Intravenous anaesthetics

9 Intravenous anaesthetics J. W . S E A R

Modern day true intravenous anaesthetic agents stem from the introduction of the short-acting barbiturates (thiopentone, hexobarbitone and butobarbitone) in the 1930s. However, thiopentone has profound cardiorespiratory depressant effects in the elderly, the debilitated, and the hypovolaemic patient; it is cumulative on repeated dosing or when given by continuous infusion, resulting in prolonged recovery; and it has a low therapeutic index. Despite these disadvantages, the thiobarbiturates have many desirable properties, such as onset of sleep within one arm-brain circulation time, no increase in muscle tone or myoclonia, and a low incidence of respiratory upsets (coughing, hiccoughing, etc.) on induction. They also show no significant interaction with neuromuscular blocking agents, and no effect on the normal neuroendocrine responses to anaesthesia, surgery and trauma. Thus one of them, thiopentone, still remains the archetypal induction agent against which others will be equated. The effects of any intravenous anaesthetic agent upon the circulation may be considered in terms of changes in heart rate, contractility and conduction; as well as those relating to coronary blood flow, and baroreceptor and chemoreceptor reflexes. Such effects may vary between those seen with an induction dose of an agent, and those associated with infusions for the maintenance of anaesthesia. In this review, these effects will be compared for the various true intravenous anaesthetic agents in both the patient or animal with normal myocardial function, and in the presence of cardiovascular pathophysiology associated with diseases such as arterial hypertension, valvular or ischaemic heart disease, and chronic renal disease. Most anaesthetic techniques are polypharmacy, and therefore different drugs may interact with one another in their effects on the heart; especial reference will be made to those interactions of importance in the patient with a compromised myocardium. CARDIOVASCULAR EFFECTS ASSOCIATED WITH INDUCTION AND MAINTENANCE OF ANAESTHESIA Induction

Thiopentone Although the depressant effects of barbiturates on myocardial contractility Bailli~re's ClinicaIAnaesthesiology--Vol. 3, No. 1, June 1989

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have been shown in vitro to be concentration-dependent (Price and Helrich, 1955), they are probably important in the healthy patient only immediately following administration of an induction dose. This was further confirmed by the studies of Chamberlain and colleagues (1977) using an intact dogheart preparation, where decreases in left ventricular maximum pressure generation, peak aortic flow rates, stroke volume (SV) and mean arterial pressure (MAP) were seen only at high thiopentone concentrations (> 60 txg/ml). On the other hand, even smaller doses of thiopentone may cause profound reduction in MAP and cardiac output in the compromised patient (Halford, 1943). There is little effect of the barbiturates on the sinoatrial or atrioventricular nodes, or on the Purkinje fibres. Unlike some of the halogenated agents and cyclopropane, the barbiturates do not have arrhythmogenic effects. The direct vascular effects of the barbiturates are also drug-dependent, the thiobarbiturates causing arterial vasoconstriction but reducing the constrictor response to adrenaline. The oxybarbiturates cause vasodilation. At high concentrations, all barbiturates decrease vasomotor tone, with abolition of the precapillary sphincter responses to adrenaline. Autoregulation is maintained at normal anaesthetic concentrations of the barbiturates. Thiopentone has been extensively investigated since its introduction into clinical practice in 1935. All studies show induction to be associated with a decrease in both cardiac output and mean arterial pressure, due to myocardial depression and peripheral vasodilatation. In a study comparing the cardiorespiratory effects of induction of anaesthesia with Althesin R (alphaxalone: alphadolone acetate) and methohexitone, Savege et al (1972) found thiopentone (5 mg/kg) to cause an increase in heart rate (HR) (+ 19%; maximal at 3 rain after induction), decreases in both systolic and diastolic arterial pressure (SAP and DAP) (-16% and -14% respectively) and a significant decrease in SV (-17%). Cardiac output was unchanged. These data are in contrast to Lebowitz et al (1982) where induction with thiopentone 4 mg/kg resulted in no change in systemic vascular resistance (SVR) or SV, but there was a significant reduction in cardiac output and MAP, coupled with an increase in right atrial pressure (RAP). In a comparison of the haemodynamic effects of thiopentone in young and elderly men, Christensen et al (1982) found induction of anaesthesia with thiopentone to decrease SV in both groups. At 5 min after induction, cardiac output was 94.6% of the awake value in the young patients compared with 87% in the elderly group. With induction of anaesthesia, thiopentone depresses the baroreflex control of heart rate (Bristow et al, 1969) such that this cannot be considered as accounting for the increase in heart rate observed following the onset of hypnosis. Induction doses of thiopentone (3-5 mg/kg) also cause mild ventilatory depression with elevation of the arterial Pco2 by 0.5-1.0kPa (Savege et al, 1972). Studies by Prys-Roberts and colleagues (197 la) demonstrated thiopentone to cause greater depression of MAP in both treated and untreated hypertensive patients than in comparable aged normotensive controls. In patients with coronary artery disease, induction of anaesthesia with thiopentone

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resulted in the same degree of hypotension (using equipotent doses) as in healthy subjects. Sonntag et al (1975) and Reiz et al (1981) have shown the tachycardia associated with induction with thiopentone may precipitate electrophysiological and metabolic signs of myocardial ischaemia. Methohexitone

Many of the early studies reporting use of methohexitone for induction of anaesthesia showed a similarity of effect with those described for thiopentone; indeed, Wyant et al (1957) have reported a greater cardiodepressant effect with the methoxybarbiturate. However, when true equipotent doses of the two barbiturates were compared, there were no apparent differences in cardiovascular response in normal patients (Savege et al, 1972) or those with cardiac disease (Lyons and Clarke, 1972; Tarabadkar et al, 1980) (Table 1). Table 1. Haemodynamic effects of induction of anaesthesia in healthy, unpremedicated patients receiving thiopentone (5 mg/kg) and methohexitone (1.8 mg/kg). Values indicate maximal change (%) in haemodynamic variables over the first 6 min after induction of anaesthesia. After Savege et al, 1972.

Systolic arterial pressure Diastolic arterial pressure Heart rate Cardiac output Stroke volume

Thiopentone

Methohexitone

- 16 - 14 + 15 - 5 - 19

- 15 - 9 +28 +14 - 22

Etomidate

Compared to the two agents discussed above, etomidate (a carboxylated imidazole derivative) causes less haemodynamic perturbation when used for induction of anaesthesia. Etomidate (0.3 mg/kg) produced no significant change in systemic or coronary haemodynamics in healthy patients and patients with coronary artery disease (Bruckner et al, 1974; Kettler et al, 1974; Patschke et al, 1977; Colvin et al, 1979; Criado et al, 1980). Maximum decreases in SAP and DAP were 12% and 18% respectively, while cardiac output fell by 8-11%. In a comparative study, Kettler and Sonntag (1974) investigated the influence of thiopentone, methohexitone, ketamine and etomidate on coronary blood flow and myocardial oxygen consumption (mVO2) in healthy patients. The first three agents all caused an increase in HR (and therefore in mVO2) (44--78%). In contrast, etomidate caused no significant effect. A second study by the same group (Kettler et al, 1974) using an infusion of etomidate (0.12 mg/kg/min) demonstrated an increase in coronary blood flow and decrease in coronary resistance; the coronary perfusion pressure was unchanged. Etomidate also reduces peripheral vascular resistance. In patients with cardiovascular disease, Gooding et al (1977) and Lindeburg et al (1982) have shown minimal haemodynamic

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depression following induction and during maintenance of anaesthesia. Recent comparisons of thiopentone and propofol with etomidate have demonstrated that all three agents when used for induction of anaesthesia result in comparable perturbations of arterial blood pressure, heart rate and cardiac output (Harris et al, 1988; Larsen et al, 1988). However, as will be discussed later in this review, differences exist between the agents in terms of their effect on obtunding the pressor responses to laryngoscopy and intubation. In addition, the study from Gottingen (Larsen et al, 1988) confirmed that there is similar reduction in myocardial blood flow and myocardial oxygen consumption by both etomidate and propofol.

Propofol This hindered phenol is water insoluble and has been formulated in three different solvents, the one in current use being 10% Intralipid R. Only data relating to the present formulation will be considered in this chapter. The haemodynamic effects of induction of anaesthesia have been studied in healthy patients, as well as in patients with hypertension, and valvular and ischaemic heart disease. In the unpremedicated patient, propofol (2.0-2.5 mg/kg) causes a transient increase in HR (+18%), and a comparable fall in arterial blood pressure (Johnston et al, 1987; O'Toole et al, 1987). In both of these studies, the fall in blood pressure was of greater magnitude than that seen with the comparator drugs, thiopentone and methohexitone. In the presence of opi0id premedication, induction with 2.0-2.5 mg/kg propofol is accompanied by significant decreases in SAP and DAP at 3 min after injection ( - 2 9 % and - 1 9 % , respectively), an 8-14% decrease in cardiac output, and a variable effect ( - 6 % to - 2 1 % ) on SVR (Grounds et al, !985; Coates et al, 1987a; Monk et al, 1987). In patients with treated hypertension (beta-adrenoceptor blocking drugs), propofol (2mg/kg) caused a 40% decrease in SAP, coupled with a 12% decrease in cardiac output and 28% reduction in SVR (Coates et al, 1987b). Other authors (Noble et al, 1988) have shown no significant differences in MAP and HR changes in normotensive, treated and untreated hypertensive patients (DAP 95-110 mm Hg) following induction of anaesthesia with propofol (2 mg/kg). The greatest decreases in MAP were seen in the untreated hypertensives ( - 2 1 % ) . The responses to laryngoscopy and intubation were similar in all three patient groups. In patients receiving 3 Ixg/kg fentanyl prior to propofol, Meinshausen et al (1987) showed a significantly exaggerated haemodynamic response to induction of anaesthesia when compared with propofol alone. This interaction may assume significance in the patient who is hypovolaemic or has pre-existing cardiac disease.

Ketamine In contrast to the above agents, induction of general anaesthesia with ketamine (2-10 mg/kg) is almost always associated with hypertension, tachycardia, an increase in cardiac output and increased left ventricular force of

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contraction (LV dp/dt) (Virtue et al, 1967). In vitro studies show ketamine to exert a direct depressant effect on the myocardium (Traber et al, 1968); the in vivo stimulant effect is the result of the increased plasma concentrations of adrenaline and noradrenaline. These hormonal responses can be suppressed by the combination of atropine and alpha-adrenergic blockade, but not by beta-adrenoceptor inhibition (Traber et al, 1971). Studies in humans have failed to show a close relationship between the increase in catecholamines and the change in central haemodynamic parameters (Tokics et al, 1983). In the absence of premedicant drugs, ketamine causes a 20--40mm Hg increase in SAP, and a smaller rise in DAP (peaking at 3-4min) and returning to preinduction values by 10-15 min. These effects appear to be mediated through direct CNS stimulation rather than as a result of the increase in noradrenaline concentration. As indicated above, in the absence of autonomic control, ketamine is a direct myocardial depressant and vasodilator. These in vivo stimulant effects may be obtunded by a number of other intravenous agents such as thiopentone, diazepam, flunitrazepam and midazolam. In a study exploring the circulatory responses to induction of anaesthesia with 2 mg/kg i.v. ketamine, Tweed et al (1972) found no significant differences in the behaviour of patients with cardiac disease and those with healthy myocardial tissue. In agreement with other published data, they reported both central and peripheral drug effects, with increases in arterial blood pressure, cardiac output (+29%), HR (+33%), PAP (+44%), but a constant SV.

Benzodiazepines The cardiovascular effects of the benzodiazepines, and in particular those of midazolam when used for induction of anaesthesia in healthy patients, are comparable with those of thiopentone (Lebowitz et al, 1982). Midazolam (0.25 mg/kg) significantly decreased MAP and slightly decreased cardiac output, SV and HR. When administered to patients with ischaemic heart disease, 0.2mg/kg caused small but significant reductions in MAP, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), SV, and right and left ventricular stroke work index (RVSWI and LVSWI). In contrast to diazepam, midazolam increased HR, but also lowered MAP, SV, and LVSWI (Reves et al, 1979). The haemodynamic effects of midazolam were not influenced by the addition of 50% nitrous oxide (Samuelson et al, 1981); while the addition of nitrous oxide to diazepam caused elevation of right atrial pressure (RAP) (McCammon et al, 1980). Studies by Schulte-Sasse et al (1982) in patients with ischaemic and valvular heart disease showed midazolam to cause significant reductions in MAP (-20%), and smaller decreases in cardiac output. Heart rate, SV, PAP, SVR and pulmonary vascular resistance (PVR) were unchanged. Samuelson and colleagues (1981) failed to show any effect of midazolam in blunting the pressure reflex to laryngoscopy and intubation. However, the increases in HR and MAP were not generally associated with myocardial ischaemia as assessed by ST-segment changes. The tachycardia may be

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obtunded by administration of an opioid or inhalational anaesthetic agent. Thus, the combination fentanyl-midazolam has been shown to cause a 24--32% decrease in MAP, a 25% decrease in SV, and a 46% decrease in LVSWI. When given to animals, diazepam (2 mg/kg) caused an increase in systemic blood pressure and renal vascular resistance, and hence a decrease in renal blood flow (Priano, 1982). Studies with diazepam in humans indicated no change in filling pressures or cardiac output; but changes in MAP, SVR and HR (Rao et al, 1973). When given to patients with coronary artery disease, diazepam did not affect the HR or aortic pressure, but stroke volume was significantly reduced (Cote et al, 1974). In both the healthy patient and the patient suffering from coronary artery disease, diazepam and midazolam have a nitroglycerine-like effect leading to reductions in left ventricular end diastolic pressure (LVEDP), PCWP and cardial oxygen consumption. Other authors have suggested that the main determinant of the haemodynamic effects of diazepam is left ventricular function. In the presence of an LVEDP of < 15 mm Hg, diazepam had no significant effect on cardiovascular indices; whilst in the patient with an elevated LVEDP, it caused a decrease in arterial pressure and a prolonged pre-ejection period (Dauchot et al, 1984). Ikram and colleagues (1973) showed diazepam to increase coronary blood flow in both normal patients and those with proven coronary artery disease. One indication for use of the benzodiazepines has been as an adjunct to opioids for induction of anaesthesia in the healthy patient and the patient with ischaemic heart disease. When alfentanil has been used to induce anaesthesia, hypotension occurred frequently especially in the older patient with atherosclerosis or treated hypertension. The combination fentanyldiazepam also caused vasodilatation and hypotension in patients with coronary artery disease (Tomichek et al, 1983). Similar changes in MAP, with obtunding of the pressor responses to laryngoscopy and intubation have been reported when diazepam (0.125 mg/kg) was given to supplement alfentanil 100 or 200 Ixg/kg for induction of anaesthesia in ASA I or II patients (Silbert et al, 1986). Of the three benzodiazepines available for induction of anaesthesia, diazepam, lorazepam and midazolam, the latter is the best suited because of its more rapid action, and its more predictable hypnotic, amnesic and haemodynamic properties. HAEMODYNAMIC RESPONSES TO LARYNGOSCOPY AND INTUBATION

Laryngoscopy and tracheal intubation are stimuli which initiate significant pressor responses (with increases in SAP, DAP and HR) in healthy and in hypertensive patients. As these events normally occur soon after the induction of anaesthesia, the choice of intravenous agents may influence the magnitude of the pressor response. In a series of studies, Prys-Roberts and colleagues have compared the

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effects of induction with methohexitone, minaxolone citrate and propofol (Prys-Roberts, 1984). In the healthy normotensive patient, minaxolone and propofol were equally successful in attenuating the increases in blood pressure and HR, methohexitone being the least successful, so confirming the earlier studies of Forbes and Dally (1970) (see Table 1). Recently, Coates et al (1987a,b) and Monk and colleagues (1987), in middle-aged and elderly, opioid premedicated, normotensive and hypertensive patients, have shown significant but transient increases in SAP, DAP and HR in response to laryngoscopy, facilitated by suxamethonium, at 9 min after induction of anaesthesia with propofoi. However, the peak values were not significantly different from those recorded in the awake patient. In other words, propofol as an induction agent may be responsible for a greater degree of hypotension, but the increases in blood pressure and HR following laryngoscopy and intubation tend to be lower than have been recorded with the use of the barbiturates (especially methohexitone). Comparison of data for propofol and methohexitone are shown in Table 2. In a comparison of the induction and larynoscopy responses to propofol (2.5 mg/kg), etomidate (0.3 mg/kg) and thiopentone (4 mg/kg) (either alone or in combination with fentanyl (2 Ixg/kg), Harris and colleagues (1988) found a significant decrease in blood pressure, following propofol, which did not exceed the awake preinduction value even after laryngoscopy and intubation. In contrast, induction with either etomidate or thiopentone was associated with significant increases in blood pressure after laryngoscopy and intubation. Increases in HR were seen in all patient groups. When preceded by fentanyl, there were greater falls in SAP and DAP following induction of anaesthesia in all three groups, and attenuation but not abolition of the pressor responses. Table 2. Haemodynamic responses to laryngoscopy and intubation during anaesthesia in

normotensive and treated hypertensive patients following induction with propofol or methohexitone (mean +SD). (Adapted from Prys-Roberts et al, 1971b, 1983; Coates et al, 1987a,b). Normotensive Awake

Before L+I

Hypertensive Post L+I

Awake

Before L + I

Post L+I

96 (12) 46 (6) 60 (4)

132 (19) 67 (8) 81 (9)

181 (32) 100 (22) 75 (21)

100 (22) 48 (11) 71 (12)

141 (25) 52 (17) 76 (14)

127 (3) 70 (8) 95 (17)

207 (42) 111 (14) 106 (14)

192 (13) 99 (18) 84 (21)

112 (26) 64 (15) 78 (24)

171 (66) 98 (32) 96 (9)

Propofol (2 mg/kg) SAP (mm Hg) DAP (mm Hg) HR (beats/min)

147 (14) 64 (6) 71 (7)

Methohexitone (1.5 mg/kg) SAP DAP HR

156 (23) 80 (6) 74 (8)

L+I, laryngoscopy and intubation; numbers in parentheses are the standard deviations.

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Other approaches used to obtund the pressor response include heavy premedication; topical or intravenous local anaesthesia (e.g. lignocaine); induction with the water-soluble benzodiazepine midazolam (Boralessa et al, 1983); beta-adrenoceptor, vasodilator, or ACE inhibitor pretreatment; or deepening of general anaesthesia prior to laryngoscopy and intubation. HAEMODYNAMIC EFFECTS DURING MAINTENANCE OF ANAESTHESIA WITH INFUSIONS OF INTRAVENOUS AGENTS

Thiopentone Although the kinetic profile of thiopentone is less suited to continuous infusion than that of some of the more recent agents, there are several reports of the drug given by infusion to supplement either nitrous oxide in oxygen or oxygen-enriched air. One of the first studies examining the cardiovascular effects of such infusions was that of Etsten and Li (1955) who gave thiopentone as a 0.2% solution to patients premedicated with morphine and scopolamine. Four levels of anaesthesia were identified-awake, sedation, general anaesthesia and deep general anaesthesia (the assessment of anaesthetic depth being monitored by the electroencephalogram). The results are shown in Table 3. As anaesthesia deepened, there were decreases in MAP (maximum -25.4%), and increases in SVR (+31.7%). The arterial carbon dioxide tension also increased (from 6.3 to 7.2 kPa), and this was the probable cause of the increased HR ( + 18.8 %). In a separate study, Carlon et al (1978) reported similar haemodynamic effects of thiopentone when used by infusion in the intensive care unit to provide sedation for controlled ventilation. Table 3. Haemodynamic effects of infusion of thiopentone to supplement oxygen. Four levels of anaesthesia were characterized using the electroencephalogram. After Etsten and Li (1955).

Awake Light sedation Anaesthesia Deep anaesthesia

Mean arterial pressure (ram Hg)

Heart rate (beats/min)

Cardiac output (l/min/m2)

SVR (dyn s/cm5)

Pacoz (kPa)

96 103 95 88

71 70 79 85

3.37 3.32 3.01 2.81

1340 1370 1520 1510

6.26 6.66 7.07 7.21

SVR, systemic vascular resistance.

In both studies, thiopentone was infused at rates between 70 and 180 mg/h resulting in thiopentone concentrations of 15-20 txg/ml. This requirement has been substantiated by the recent studies of Crankshaw and colleagues (1985, 1987). The cardiovascular response to induction of anaesthesia (2.02.5 mg/kg) and then maintenance by an infusion of 1.0-1.5 mg/kg/min was studied in healthy patients by Becker and Tonneson (1978). Increasing the depth of anaesthesia resulted in firstly loss of the eyelid reflex; then loss of the corneal reflex (total thiopentone concentration 38,0 and free drug

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concentration 5.41zg/ml respectively), and finally loss of the trapezius response (42.0 and 6.1 g~g/ml). The latter two indices equate well with a lack of response to surgical stimulation. Haemodynamic responses to the infusion of thiopentone were determined from the blood pressure, phonocardiogram and ECG. These are shown in Table 4. Pre-ejection period (PEP) correlates well with LV dp/dt, PEP/LVET increases inversely with decreases in stroke volume, and I/PEP 2 correlates with peak ascending aortic blood flow acceleration. Table 4. Relationship between plasma thiopentone concentration (total and free drug: txg/ml) and cardiovascular effects during infusion of the barbiturate to supplement air (mean + SEM). After Becker and Tonneson (1978). Thiopentone Total Free (~g/ml) Awake

-

-

Loss of eyelid reflex

-

-

Loss of corneal reflex

37.6

5.5

(4.2) (0.5) Loss oftrazepius reflex

41.6 (4.5)

6.1 (1.3)

PEP-I SAP

HR

136 (7) 130 (8) 120

80 (4) 94f (3) 95f

(8)

(4)

l17f (4)

100f (4)

LVET-I PEP-I LVET-I 1/PEp2-I (%) (%) (%) (%) 100

100

100

100

103

110

106

85

100

117

115

74f

103

117

113

73f

SAP, systolic arterial pressure; HR, heart rate; LVET-I, left ventricular ejection time (corrected for heart rate); PEP-I, pre-ejection period; significance f: p<0.05; numbers in parentheses indicate the SEM.

The main effects of thiopentone were an increase in HR following induction of anaesthesia, and reduction in 1/PEP2 and SAP with increasing depth of anaesthesia. None of the other vascular variables changed significantly from the preinduction values. If these data are compared with those seen at similar anaesthetic depths for the volatile agents (halothane 1.25 MAC or 1.23% enflurane), thiopentone causes less cardiac depression (Filner and Karliner, 1976; Kaplan et al, 1976). More recently, Christensen et al (1983) have described use of increments of thiopentone to supplement 67% nitrous oxide, pethidine relaxant anaesthesia. The mean maintenance rates of thiopentone were 2.3 mg/kg/h and 1.3 mg/kg/h in women aged 20--40 years and 60-85 years respectively. Cardiovascular parameters were measured every 10min throughout anaesthesia in the elderly patient group using an impedance cardiographic technique. MAP did not alter during anaesthesia, but there was significant reduction in SV (maximum -20%). Coupled with the decrease in HR, there was a 30-40% decrease in cardiac output. In individual patients, there was no correlation between blood thiopentone concentrations and changes in the haemodynamic indices. The haemodynamic and encephalographic effects of high-dose thiopentone (1.25 mg/kg/min) were studied by Todd and colleagues (1985) in ten patients without cardiorespiratory disease undergoing neurosurgical procedures. At drug concentrations of 51 ixg/ml, the EEG was rendered iso-

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electric; the associated cardiovascular effects were an increase in H R (+16%), and decreases in MAP ( - 1 3 % ) , SV ( - 1 6 % ) , SVR ( - 1 6 % ) , and LVSWI and RVSWI ( - 3 4 % and - 3 1 % respectively). The left ventricular filling pressure (pulmonary capillary wedge pressure or PCWP) was maintained throughout by infusion of crystalloids and hence cardiac output was unchanged. Similar results have been reported by Koht et al (1981) following 15 mg/kg thiopentone given for induction of anaesthesia. Other intravenous agents Methohexitone

When administered by repeated increments or continuous infusion for maintenance of anaesthesia, methohexitone shows less accumulation than thiopentone. Its use has been described as a sole agent, either to complement and 67% nitrous oxide in oxygen or infusions of opioids. However many of these studies have failed to adopt a standardized infusion regimen, and few have measured the cardiovascular effects. To allow comparison between intravenous anaesthetic agents, PrysRoberts and I recognized the need for an index of equipotency similar to MAC for the volatile agents. The minimum infusion rate (MIR) is one such index, and has been defined as that rate of infusion of an intravenous agent needed to prevent response to the initial surgical incision in 50% of subjects (i.e. an EDs0 rate) (Sear and Prys-Roberts, 1979). From studies in healthy patients premedicated with either morphine 0.15mg/kg or a benzodiazepine, and receiving an infusion to supplement 67% nitrous oxide or an infusion of alfentanil, comparable rates have been determined for Althesin, minaxolone citrate, methohexitone and propofol (Sear and Prys-Roberts, 1979; Sear et al, 1981, 1983, 1984; Prys-Roberts et al, 1983; Spelina et al, 1986; Turtle et al, 1987; Richards et al, 1988). The respective EDs0 and ED95 rates, and in some cases the associated blood concentrations, are shown in Table 5. On the basis of this data, Prys-Roberts et al (1983) reported the haemoTable 5. MIR [minimum infusion rate] (EDso) and ED95 infusion rates, and the respective ECso and EC95 drug concentrations for patients receiving infusions of propofol or methohexitone to supplement 67% nitrous oxide on oxygen, or oxygen-enriched air and an infusion of alfentanil. All patients were aged 20-65 years, and premedicated with either morphine 0.15 mg/kg or a benzodiazepine. Morphine premedication

Benzodiazepine premedication

EDso

ECso

ED95

EC95

EDso

ECso

ED95

EC95

53.5 48.8

1.66 -

112.2 75.9

3.39 -

130.0 66.0

2.50 -

348.0 80.7

5.92 -

49.7

1.63

79.5

2.66

Nitrous oxide Propofol Methohexitone

Alfentanil infusion Propofol

Drug concentrations: t~g/ml; infusion rates: ~xg/kg/min.

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dynamic effects of infusions of methohexitone to supplement 67% nitrous oxide. At the EDs0 rate (60 ixg/kg/min), and in the absence of surgery, there were significant decreases in SAP and D A P ( - 3 3 % and - 2 2 % ) , and a 6% increase in HR. These changes were accompanied by a 25% fall in cardiac output, and a smaller decrease in SVR ( - 1 2 % ) . With the onset of surgery, both SAP and DAP increased due to the increase in SVR. At 2 • MIR (= 2 • EDs0; 120 ixg/kg/min), the haemodynamic changes were not significantly greater during either spontaneous or controlled ventilation. At the lower infusion rate, ventilatory depression was of a similar magnitude to that seen with other anaesthetic techniques with the exception of infusions of Althesin. In a similar study to that described for thiopentone, the effects of highdose infusions of methohexitone (400 ixg/kg/min) on the circulation have been studied by the group in San Diego in neurosurgical patients breathing 50% oxygen, and in whom ventilation was assisted to maintain an end-tidal CO2 between 4.0 and 4.5 kPa (Todd et al, 1984). The cardiovascular changes associated with these drug concentrations were broadly similar to those reported for thiopentone (Todd et al, 1985). There are several differences between this study and that of Prys-Roberts et al (1983). The latter observed a significant increase in R A P and decrease in cardiac output. However, the patients were breathing spontaneously, receiving nitrous oxide, and their Paco2 was increased. Both studies show similar reductions in SVR with infusion of the methoxybarbiturate. The increase in SVR between the 30 and 60 min data points in the study of Todd and colleagues (1984) may represent a reflex vasoconstriction in response to the fall in MAP. Cardiac output was maintained due to the increase in H R , animal data suggesting methohexitone inhibits vagal innervation of the heart (Inoue and Arndt, 1982).

Propofol Of the presently available anaesthetic agents, propofol has the most suitable kinetic profile for use by continuous infusion (clearance: 800-2000 ml/min; effective elimination half life: 60-100 min). Infusions of the hindered phenol to supplement nitrous oxide have been studied at the MIR and 2 • MIR by Coates et al (1987a) and Monk et al (1987); and may be compared with data of Claeys et al (1988) where comparable infusion rates were administered to patients breathing 100% oxygen. The haemodynamic effects of 30min infusion at 1 or 2 MIR to supplement 67% nitrous oxide, in the absence of surgical stimulation and during spontaneous ventilation, show a 30% reduction in cardiac output from preinduction values. When nitrous oxide is replaced by oxygen, there is greater stability of cardiac output, with the decrease in MAP being due to a reduction in SVR rather than a fall in cardiac output. Taken together, these three studies demonstrate the significant cardiovascular effects of nitrous oxide. With the onset of surgery, Coates and colleagues showed no change in MAP or SVR; however, in an elderly group of arteriopaths, Monk found significant increases in SAP, DAP and HR. Institution of controlled ventilation to normocapnia led to

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further increases in SVR (as a reflection of the decrease in Paco2), but no change in cardiac output. Recently, Roberts and colleagues (1988) have described an infusion scheme where anaesthesia was induced with the combination of a bolus dose (1 mg/kg propofol) and an infusion (lmg/kg per minute) for 10min. All patients lost consciousness within one minute of the loading dose and start of the infusion. A major advantage of this technique was attenuation of the haemodynamic responses to the onset of anaesthesia. The decrease in SAP and DAP were 3 0 m m H g and 1 0 m m H g respectively. This compared favourably with typical values of - 4 6 mm Hg and - 1 2 mm Hg following a single induction dose of 2 mg/kg in patients of comparable age (Coates et al, 1987a). Such an approach would obviously be beneficial in patients with myocardial disease. Although much published data on the cardiovascular effects of infusions of propofol has been obtained from patients receiving nitrous oxide, other studies have explored use of alfentanil or fentanyl as the analgesic component of total intravenous anaesthesia (TIVA) in patients breathing oxygenenriched air. One such example has been reported by Schuttler et al (1988) who administered propofol-alfentanil by microprocessor control to achieve predetermined blood concentrations of 2.5txg/ml and 100-300ng/ml respectively. With an alfentanil concentration of 100ng/ml, the haemodynamic response to laryngoscopy and intubation were completely abolished and there was considerable cardiovascular stability during surgery.

Midazolam

Recent interest has centred on the use of infusions of midazolam to supplement either fentanyl or alfentanil as a total intravenous anaesthetic technique. In patients receiving midazolam plus increments of fentanyl, Nilsson et al (1986) reported induction with midazolam 0.3mg/kg and fentanyl 0.2-0.3 mg to decrease SAP by 10-15 mm Hg, with little accompanying effect on DAP or HR. Intubation caused little perturbation of these variables; and the onset of surgery caused the SAP to return to its preinduction value but not to exceed it. With a maintenance infusion rate of 0.25 mg/kg/h, cardiovascular stability was a prominent feature. The only major disadvantage of the technique was prolonged recovery. In combination with alfentanil, and a lower infusion of midazolam (0.125 mg/kg/h), Nilsson and colleagues (1988) have shown the TIVA to offer similar haemodynamic stability. In comparison with alfentanil-nitrous oxide anaesthesia, TIVA was associated with lower heart rates at 15 and 45 mins after induction, and prior to the onset of surgery. Comparison of the cardiovascular effects of midazolam and propofol has recently been provided by Blake et al (1988) in patients receiving spinal anaesthesia. After establishment of spinal blockade, sedation was induced with either propofo1100 txg/kg/min reducing to 50 ixg/kg/min after 10 min, or midazolam 20~g/kg and an infusion of 0.8~g/kg/min. The rates were adjusted at 5 min intervals to provide a constant level of sedation so that the

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patient would just respond to verbal command. The average infusion rates from 20min post infusion onwards were 51 ixg/kg/min and 1.4 txg/kg/min respectively. Spinal anaesthesia p e r se decreased SAP and DAP by 18 and 9 m m Hg, and was associated with a 32% decrease in forearm blood flow (due to reflex vasoconstriction). Both sedative infusions further reduced SAP and DAP by 10 and 4 mm Hg, as well as decreasing the HR. However, forearm blood flow was not altered further.

EFFECTS OF INTRAVENOUS ANAESTHETICS ON BAROREFLEX ACTIVITY Physiologically the MAP is maintained within narrow limits by baroreflex mechanisms. During anaesthesia, however, there is impairment of these reflexes. Studies by Ghazwinian and colleagues (1974) in paralysed and ventilated dogs looked at baroreflex activity during nitrous oxide anaesthesia supplemented by ketamine, etomidate or methohexitone. These showed that the reflexes were not affected by ketamine; affected to a small extent only by etomidate and most affected by methohexitone--with alterations of both sensitivity and set points. Induction of anaesthesia in man usually causes a decrease in MAP coupled with increases in HR. This is not baroreflex mediated, as anaesthesia is associated with an almost complete suppression of the HR response to a pressor stimulus. The transient tachycardia is related to the release of vagal activity rather than to direct sympathetic stimulation (Skovsted et al, 1970). During maintenance of anaesthesia, methohexitone resulted in faster heart rates at lower MAPs compared with awake values (Carter et al, 1986). This is the opposite to the resetting seen with both halothane and Althesin R (Bristow et al, 1969; Jones and Prys-Roberts, 1983). There is only limited data for other intravenous agents. Marty and colleagues (1983) showed 0.4 mg/kg diazepam to cause transient depression of baroreflex activity, while Bernards et al (1985) using a closed chest dog model found thiopentone and ketamine to depress the reflex activity for at least 20rain following single intravenous dosing. Diazepam's effect was only transient, and etomidate did not appear to depress the reflex. In contrast, propofol appears to cause hypotension by a number of different mechanisms--direct myocardial depression, peripheral vasodilatation, and a central sympatholytic and/or direct central vagotonic effect (Cullen et al, 1987; Vermuyen et al, 1987; Claeys et al, 1988). Cullen and colleagues further investigated the baroreflex control of H R and MAP in the absence of surgical stimulation in patients receiving an infusion of propofol (56 or 112 ~g/kg/min) as supplement to nitrous oxide. Neither dose of propofol decreased the sensitivity of the baroreflex, but there was resetting of the reflex to allow lower arterial pressures for a given heart rate.

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COMPARISON OF DIFFERENT INTRAVENOUS ANAESTHETIC TECHNIQUES There have been few studies comparing the haemodynamic effects of the intravenous anaesthetic agents by continuous infusion in a randomized controlled manner; nor comparing intravenous agents with techniques employing volatile supplementation to nitrous oxide in oxygen. Studies by the group in Bristol, UK, have compared four intravenous agents (Althesin, methohexitone, minaxolone citrate and propofol) under equipotent conditions (MIR and multiples thereof) (Prys-Roberts, 1984). Data from their investigations for propofol (in middle-aged and elderly patients) and methohexitone are shown in Figure 1. There were no differences between patient groups with respect to SAP, cardiac output and arterial Pco2. However there were significantly higher heart rates in the methohexitone group in the absence and presence of surgery at 1 MIR, and at 2 MIR in the surgical patient. Doze ot al (1986) have also compared the cardiovascular effects of variable rate infusions of methohexitone and propofol to supplement nitrous oxide in the spontaneously breathing patient. The me an maintenance rates of infusion were 6 and 7mg/min (97 and 115 ixg/kg/min respectively). There were no differences between the groups with respect to the percentage end-tidal carbon dioxide, and the arterial blood pressure. However, for a given arterial blood pressure the methohexitone group showed significantly greater heart rates (92 vs. 76 beat/min). Two further reports from Nijmegen have compared propofol (as part of a TIVA technique) with etomidate; and with nitrous oxide-isoflurane. In patients receiving etomidate, there was an initial non-significant decrease in MAP; thereafter the arterial pressure remained above the preoperative levels. The same pattern was seen with regard to the HR. However with propofol (2mg/kg), MAP decreased to a maximum of - 2 0 % , and then continued at about 10% below the preinduction value throughout the maintenance infusion (de Grood et al, 1987a). When these two TIVA techniques were compared with a fentanyl-nitrous oxide-isoflurane technique where anaesthesia was induced with a bolus dose of thiopentone, etomidate or propofol, the hypnotic agent caused a significant increase in HR which returned towards the preinduction values by 8-10 min. MAP fell during the maintenance phase with all five anaesthetic techniques; the greatest decreases (>25%) being seen following induction of anaesthesia in the propofol-isoflurane group (de Grood et al, 1987b). In separate studies, Sear et al (1988) and Youngberg et al (1987) investigated the use of either halothane or isoflurane to supplement nitrous oxide in oxygen anaesthesia, and a variable rate continuous infusion of propofol. Again, there were no significant cardiovascular differences between the different techniques in terms of the effects of anaesthesia and surgery; although Sear and colleagues reported a greater incidence of bradycardia (HR < 40/min) in those patients receiving halothane. More recently, Doze et al (1988) compared a variable rate infusion of propofol with thiopentone-nitrous oxide-isoflurane. The range of infusion

231

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t AWAKE MIR-NS ~180 "~

'~176 N

1MIR-S

2MIR-S

T

o~ 6 0 4O Tc 7

90

70 "1-

6

8.0~ i"~

-

I TT

Figure 1. Cardiovascular indices (systolic arterial pressure, mm Hg; cardiac output per 70 kg, Vmin; heart rate, beats/rain) and arterial Pco2 (kPa) during infusions of methohexitone and propofol to supplement 67% nitrous oxide in opioid premedicated patients ( [ ] = methohexitone; [ ] = young propofol group---mean age 47 years; [ ] = old propofol group--mean age 65 years). Data shown during awake state, breathing spontaneously at 1 MIR in the absence of surgery (MIR-NS), and at 1 and 2 MIR with spontaneous breathing in the presence of surgical stimulation (1 MIR-S and 2 MIR-S). Mean + SD. After Prys-Roberts et al (1983); Coates et al (1987a); Monk et al (1987).

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requirements varied between 1 and 20 mg/min (mean 108 ~g/kg/min). HR and MAP increased significantly after laryngoscopy and intubation with both techniques. However the increase in MAP was significantly greater in the volatile group. This type of difference in haemodynamic responses to pressor stimuli may be of importance in the choice of technique in patients with a compromised myocardium (see later). EFFECTS OF INTRAVENOUS ANAESTHETICS ON MYOCARDIAL FUNCTION IN PATIENTS WITH ISCHAEMIC HEART DISEASE In patients with coronary artery disease, an increase in cardiac work may cause myocardial oxygen demand to exceed oxygen supply in tissues distal to a coronary stenosis, so leading to infarction. Thus, the anaesthetist must aim for techniques which either cause myocardial depression, or prevent the hypertensive pressor responses (and hence increase in cardiac work) to noxious stimuli such as intubation, sternotomy etc. Such approaches are usually achieved by use of volatile agents (Moffitt and Sethna, 1986) or high-dose opioid anaesthesia (de Lange et al, 1982). In unpremedicated patients with coronary artery disease, Reiz et al (1981) showed thiopentone (6 mg/kg) to significantly decrease MAP and SVR, but to cause only a small increase (+10%) in HR. Coronary blood flow decreased in parallel with the decrease in perfusion pressure. Myocardial oxygen consumption fell by 39%; but based on the ECG and coronary lactate estimations, there was maintenance of myocardial oxygen supply to demand. These data are in contrast to Sonntag and colleagues (1975) where thiopentone 5 mg/kg had little effect on MAP or cardiac output, but increased HR significantly in patients with normal myocardial function. The differences between these studies may reflect the depression of baroreflex activity, associated beta-receptor blockade, and impaired LV function in the compromised patients. More recently Reiz, (1988) has alluded to further data on the effects of thiopentone on myocardial oxygen balance. After opioid premedication, anaesthesia was induced with fentanyl 3 txg/kg and thiopentone 2-4 mg/kg. In healthy patients and in patients with depressed LV function (EF < 0.4), induction caused similar decreases in MAP. There were increases in HR in both groups, but the LV filling pressure increased in the healthy subjects, while it fell progressively in patients with impaired LV function. Left ventricular myocardial blood flow remained unchanged following induction in the healthy patients; but it decreased significantly in the other group with evidence of lactate production in one third of the patients. These data emphasize the importance of preventing any increase in HR and decrease in coronary perfusion pressure in patients with coronary stenosis. Ketamine (2 mg/kg) increased MAP, HR, PCWP and SVR in patients with generalized atherosclerotic disease (Balfors et al, 1983). Both coronary blood flow and mVO2 increased by 50%, but the supply-demand ratio was maintained with no evidence of myocardial ischaemia.

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When used to induce anaesthesia, etomidate causes approximate 10% increases in HR and cardiac output, with small and insignificant decreases in MAP and SVR. Hempelmann and colleagues (1974) examined invasively the effects of etomidate on myocardial oxygen consumption in patients with ischaemic heart disease, and found the increase in mVQ2 to mimick the increase in HR. Greater increases in HR (and hence in mVO2) were found for ketamine and methohexitone; and while these differences may not matter in healthy subjects, they may be important in patients with impaired coronary reserve. There have recently been a series of studies comparing different intravenous agents in terms of their global cardiovascular effects following induction of anaesthesia, laryngoscopy and intubation, and sternotomy in patients undergoing coronary artery bypass surgery. In a comparison of thiopentone (2 mg/kg) and propofol (1.5 mg/kg) for induction of anaesthesia in opioid premedicated patients maintained on their beta-adrenoceptor and calcium channel blocking drugs, Patrick et al (1985) found the latter anaesthetic to cause significantly greater falls in MAP and SVR. In eight out of ten patients, the SAP fell below 100mmHg and, in 2 of 10, below 70 mm Hg. However, in the thiopentone group laryngoscopy and intubation resulted in marked increases in the arterial pressure to above the preinduction value. This was not seen in the propofol group. Similar findings have been reported by Kaplan et al (1988) in a comparison of propofol and thiamylal; and by A1-Khudhairi and colleagues (1982). A fourth study, comparing thiopentone (4 mg/kg), etomidate (0.3 mg/kg) and propofol (2.5 mg/kg) in lorazepam premedicated patients, showed no changes in SVR with any of the agents, although there were decreases in PCWP and cardiac output with both thiopentone and propofol (Williams et al, 1986). Thus, the decrease in MAP was postulated to be due to the reduction in preload (reflected as a 16--29% fall in CVP in the propofol group, and 4--8% with thiopentone) rather than myocardial depression and peripheral vasodilatation. More recently, Kling and colleagues (1987) have studied the haemodynamic effects of propofol (2 mg/kg) or midazolam (0.15 mg/kg), again in patients undergoing coronary artery bypass surgery. Anaesthesia was induced with fentanyl (3 ~g/kg) and etomidate (0.3 mg/kg), and maintained with 50% nitrous oxide in oxygen. The two test drugs were administered once stable anaesthesia was attained, prior to left ventricular cannulation (for assessment of their effects on LV performance) or during bypass (to assess their effects on arterial perfusion). Propofol decreased SAP and DAP to a greater extent than midazolam, but there were similar reductions in cardiac output and stroke volume ( - 15% and - 10%, respectively). SVR decreased with propofol; whilst LV dp/dtmax was reduced by 24% with propofol and by 18% with midazolam. During bypass, midazolam had little effect on perfusion pressure, whilst there was a significant reduction with propofol. This latter finding has been supported by the studies of Boer et al (1988). Stephan et al (1986) have examined further the effects of propofol on the compromised heart by investigation of myocardial blood flow and myo-

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cardial metabolism. The twelve patients undergoing bypass surgery maintained their normal drug therapy up to the morning of surgery. Induction with propofol (2 mg/kg) decreased MAP and cardiac output (-19%), and heart rate was increased (+12%). Myocardial blood flow and myocardial oxygen consumption decreased by 26% and 31% respectively. One of the twelve patients showed lactate production--evidence of myocardial oxygen imbalance. During maintenance anaesthesia with propofol by infusion (2001xg/kg/min) and fentanyl (10~g/kg), surgical stimulation caused increases in MAP and HR towards preinduction values. Sternotomy was followed by return of all systemic haemodynamicindices to normal with the exception of cardiac output. Lactate production, probably due to coronary vasospasm, was observed at sternotomy in a further patient. The significance of these findings has not fully been evaluated to date. More usually hypnotic drugs are used in conjunction with opioids for both induction and maintenance of anaesthesia. Vermuyen et al (1987) examined the effects of propofol 1.5mg/kg and fentanyl 8 txg/kg for induction of anaesthesia in 15 patients with 2- or 3-vessel disease and with ejection fractions greater than 55% and LVEDP < 14mmHg. All patients were maintained on their current anti-anginal therapy. Induction of anaesthesia resulted in a decrease in MAP (-25%), SVR (-25%) and LWSWI (-32%). These changes were not found to be associated with any increase in HR or cardiac output. During maintenance of anaesthesia with propofol 5-15 mg/kg/h, there was only an increase in SVR. No clinical signs indicative of ischaemia were seen during surgery. The decrease in LVSWI in the presence of unchanged filling pressures were taken to indicate myocardial depression. With this technique, only one of the 15 patients became hypertensive following sternotomy. This incidence of response to sternal splitting was lower than that reported in the literature for patients receiving a high-dose fentanyl technique. Two further abstracts from LePage and colleagues (1988a,b) confirm that propofol, when used in unpremedicated patients with proven coronary artery disease, does not increase left ventricular end-diastolic or -systolic volume (LVEDV or LVESV), despite an increase in SV. In combination with fentanyl 5 Ixg/kg, there was also no impairment of LV function, although there was a significant decrease in HR (-16%) associated with reductions in both MAP and cardiac output. Taken together, all these studies with propofol in patients with ischaemic heart disease show significant decreases in arterial blood pressure, and the possibility of oxygen supply-demand imbalance. However, in combination with fentanyl, the two drugs are capable of blocking the pressor responses to surgery to a greater extent than has previously been reported for the opioid alone. EFFECTS OF INTRAVENOUS ANAESTHETICS IN PATIENTS WITH CHRONIC RENAL FAILURE The patient with end-stage renal disease has a number of medical problems

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which may influence systemic and coronary haemodynamics during the conduct of anaesthesia. These may include severe hypertension, high cardiac output, congestive cardiac failure and uraemic pericarditis. Review of the literature however reveals few data examining the cardiovascular effects of intravenous anaesthetic agents in such patients. Ketamine (2mg/kg) caused significant increases at 5 min after induction in cardiac output (+16%), right ventricular systolic pressure (RVSP) (+36%), MAP and HR (+17% and +19% respectively) (Hobika et al, 1972). These are similar magnitude effects to those seen in healthy individuals. When fentanyl (0.5 mg) was given as a bolus dose, there were no changes in cardiac output or MAP, but significant decreases in RVSP, SVR and HR ( - 2 0 % , - 2 7 % and - 17%, respectively) (Mostert et al, 1971). In a small study in opioid premedicated patients, Morcos and Payne (1985) reported the cardiovascular effects of fentanyl (5 Ixg/kg) followed by propofol 2.5 mg/kg given 2 min later to six healthy patients and four with impaired renal function. There were maximum decreases in SAP, DAP and HR of 30%, 22% and 3%, respectively, in the healthy subjects, and 39%, 40% and 10% in the uraemic patients. It is possible that these exaggerated haemodynamic responses to intravenous barbiturates in uraemic patients may be due to alterations in plasma protein binding, and deficiencies in the integrity of the blood-brain barrier. Further comparative studies of the haemodynamic effects of hypnotic agents in patients with dialysis-dependent renal failure are clearly needed. HAEMODYNAMIC EFFECTS OF NEUROMUSCULAR BLOCKING DRUGS: IMPLICATIONS FOR PATIENTS WITH THE COMPROMISED MYOCARDIUM

Use of neuromuscular blocking agents will normally have little effect on systemic haemodynamics in the healthy patient. However, the interaction of these agents with other components of general anaesthesia may be of prime importance in the patient with impaired myocardial function and especially those with valvular heart disease. For example, any increase in HR will not only increase m~O2 but also reduce diastolic time, with reduction of ventricular filling. Conversely, bradycardias should be avoided because of the resulting ventricular over-distension, with increase in pulmonary venous congestion. The general haemodynamic effects of the neuromuscular blocking agents now in use are shown in Table 6. Of particular interest are the drug interactions relating to the two newer agents, vecuronium and atracurium. There have been several reports of bradycardia occurring when atracurium or vecuronium have been used to provide relaxation. Other neuromuscular blocking agents cause vagal blockade at those doses given to achieve muscle paralysis, so resulting in tachycardia. Such increases in HR will counteract the bradycardia induced by agents such as morphine, fentanyl and halothane, as well as by vagal stimulation during surgery. In contrast atracurium has a wider dose-range difference between neuromuscular blockade and cholinergic blockade. The

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Table6. Cardiovasculareffectsof neuromuscularblocking agents. Heart rate Bloodpressure SVR Histaminerelease Suxamethonium $ ~ ~ ++ d-Tubocurarine t ~ ~ ++++ d-Methyl tubocurarine ---~,i' --->,$ ->, ~ ++ Gallamine 1' t 1' none Pancuronium 1' 1' ~ none Alcuronium ~ , 1' ~ ~ none Atracurium ~ $ i' ($) ++ Vecuronium ~, $ --* $ + (+)

same discrepancy can be seen with vecuronium, with the ED50 for blockade of cardiac muscarinic receptors being about 80 times that needed for myoneural blockade. Thus any bradycardia occurring with these agents must either be due to the effects of other anaesthetic agents on the sympathetic ganglia, or due to vagal stimulation during surgery in the absence of a blocked vagus nerve.

NEUROMUSCULAR BLOCKING AGENTS AND CARDIOVASCULAR DISEASE

Hypertension In patients with treated hypertension (and especially in patients receiving beta-adrenoceptor blocking agents), the vasodilating properties of dtubocurarine and d-methyl tubocurarine may result in significant hypotension. Pancuronium would appear to be the agent of choice. The autonomic stimulating effects of succinylcholine can result in significant increases in FIR and M A P during laryngoscopy and intubation, especially in the lightly anaesthetized hypertensive patient (Prys-Roberts et al, 1971b). This response may be attenuated by pre-treatment with betaadrenoceptor blockade. The occurrence of ventricular dysrrhythmias following intubation under succinylcholine blockade is thought to be greater in the hypertensive patient and the patient with ischaemic heart disease. Pre-treatment with d-tubocurarine (3 mg) may decrease the incidence and severity of these cardiac effects.

Coronary artery disease As already discussed, it is important to control both H R and M A P in these patients because both will, in turn, influence mVO2. Renal impairment, a common sequelae of hypertension, ischaemic heart disease and congestive cardiac failure, may also influence the effects of myoneural blocking agents through decreased elimination from the body (renal elimination: gallamine > 95%; pancuronium, d-tubocurarine and alcuronium 60-90%),

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Pancuronium

The main cardiovascular effects of pancuronium are mediated via the cardiac muscarinic receptors, such that in the healthy patient there is a significant increase in HR. Other effects include increases in MAP and plasma catecholamines following laryngoscopy and intubation. In the presence of cardiac disease, pancuronium also increases MAP, H R and Cardiac output. The relaxant enhances atrioventricular conduction, and may therefore increase the ventricular rate in patients with atrial fibrillation. During highdose fentanyl anaesthesia, Salmanpera et al (1983) have shown pancuronium to increase both H R and cardiac output. Vecuronium

This is less potent than pancuronium in potentiating cardiac sympathetic ganglion transmission; and in addition does not inhibit neuronal noradrenaline re-uptake. At normal doses in healthy patients (0.05-0.1mg/kg), vecuronium does not change H R or MAP. In the patient with coronary artery disease, anaesthetized with halothane, 0.28mg/kg vecuronium caused a slight increase in cardiac output (+9%), a 12% reduction in SVR and unchanged MAP and H R (Morris et al, 1983). In the presence of high-dose fentanyl anaesthesia, vecuronium decreased both H R and cardiac output (Salmanpera et al, 1983). Atracurium

In the healthy patient, atracurium 0.6mg/kg produces little effect on H R , and only a transient decrease in MAP during nitrous oxide-oxygen anaesthesia. Studies in patients with coronary artery disease and normal left ventricular function behave in the same manner as healthy individuals (Philbin et al, 1983). SUMMARY

The effects of intravenous hypnotic agents on the vascular responses to anaesthesia and surgery may be influenced by both inherent cardiac disease and drug-drug interactions in the patient with the compromised myocardium. Careful preoperative patient evaluation and an understanding of the altered pathophysiology, coupled with appropriate drug usage, may limit these adverse effects. Failure to do so may lead to significant cardiac related morbidity and mortality. REFERENCES

AI-Khudhairi D, Whitwam JG, Chakrabarti MK, AskitopoulouH, Grundy EM & PowrieS (1982) Haemodynamic effects of midazolam and thiopentone during induction of anaesthesia for coronary artery surgery. British Journal of Anaesthesia 54: 831-836.

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Balfors E, Haggmark S, Nyhman H, Rydvall A & Reiz S (1983) Droperidol inhibits the effects of intravenous ketamine on central hemodynamics and myocardial oxygen consumption in patients with generalised atherosclerotic disease. Anesthesia and Analgesia 62: 193-197. Becker KE & Tonneson AS (1978) Cardiovascular effects of plasma levels of thiopental necessary for anesthesia. Anesthesiology 49: 197-200. Bernards C, Marrone B & Priano L (1985) Effect of anesthetic induction agents on baroreceptor function. Anesthesiology 63: A 31. Blake DW, Donnan G, Novella J & Hackman C (1988) Cardiovascular effects of sedative infusions of propofol and midazolam after spinal anaesthesia. Anaesthesia and Intensive Care 16: 292-298. Boer F, Ros P & Bovill JG (1988) Propofol decreases systemic vasular resistance during cardiopulmonary bypass. British Journal of Anaesthesia 61: 108pp. Boralessa H, Senior DF & Whitwam JG (1983) Cardiovascular response to intubation. A comparative study of thiopentone and midazolam. Anaesthesia 38: 623-627. Bristow JD, Prys-Roberts C, Fisher A, Pickering TG & Sleight P (1969) Effects of anesthesia on baroreflex control of heart rate in man. Anesthesiology 31: 422-428. Bruckner JB, Gethmann JW, Patschke D, Tarnow J & WeymarA (1974) Untersuchungen zur wirkung yon etomidat auf dem kreislauf des menschen. Der Anaesthesist 23" 322. Carlon GC, Kahn RC, Goldiner PL et al (1978) Long term infusion of sodium thiopental-hemodynamic and respiratory effects. Critical Care Medicine 6- 311-316. Carter JA, Clarke TNS, Prys-Roberts C & Spelina KR (1986) Restoration of baroreflex control of heart rate during recovery from anaesthesia. British Journal of Anaesthesia 58: 415-421. Chamberlain JH, Seed RGFL & Chung DCW (1977) Effect of thiopentone on myocardial function. British Journal of Anaesthesia 49: 865-870. Christensen JH, Andreasen F & Jansen JA (1982) Pharmacokinetics and pharmacodynamics of thiopentone. A comparison between young and elderly patients. Anaesthesia 37: 398--404. Christensen JH, Andreasen F & Jansen JA (1983) Thiopentone sensitivity in young and elderly women. British Journal of Anaesthesia 55: 33-40. Claeys MA, Gepts E & Camu F (1988) Haemodynamic changes during anaesthesia induced and maintained with propofol. British Journal of Anaesthesia 60: 3-9. Coates DP, Monk CR, Prys-Roberts C & Turtle M (1987a) Hemodynamic effects of infusions of the emulsion formulation of propofol during nitrous oxide anesthesia in humans. Anesthesia and Analgesia 66: 64-70. Coates DP, Monk CR, Prys-Roberts C & Turtle M (1987b) Haemodynamic responses of hypertensive patients to an infusion of propofol to supplement nitrous oxide anaesthesia. Beitrage zur Anaesthesiologie und lntensivmedizin 20: 107-108. Colvin MP, Savege TM, Newland PE et al (1979) Cardiorespiratory changes following induction of anaesthesia with etomidate in patients with cardiac disease. British Journal of Anaesthesia 51: 551-556. Cote P, Gueret P & Bourassa MG (1974) Systemic and coronary hemodynamic effects of diazepam in patients with normal and diseased coronary arteries. Orculation 50: 12101216. Crankshaw DP, Edwards NE, Blackman GL, Boyd MD, Chan HNJ & Morgan DJ (1985) Evaluation of infusion regimens for thiopentone as a primary anaesthetic agent. European Journal of Clinical Pharmacology 28: 543-552. Crankshaw DP, Boyd MD & Bjorksten A R (1987) Plasma drug efflux--a new approach to optimalization of drug infusion for constant blood concentration of thiopental and methohexital. Anesthesiology 67: 32-41. Criado A, Maseda J, Navarro E et al (1980) Induction of anaesthesia with etomidate: haemodynamic study of 36 patients. British Journal of Anaesthesia 52: 803-806. Cullen PM, Turtle M, Prys-Roberts C, Way WL & Dye J (1987) Effect of propofol anesthesia on baroreflex activity in humans. Anesthesia and Analgesia 66" 1115-1120. Dauchot P J, Staub F, Berzina L e t al (1984) Hemodynamic response to diazepam: Dependent on prior left ventricular end diastolic pressure. Anesthesiology 60: 499-503. de Grood PMRM, Mitsukuri S, van Egmond J, Rutten JMJ & Crul JF (1987a) Comparison of etomidate with propofol for anaesthesia for microlaryngeal surgery. Anaesthesia 42: 366--372. de Grood PMRM, Harbers JBM, van Egmond J & Crul JF (1987b) Anaesthesia for laryngoscopy. A comparison of five techniques including propofol, etomidate, thio-

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