. Anaesth. (1969), 41, 534 THE HAEMODYNAMIC EFFECTS OF SHORT-ACTING BARBITURATES A Review BY C. M. CONWAY AND D. B. ELLIS The circulatory effects of intravenous barbiturates have been the subject of investigation by pharmacologists and anaesthetists for many years. Depression of the circulatory system by these drugs has been recognized by most workers and at different times many mechanisms have been invoked as being responsible for this depression. Some aspects of this subject have been reviewed by Dundee (1956,1965) and Price (1960). In reviewing this subject it is convenient to consider first the effect of various barbiturates on individual organs before discussing changes caused by these drugs on various physiological functions. EFFECT OF BARBITURATES ON MAMMALIAN HEARTS Myocardial depression has been demonstrated with even moderate doses of barbiturates on many occasions in animal preparations. Gruber and Baskett (1924) demonstrated a fall in heart rate, decreased force of heart beat and cardiac dilatation when phenobarbitone was administered to dogs and cats. In this study auricular depression was greater than ventricular depression. Olmstedt and Ogden (1930) showed that small doses of amylobarbitone increased the diastolic volume and reduced non-coronary outflow in a heart-lung preparation in which venous pressure was kept constant. Das (1942) showed that hexobarbitone always caused a fall in blood pressure in cats and that this was due to cardiac depression and vasodilatation. Myocardiographic records of the cat's heart in situ showed auricular and ventricular depression even with doses of hexobarbitone so small as to cause minimal changes in arterial pressure; again auricular depression was more marked than ventricular. When the arterial blood pressure was reduced by arteriotomy to the same degree as by hexobarbitone auricular and ventricular contraction were not affected. Gruber (1937) found that thiopentone had the same effect jon the heart as he had observed previously with phenobarbitone (Gruber and Baskett, 1924) but he noted that the recovery from a fall in blood pressure was much more rapid in the case of the thiopentone and that slow injections produced no change or even a rise in arterial blood pressure. Gordh (1945), Woods, Wyngaarden and Seevers (1949) and Prime and Gray (1952) confirmed the depressant effect of thiopentone on the heart-lung preparation. Price and Helrich (1955) have shown that such myocardial depression of the dog heartlung preparation is less than that produced by ether, cyclopropane and nitrous oxide. Daniel and colleagues (1956) studied the effect of thiopentone given with sympathomimetic amines and found that in intact dogs the cardiovascular depressant effect of thiopentone was reduced by the /3-effect of noradrenaline when the latter drug was combined with the a-blocker dibenzyline. They considered that although the tropic effects of noradrenaline might overcome the effects of vasodilatation caused by another drug, it was more probable that the improvement was due to an effect on thiopentone-induced cardiac depression. Gordh (1964) found that small doses of thiopentone, insufficient to cause respiratory arrest in rabbits, were associated with hypotension, marked dilatation of the heart, increased central venous pressure and reduced aortic blood flow, and concluded that hypotension was due primarily to direct myocardial depression rather than peripheral vasodilatation. Cotten and Bay (1956) showed that the administration of thiopentone 20 mg/kg to dogs reduced the contractile force of the left ventricle by 15 per cent as measured by Walton-Brodie strain gauge; similar results were observed by Bendixen and Laver (1962). C. M. CONWAY, M.B., B.S., F.F.A.R.C.S.; D. B. ELLIS, M.B., B.S., F.F.A.R.C.S.; Research Department of Anaesthetics, Royal College of Surgeons of England, Lincoln's Inn Fields, London W.C.2.

2 THE HAEMODYNAMIC EFFECTS OF SHORT-ACTING BARBITURATES 535 EFFECT OF BARBITURATES ON LIMB BLOOD FLOW AND VASCULAR DISTENSIBILITY The effect of barbiturates on peripheral blood flow has been studied in perfused limbs in situ, in isolated limbs in animals and in human forearms by plethysmography. Venous distensibility has been studied in human forearms and hands. Gruber and Baskett (1924) used a preparation of isolated cat hind-limb muscles perfused at constant pressure with oxygenated blood-ringer solution. They showed that phenobarbitone 200 mg caused a mean 164 per cent increase in blood flow and confirmed that this also occurred when the dog's hind limb was studied in situ by plethysmography. Das (1942) showed that hexobarbitone caused vasodilatation in an isolated perfused cat's hind limb and went on to examine the mechanism controlling the vasodilatation in a cat's hind limb perfused in situ. In this experiment the hind limb was supplied from the heart via a constant volume pump, thereby eliminating any effect of the drug on the heart directly affecting blood flow into the limb. Intravenous administration of hexobarbitone 10 mg/kg caused vasodilatation in the limb. If the limb was then denervated vasodilatation still occurred following hexobarbitone but was less than before. Das considered that the drug had a direct effect in the denervated preparation which was enhanced in the non-denervated preparation by reduction of venomotor tone. Forearm blood flow in man during barbiturate anaesthesia has been studied by Prime and Gray (1952) and Pauca and Sykes (1967). Prime and Gray (1952) used air plethysmography of the upper limb and observed a blood flow of ml/100 ml forearm/min in fifteen subjects awaiting surgery premedicated with morphine and atropine. Anaesthesia was induced with thiopentone and following curarization the subjects were ventilated with 50/50 per cent nitrous oxide and oxygen. Ten minutes later forearm blood flow had increased threefold to 17.5 (±3.7) ml/100 ml forearm/min. Ventilation was controlled but details were not given. Pauca and Sykes (1967) studied the effect of mg thiopentone alone on unpremedicated patients awaiting surgery and found that forearm blood flow fell by 19 per cent. The mean control value in this series was 7.81 ml/100 ml tissue/min (+ 2.92) whereas the mean value obtained in sixteen volunteers who were not awaiting surgery was 3.69, apprehension probably having an effect on those awaiting surgery. The study differed from that of Prime and Gray (1952) in that the flow to the hand was abolished by an occlusion cuff and the flow in the forearm muscle compartment studied by a Whitney strain gauge (Whitney, 1953). The results of the two studies cannot be compared. Eckstein, Hamilton and McCammond (1961) measured forearm venous distenibility in seven unpremedicated patients awaiting surgery. Thiopentone ( mg), administered over minutes, caused a 13 per cent fall in mean arterial pressure associated with a highly significant 30 per cent increase in venous distensibility. The patients breathed spontaneously and maintained end-expiratory carbon dioxide in a normal range throughout the study. Watson (1961) and Watson, Seelye and Smith (1962) measured the distensibility of the veins of the hand in seven healthy subjects given thiopentone. In six subjects 6 mg/kg given over 15 seconds caused a 19.2 per cent fall in diastolic blood pressure associated with a probably significant (P<0.05) increased distensibility of the veins of the hand which was maximal for 1 minute and persisted for 2 minutes. HAEMODYNAMIC STUDIES IN INTACT ANIMALS AND HUMANS Haemodynamic changes induced by intravenous barbiturates have been studied in both animals and man. In much of the work details of timing of drug administration, dosage employed, and measurement of induced chanage is lacking. In many cases the changes recorded represent the body's adaptation to the drug many minutes after its administration. Much of the work done cannot be compared because of species and methodological differences. In reviewing the effect of barbiturates on various haemodynamic functions the studies in humans will be considered first in each case. Cardiac output, stroke volume and heart rate. In resting man breathing air the normal cardiac index is given as 3.5 l./min/m 2 with 95% confidence limits of 0.7 l./min/m 2 (Barratt-Boyes and Wood, 1958). An average subject with a body

3 536 BRITISH JOURNAL OF ANAESTHESIA surface area of 1.73 m 2 would be expected to have a cardiac output within the range of l./min. Johnson (1951) investigated the changes produced by the short-acting barbiturate narkotal (sodium iso-propyl-bromallyl-methyl barbiturate) on six patients who had been premedicated with morphine and hyoscine and were awaiting surgery. The patients breathed air or oxygen at the time when measurements were made. Cardiac index fell by an average of 29 per cent from a mean control of 4.64 l./min/m 2 to a normal resting level of 3.14 l./min/m 2 ; average stroke volume fell 47 per cent from 125 ml to 66 ml and heart rate rose from 69 to 92 beats/min. Etsten and Li (1955) investigated fourteen patients premedicated with morphine and hyoscine and awaiting surgery; control conditions were only considered satisfactory when normal resting values of 3.37 (±0.72) l./min/m 2 were obtained for cardiac index and heart rate was less than 84 per minute. Cardiac index fell by 12 per cent (P>0.3) during slow induction of light thiopentone anaesthesia and by 25.4 per cent (P<0.001) on deepening anaesthesia. At both light and deep levels highly significant (P<0.001) falls in stroke volume of 20 and 35 per cent respectively were observed. Associated with these changes were increases in heart rate of 11.9 per cent (P>0.05) and 18 per cent (P<0.02). Elder and associates (1955) studied patients awaiting surgery and premedicated with morphine and either atropine or hyoscine. Control values for cardiac index were high with a mean value of 4.79 l./min/m 2. Thiopentone induction caused this to fall 24 per cent to a normal resting level of 3.75 l./min/m 2. Fieldman, Ridley and Wood (1955) studied the effects of more rapid injections of thiopentone in thirteen patients awaiting surgery. Their mean control value for cardiac index after premedication with morphine and atropine was 3.6 l./min/m 2 (range l./min/m 2 ). Induction of light thiopentone anaesthesia, as judged by the e.e.g., caused significant falls of 24 per cent in cardiac index and 27 per cent in stroke index. Cardiac index fell a further 24 per cent when deeper planes of anaesthesia were induced. There were no significant changes in heart rate. Unfortunately in this study respiration was not controlled, arterial ph falling as low as 7.25 in some patients. Ten patients breathed either 100 per cent oxygen or a 50/50 per cent nitrous oxide-oxygen mixture and in these patients arterial oxygen desaturation did not occur. In the remaining three patients who initially breathed air a mean fall of 11 per cent in oxygen saturation occurred returning to above 98 per cent when 50 per cent oxygen was given. Flickinger and colleagues (1961) premedicated a series of twelve patients awaiting surgery with morphine or pethidine and atropine or hyoscine. An hour later the mean cardiac index of 3.53 l./min/m 2 was within the normal range. Administration of mg of 2 per cent thiopentone given over minutes caused an immediate 22 per cent fall in cardiac index. There was no significant change in heart rate. Rowlands and others (1967) observed the circulatory effects of methohexitone induction in twelve patients who had supraventricular arrhythmia caused by either rheumatic or ischaemic heart disease. Premedication was with papaveretum 20 mg and promethazine 25 mg. Control measurements of cardiac index varied from 1.5 to 3.8 l./min/m 2 and stroke index varied from 15 to 40 ml./min/m 2. Half to one minute after 1.2 mg/kg methohexitone the mean value of stroke index fell by 23.9 per cent but as there was an associated 18.5 per cent increase in heart rate the cardiac index fell by a mean value of 12.2 per cent, and in only half of the patients were these falls significant. Dobkin and Wyant (1957) studied the haemodynamic effects of double the sleep dose of six barbiturates buthalitone, hexobarbitone, methohexitone, methothiourate, thiopentone, and thiamylal in unpremedicated volunteers, each experiment being performed at weekly intervals. Changes from control values for cardiac output were not significant. Prime and Gray (1952) studied the effect of morphine premedication and thiopentone-curarenitrous oxide-oxygen anaesthesia in fifteen patients. Control cardiac outputs obtained 2 hours before surgery had a mean value of 4.8 (±0.9) l./min which rose after premedication to 6.7 (±1.14) l./min. Ten minutes after induction of anaesthesia the cardiac output had fallen to the control range of 5.0 (±0.77) l./min. Sankawa (1965) used an electromagnetic flow-

4 THE HAEMODYNAMIC EFFECTS OF SHORT-ACTING BARBITURATES 537 probe on the ascending aorta to measure cardiac output continuously in twenty dogs basally anaesthetized with pentobarbitone 10 mg/kg. Ventilation was controlled with an end-expired carbon dioxide of from 4.1 to 5.0 per cent. In these animals methohexitone in a dose of 5 mg/kg caused a 5-12 per cent fall in cardiac output lasting 7 minutes; the larger dose of methohexitone 9 mg/kg produced a 50 per cent fall in cardiac output of 12 minutes duration. Greisheimer and co-workers (1953) showed no correlation between simultaneously measured cardiac output and blood thiopentone levels in dogs (r=0.253 ±0.98). Thus reductions of cardiac output below the normal human range after thiopentone anaesthesia have been observed by Etsten and Li (1955), Fieldman, Ridley and Wood (1955), Flickinger and co-workers (1961), and after methohexitone by Rowlands and co-workers (1967). In Johnson's series (1951) cardiac output fell to the lower limit of normal. Stroke volume fell proportionally more than cardiac output (Johnson, 1951; Etsten and Li, 1955; Rowlands et al., 1967) and was associated with tachycardia. These changes cannot be entirely attributed to reduction of oxygen consumption during anaesthesia or to relief of anxiety, as with neither cause would tachycardia be expected. It would appear rather that thiopentone was causing a reduction in stroke volume which led to a fall in cardiac index despite some compensatory techycardia. Prime and Gray (1952) studied the effects of a method of anaesthesia of which thiopentone was only a part although their findings do not differ from workers studying thiopentone alone. Flickinger and associates (1961) observed a 22 per cent fall in cardiac index without a change in heart rate. Elder and associates (1955) observed cardiac output values above the normal range both before and after thiopentone. Sankawa (1965) showed significant reduction of cardiac output in dogs given large doses of methohexitone. Total systemic vascular resistance. In resting man breathing air the normal value for total systemic vascular resistance is given as dyne-sec cm" 5 (Barratt-Boyes and Wood 1958). Various authors have estimated total systemic vascular resistance during haemodynamic studies on barbiturates, the results usually being obtained by calculation from mean arterial blood pressure and cardiac output. Johnson (1951) showed that in six patients in whom anaesthesia was maintained with narkotal total systemic vascular resistance rose by a mean of 17 per cent from a control level of 1010 dynesec cm" 5 but remained within the normal range. Etsten and Li (1955) obtained resting control values of 1340 (±350) dyne-sec cm- 5. Slow administration of 0.2 per cent thiopentone caused this to rise by 19 per cent during light anaesthesia and by 32 per cent in deeper planes. In the study of Fieldman, Ridley and Wood (1955) control values of total systemic vascular resistance varied from 870 to 2020 dyne-sec cnr 5. The mean value of 1450 dyne-sec cm" 5 is above the normal range. Light thiopentone anaesthesia caused no significant change in total systemic vascular resistance; deep levels caused a mean 53.8 per cent rise in resistance to 2120 dyne-sec cm" 5. Elder and co-workers (1955) showed a wide variation in the effects of thiopentone-nitrous oxide-oxygen anaesthesia upon the total systemic vascular resistance, changes varying from a 30 per cent fall in resistance to a 53 per cent rise. There was a mean rise of 9 per cent which was not statistically significant. No significant changes were observed in total systemic vascular resistance when Dobkin and Wyant (1957) compared the circulatory effects of six barbiturates. Flickinger and colleagues (1961) gave a mean control value for total systemic vascular resistance of 1375 dyne-sec cm" 5. This rose 19 per cent to 1630 dyne-sec cm" 5 immediately after induction with mg of 2 per cent thiopentone. Rowlands and co-workers (1967) observed minimal non-significant changes in total systemic vascular resistance when methohexitone was given to patients with supraventricular tachycardia. When aortic pressure and flows were measured continuously in dogs falls of up to 50 per cent in total systemic vascular resistance followed the injection of methohexitone 5 and 9 mg/kg (Sankawa, 1965). These dogs were basally anaesthetized with pentobarbitone, itself a potent depressor of barostatic reflexes (Heymans and Neil, 1958). There is no similarity in the findings of these different investigators. Sankawa (1965) demonstrated peripheral vasodilatation for a period immediately after injection of methohexitone in

5 538 BRITISH JOURNAL OF ANAESTHESIA the dog. Etsten and Li (1955) showed that vasoconstriction had occurred after the very slow infusion of thiopentone in man during which circulatory adaptation could have occurred. Fieldman, Ridley and Wood (1955) observed vasoconstriction in the deeper but not in lighter levels of anaesthesia. Flickinger and co-workers (1961) demonstrated vasoconstriction immediately after induction. Johnson (1951), Elder and associates (1955), Dobkin and Wyant (1957), Rowlands and associates (1967) found no significant change in total systemic vascular resistance with various intravenous barbiturates. Blood pressure. Changes in blood pressure observed after the administration of a barbiturate in the reports reviewed may now be considered in relation to the changes in cardiac output and total systemic vascular resistance. Johnson (1951) observed a 19 per cent fall in mean arterial pressure when narkotal caused a 29 per cent reduction of cardiac output which was still within the normal range. Etsten and Li (1955) observed no significant change in mean arterial blood pressure in patients given a slow infusion of 0.2 per cent thiopentone, as although cardiac output fell by 12 per cent during light anaesthesia and 25.4 per cent during deep anaesthesia, there was a compensatory increase of total systemic vascular resistance of 19 and 32 per cent at the two respective anaesthetic levels. Elder and others (1955) observed an 18 per cent fall in mean arterial pressure when thiopentone caused a 24 per cent fall in cardiac output to a value which was still above the normal range. There was no significant change in total systemic vascular resistance. Fieldman, Ridley and Wood (1955) observed a highly significant (P<0.001) fall in mean arterial blood pressure when light thiopentone anaesthesia caused a significant 24 per cent fall in cardiac output associated with no significant change in total systemic vascular resistance. On deepening anaesthesia there was no further change in blood pressure; a further 24 per cent fall in cardiac output was compensated by a 53.8 per cent increase in total systemic vascular resistance. The speed of injection of thiopentone was shown to be a highly significant factor in the depression of mean arterial pressure, as with injection rates greater than 175 mg/min blood pressure fell by 23 per cent but when injected at less than 50 mg/min the fall was only 8 per cent. In both series falls in pressure occurred within 90 seconds of injection of thiopentone and recovery had started within 3 minutes. Flickinger and associates (1961) observed a 9.6 per cent fall in mean arterial pressure immediately after thiopentone induction associated with a 22 per cent fall in cardiac index and a 19 per cent rise in total systemic vascular resistance. Rowlands and associates (1967) observed a 12.9 per cent fall in mean arterial pressure when methohexitone (1.2 mg/kg) was administered to patients with supraventricular tachycardia. The fall was associated with a mean 12.2 per cent fall in cardiac index and random minor changes in total systemic vascular resistance. Sankawa (1965) found that methohexitone caused falls in blood pressure of mm Hg in dogs. With a dose of 5 mg/kg the main cause of hypotension was a fall in vascular resistance as cardiac output only fell 5-12 per cent, but when 9 mg/kg was administered there was a fall in cardiac output of up to 50 per cent. Falls in arterial blood pressure were seen as transient phenomena in man and dogs immediately after injection of thiopentone or methohexitone or as a prolonged phenomenon after a larger dose (Johnson, 1951; Fieldman, Ridley and Wood, 1955; Flickinger et al., 1961; Sankawa, 1965; Rowlands et al., 1967). The degree of fall depended on the change of the balance between stroke volume, cardiac output and total systemic vascular resistance. For accurate analysis of these factors both flow and pressure must be measured continuously. The only study where this has been done was in dogs where a fall in arterial pressure associated with reduction of both cardiac output and total systemic vascular resistance occurred (Sankawa, 1965). In other studies where cardiac output was measured (after delay) by indicator dye dilution techniques hypotension was seen to have been caused by reduced cardiac output in the presence of increased total systemic vascular resistance (Fieldman, Ridley and Wood, 1955). Slow injection of thiopentone was seen to cause less hypotension than the normal rate of administration (Fieldman, Ridley and Wood, 1955) and the very slow infusion of a dilute solution caused no hypotension as the fall in cardiac

6 THE HAEMODYNAMIC EFFECTS OF SHORT-ACTING BARBITURATES 539 "i output was fully compensated by an increased total systemic vascular resistance (Etsten and Li, 1955). Dobkin and Wyant (1957) compared the circulatory effects of twice the sleep-dose of six barbiturates buthalitone, hexobarbitone, methohexitone, methothiourate, thiamylal and thiopentone in unpremedicated volunteers. Falls in mean arterial pressure ranged from 7 to 17 per cent but no significant differences between agents were demonstrated. Dundee and Moore (1961) used either thiopentone or methohexitone in a series of healthy women undergoing minor gynaecological surgery and observed that thiopentone caused a markedly higher incidence of hypotension than did the equivalent dose of methohexitone, the difference between the groups being probably significant (P=0.05). In a later study Dundee (1963) was unable to confirm this observation. Conway, Ellis and King (1968) found that in anaesthetized dogs methohexitone had a potency 3.59 times greater than thiopentone when the effect of these drugs on systolic pressure was compared. They predicted that when given in an equivalent narcotic dosage the effect on systolic blood pressure would be in the ratio thiopentone 1 to methohexitone 1.42, itself not a significant difference. It would appear that equi-anaesthetic doses of short-acting barbiturates can be expected to produce similar degrees of circulatory depression. Central blood volume. When cardiac output is measured by indicatordilution methods the theoretical "central blood volume" may be derived from cardiac output and mean circulation time. Fishman (1963) considers "The limits of this volume are wide and vague: it includes not merely the blood volume between the needles (injection and sampling sites), but also the volume of blood contained in the other branches of the venous and arterial trees having equivalent circulation times. It is a virtual volume which corresponds to an anatomical volume only under ideal conditions: if mixing of blood and tracer is complete and uniform, if the system contains neither stagnant nor sequestered blood and if there are no preferential channels which are operating to short-circuit the system." The normal value in resting man, corrected to a body surface area of 1.73 m 2 is given as 1045 ml (±200 ml) (Ebert et al, 1949). This "central blood volume" has also been called "pulmonary blood volume" (Johnson, 1951) and "intrathoracic blood volume" (Sjostrand, 1951; Etsten and Li, 1955; Flickinger et al., 1961). Johnson (1951) showed that narkotal caused a 25 per cent fall in central blood volume in subjects whose mean control value of 1380 ml was at the upper limit of normality when corrected for body surface area. The fall in volume varied from 130 to 620 ml. Etsten and Li (1955) obtained a resting control mean value of 1038 ml (+ 238 ml) and observed a probably significant (P<;0.05) mean reduction of 12.5 per cent with light thiopentone anaesthesia and a highly significant (P<0.001) mean reduction of 23 per cent in deeper levels. The range of fall of central blood volume was per cent and there was a positive correlation with the reduction in stroke volume (r=+0.765). Fieldman, Ridley and Wood (1955) demonstrated a significant (P<0.01) reduction in central blood volume during light thiopentone anaesthesia and a highly significant (P<0.001) reduction during deeper levels. Flickinger and associates (1961) in twelve subjects in whom anaesthesia was induced with thiopentone observed a fall in central blood volume in eight of ten subjects showing a fall in cardiac output, and an increase in central blood volume in the one subject with an increase in cardiac output. There was a 25 per cent fall in the mean value for the whole group. Thus all investigators agree that barbiturates administered intravenously cause significant reductions of central blood volume which in the case of Etsten and his study has been shown to correlate positively with reduction of stroke volume. Fishman (1963) cautions that it is meaningless to use the term central blood volume with its vague boundaries and its potential for internal rearrangement so long as the indicator substance is injected into a peripheral vein, but that some improvement in defining the boundaries can be obtained by injecting the indicator into the pulmonary artery. In the work reviewed, Johnson (1951) injected tracer into the pulmonary artery, Fieldman, Ridley and Wood (1955) into the superior vena cava, Flickinger and associates (1961) into the subclavian vein, and Etsten and Li (1955) into the median basilic vein.

7 540 BRITISH JOURNAL OF ANAESTHESIA Central venous pressure. Elder and co-workers (1955) noted a 15 per cent fall in central venous pressure when thiopentone was given to apprehensive subjects in whom the mean control value was 6.09 cm H,0. Fieldman, Ridley and Wood (1955) observed a probably significant (P<0.05) rise in central venous pressure associated with a 24 per cent fall in cardiac output on induction to light levels of thiopentone anaesthesia and a probably significant fall on deepening anaesthesia. Rowlands and associates (1967) observed methohexitone (1.2 mg/kg) to cause an average 50.5 per cent rise in mean right atrial pressure in six patients suffering from heart disease with supraventricular tachycardia. No significant changes in venous pressure were observed by Johnson (1951), Etsten and Li (1955), Flickinger and others (1961) when thiopentone was administered. Sankawa (1965) gave methohexitone 9 mg/kg to dogs basally anaesthetized with pentobarbitone and observed a rise in central venous pressure which remained elevated until the reduced cardiac output returned to the control value 12 minutes after injection. A rise in central venous pressure with fall in cardiac output indicates depressed cardiac action. This has been observed infrequently in studies of intravenous barbiturates (Fieldman, Ridley and Wood, 1955; Sankawa, 1965; and Rowlands et al., 1967). In the study of Sankawa the doses were large and the dogs had already received pentobarbitone. In Rowlands' study the patients had heart disease with supraventricular tachycardia. Nevertheless it must be realized that a drug which causes reduction of central blood volume may cause depression of cardiac action without any increase in central venous pressure. CONCLUSIONS Although the depressant effect of intravenous barbiturates on the cardio-vascular system have been observed for many years, the exact mechanism causing this depression is still undecided. Depression of the dog heart-lung preparation has been demonstrated by Olmstedt and Ogden (1930), Woods, Wyngaarden and Seevers (1949), Prime and Gray (1952) and Price and Helrich (1955). In intact animals Gruber and Baskett (1924), Gruber (1937), Das (1942) and Gordh (1964) have shown increased heart size and Cotten and Bay (1956) and Bendixen and Laver (1962) have shown reduction of the contractile force of the left ventricle when intravenous thiopentone was administered. Sankawa (1965) has demonstrated that methohexitone, in the presence of pentobarbitone, causes elevation of central venous pressure with reduction of cardiac output and peripheral vasodilatation. In humans increased central venous pressure has been demonstrated by Fieldman, Ridley and Wood (1955) during light thiopentone anaesthesia and by Rowlands and associates (1967) in patients with cardiac disease. In the presence of venous pooling any tendency for central venous pressure to rise due to myocardial depression might be masked by reduction of venomotor tone. Thus myocardial depression by intravenous barbiturates is well proven in heart-lung and intact animal preparations but not adequately substantiated in man. Variable effects of barbiturates upon the peripheral vascular system have been demonstrated. Dilatation of resistance vessels has been demonstrated in perfused limbs in situ and in isolated limbs (Gruber and Baskett, 1924; Das, 1942). In man the evidence is conflicting; Prime and Gray (1952) observed an increase in blood flow to the forelimb whereas Pauca and Sykes (1967) recorded a reduction of flow to the forearm excluding the hand. Thus barbiturates have been shown to cause dilatation of resistance vessels in the limbs of animal preparations but this has not been confirmed to occur in man. In man, Johnson (1951) demonstrated that narkotal reduced cardiac output and stroke index. A similar effect of thiopentone in man has been shown by Etsten and Li (1955), Fieldman, Ridley and Wood (1955) and Flickinger and others (1961). Methohexitone has also been shown to reduce cardiac output in dogs (Sankawa, 1965) and in patients with heart disease (Rowlands et al., 1967). In these studies total systemic vascular resistance behaved in a variety of ways. Etsten and Li (1955) observed vasoconstriction after slow infusion of thiopentone; Fieldman, Ridley and Wood (1955) noted vasoconstriction at deeper levels of anaesthesia and Flickinger and others (1961) observed vasoconstriction immediately after induction. Johnson (1951), Rowlands and others (1967), and Fieldman, Ridley and Wood

8 THE HAEMODYNAMIC EFFECTS OF SHORT-ACTING BARBITURATES 541 (1955) observed no significant change in total systemic vascular resistance after narkotal, methohexitone and lighter levels of thiopentone respectively. Sankawa (1965) is the only worker who measured blood pressure and cardiac output continuously and he has shown vasodilatation for a period immediately after injection of methohexitone in the dog. Prime and Gray (1952), while studying a method of anaesthesia in which thiopentone was used for induction, found falls in cardiac output within the normal range. Elder and associates (1955) observed falls in cardiac output but all values were above the normal range and changes in resistance occurred over a wide range. Dobkin and Wyant (1957) observed no significant change in cardiac output. The available evidence in humans points to a reduction of cardiac output after intravenous injection of barbiturates, with or without compensatory increase in total systemic vascular resistance. A reservation must be made to the latter conclusion in that in dogs, where it has been possible to measure pressure and flow simultaneously, vasodilatation after methohexitone in the presence of pentobarbitone was observed. When cardiac output is measured by indicator dilution technique the flow measured will be the mean of that occurring during the time from injection of indicator to the point where the extrapolated downslope intersects the baseline. Also in many studies time has been allowed to elapse between injection of the drug under investigation and injection of the indicator. It can be seen that rapidly changing flow patterns occurring immediately after injection of a drug although easily detected by continuous measurement with electromagnetic blood flow probes will be unlikely to be detected by indicator dilution methods. This may be the reason why the vasodilatation demonstrated by Sankawa (1965) has not been shown by all other workers. Such temporary vasodilatation, if it occurs, would be in agreement with the effect of barbiturates in perfused limbs in situ and in isolated limbs (Gruber and Baskett, 1924; Das, 1942). Alternatively the vasodilatation seen by Sankawa (1965) may be due to the potentiating effect of pentobarbitone used for basal sedation (Heymans and Neil, 1958). Changes in blood pressure depend on the balance between changes of cardiac output and total systemic vascular resistance. Rapid injection of barbiturates led to greater falls in pressure than did slow injections (Fieldman, Ridley and Wood, 1955) whereas very slow infusion led to no change (Etsten and Li, 1955). Equivalent narcotic doses of short-acting barbiturates appear to produce similar degrees of circulatory depression. The central blood volume has vague boundaries and is only meaningful if these boundaries have been limited by the central injection of indicator substance (Fishman, 1963). Sjostrand (1951) suggested that a reduction of the central blood volume with a reduction of blood in the pulmonary veins would lessen left ventricular diastolic rilling and stroke volume and provided that a compensatory increase in heart rate did not occur this would lead to a fall in cardiac output. Johnson (1951) injected dye into the pulmonary artery and showed that narkotal caused a reduction of central blood volume with a stroke volume almost halved; some increase in heart rate meant that the reduction of cardiac output although still significant was lessened. In one case when the patient was tilted head down central blood volume and stroke volume were restored to preinjection levels. Johnson proposed that narkotal reduced venomotor tone with a consequent shift of blood from the lung to systemic capacitance vessels. The associated fall in stroke volume supported Sjostrand's theory (1951). Flickinger and associates (1961) also showed thiopentone to cause a reduction of central blood volume with reduction of cardiac output; the indicator was injected into the subclavian vein. Etsten and Li (1955) had obtained similar results but the indicator was injected peripherally into the median basilic vein. Eckstein, Hamilton and McCammond (1961) showed that thiopentone caused a highly significant increased distensibility of the vein of the forearm and thought that this was caused by reduction of venomotor tone. A similar increased distensibility of the veins of the hand was shown by Watson, Seelye and Smith (1962). Accordingly it appears that barbiturates given intravenously cause reduction of the tone of systemic capacitance vessels leading to pooling of blood in these sites in preference to pooling in the capacitance vessels of the lung. This shift of

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