7 Interactions involving inhalational agents

7 Interactions involving inhalational agents T. J. GAN* MB, FRCA, FFARCS Assistant Professor

R S. A. GLASS MB, FFA Associate Professor Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA

A combination of intravenous and inhalational agents to achieve a balanced anaesthetic state is common practice in modem day anaesthetic management. A recent survey of mortality in 100 000 anaesthetics revealed that the practice of combining several drugs to administer anaesthesia may be safer than the use of only one or two drugs (Cohen et al, 1988); the relative odds of dying within 7 days was 2.9 times greater when one or two anaesthetic drugs were used compared to when three or more were used. Hence, the skilful use of multiple anaesthetic agents is preferable in maintaining smooth anaesthesia and optimal patient care while reducing side-effects of the component drugs. Drug combinations may produce additive, synergistic and even antagonistic effects. Through an understanding of the pharmacodynamic interaction involving volatile anaesthetics and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can be developed. This chapter aims to provide a review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anaesthetic and achieve a more rapid recovery. Key words: anaesthetics; drug interactions; inhalational drugs; intravenous drugs. Anaesthesia was first c o n d u c t e d with a single anaesthetic d r u g w e i t h e r nitrous oxide, ether or chloroform. These drugs were used as sole anaesthetic agents for m o s t o f the first 100 years o f anaesthesia with the exception of the introduction o f the traditional G O E , ' g a s - o x y g e n - e t h e r ' combination o f nitrous oxide and ether, b y C l o v e r in 1873. In 1926 John L u n d y first advocated the use o f a combination o f anaesthetic agents during a single operation (Lundy, 1926). He c o i n e d the term 'balanced anesthesia' and this n e w c o n c e p t led to greater flexibility and patient safety. The rationale o f this practice is that with the use o f small * To whom correspondenceshould be addressed. Baillidre "s Clinical Anaesthesiology--

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amounts of each drug, the side-effects caused by one large single dose of a drug will be avoided. A decade earlier, Dennis Jackson had described a method for the production and maintenance of prolonged anaesthesia or analgesia by means of nitrous oxide, ethyl chloride, ether, chloroform, ethyl bromide, somnoform, and others, with oxygen (Jackson, 1915). In 1938, Organe and Broad combined thiopentone and nitrous oxide and oxygen (Organe and Broad, 1938). The resulting anaesthesia was superior to that obtained with thiopentone alone, as the analgesic action of the nitrous oxide permitted a marked reduction of the amount of barbiturate needed with a consequently quicker return of consciousness. In 1952 the synergism between these two drugs was further demonstrated by Paulson who studied the combination of thiopentone, ether and nitrous oxide. The total dose of thiopentone required was markedly reduced, no laryngeal spasm was encountered, endotracheal intubation could be accomplished with relative ease and safety and patient satisfaction was high (Paulson, 1952). With the introduction of curare by Griffith and Johnson (1942), anaesthesiologists began to use neuromuscular blocking drugs to achieve relative control of muscle relaxation without having to resort to very deep levels of general anaesthesia. Muscle relaxation was one of the essential components of the anaesthetic state, defined as narcosis, analgesia and muscle relaxation by Gray and Rees (1952). Several techniques of balanced anaesthesia were described involving anaesthetic induction with sodium thiopental, maintenance with nitrous oxide and oxygen supplemented with small additional doses of thiopentone, and muscle relaxation with d-tubocurarine (Gray and Halton, 1946; Chadwick and Swerdlow, 1949). T H E C O N C E P T OF D R U G I N T E R A C T I O N S The anaesthetic state consists of hypnosis, analgesia and amnesia. There are several ways of trying to establish the interaction of drugs in providing anaesthesia. In addition, there are different endpoints (i.e., measures of effect) that may be used to assess these interactions. The two most commonly used measures of assessing the adequacy of anaesthetic effect are loss of response to a verbal stimulus and purposeful movement to a skin incision. These two measures of effect clearly measure different endpoints (or different depths of anaesthesia) and thus the interaction of the same two drugs for each of these endpoints may be different. Both of these endpoints have clinical significance and guide our dosing regimens for loss of consciousness, i.e., induction, and for an adequate anaesthetic state during surgery.

Quantification of drug interaction To measure the effect of combining two agents, dose-response curves are determined for the individual agents separately and then for the combination

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using a probit procedure. These curves provide data that will allow the effect of the combination to be analysed using one of the methods described in the chapter by Bovill in this issue, such as isobolographic analysis. While isobolograms enable the assessment of the interaction between two drug doses, there is no attempt to discern whether the synergistic/antagonistic interaction is due to an effect on the drug's pharmacokinetics resulting in higher concentrations, or due to a pharmacodynamic effect, i.e. greater sensitivity due to the combination. Owing to the pharmacokinetic properties, all drugs demonstrate some delay between dosing and peak effect. This delay is different for each drag and thus it is possible that many of the interactions are not measured at the peak effect of both drugs. A different approach to evaluating the interaction between the intravenous anaesthetics and inhalational and intravenous agents is to administer both drugs to a constant concentration and assess their effects only when the plasma concentration and biophase (effect site concentration) have equilibrated. For intravenous drugs this has been made possible with the advent of pharmacokinetic model-driven drug-delivery systems in which biophase concentrations can be rapidly achieved (much like volatile anaesthetics) and maintained. This method ensures that any pharmacokinetic differences are accounted for by evaluating the concentration response of the drug, and thus only the pharmacodynamic interaction is assessed. Utilizing such systems, it is possible to determine the concentration-effect relationship of anaesthetics for induction and maintenance of anaesthesia as well as the interaction of the many drugs used for these similar endpoints of anaesthesia. PHARMACODYNAMIC INTERACTIONS Pharmacodynamic interactions occur as a result of several mechanisms, most of which are presently ill understood (Sear, 1991; Mueller and Lundberg, 1992). At the cellular level, one drug may enhance the binding of a second drug to its receptor or, conversely, inhibit its binding (e.g. agonist, antagonist). A drug may also alter the intracellular signal transduction pathway of another drug (e.g. the potentiation of the arrhythmogenic effects of ~3-agonists by volatile anaesthetics by both increasing adenylyl cyclase activity, or the increased MAC in alcoholics due to development of tolerance of the GABAergic receptor), or one drug may effect the uptake or production of neurotransmitters whose release are altered by the second drug (e.g. reversal of neuromuscular blockers by anticholinesterases). A pharmacodynamic interaction may also occur as a result of two drugs acting on two separate receptor systems, but whose final common pathway either at the cellular or subcellular levels are similar. This later mechanism is probably the most common for the pharmacodynamic drug interactions seen between drugs used to provide anaesthesia. Inhalational anaesthetic depth has been classically characterized by the minimum alveolar concentration (MAC) concept as developed by Eger and

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associates (Eger et al, 1965). The measurement of MAC has several important elements. A constant partial pressure of volatile anaesthetic at the site of action must be achieved before measurement of response. A specific, noxious stimulus (initial skin incision in humans, tail clamping in animals) is applied, and observation is made for a defined clinical response, usually a purposeful movement. Our understanding of the pharmacology of inhalational anaesthetics has been significantly enhanced with the determination of MAC. In parallel with MAC, a measure of the concentrationeffect response of the intravenous anaesthetics for drag interactions needs to be quantified. This measure has been termed Cp50 and represents the steady-state plasma concentration (once it has equilibrated with the biophase) that will prevent a pre-defined response (e.g. movement, hypertension, catecholamine release) to a given stimulus (e.g. skin incision, intubation, sternal spreading, skin closure) in 50% of patients. Ausems et al (1986) defined Cp50 for several noxious stimuli for alfentanil in the presence of 66% nitrous oxide (Figure 1). It was the first attempt to mirror the concept of MAC for inhalational agents.

DRUG INTERACTIONS: INHALATIONAL-INHALATIONAL AGENT According to classic theories of anaesthesia based on unitary non-specific mechanisms of anaesthetic actions, one anaesthetic agent may be replaced freely by another, and, in the case where several inhalational anaesthetic agents are combined, the anaesthetic effect of the mixture is expected to be additive (Eger et al, 1965), i.e. their combined effect is the result of adding their individual effects. Hence, 30% of the MAC of an agent combined with 40% of the MAC of another agent will produce the same effect as 70% of the MAC of either agent. The apparent additivity of MAC can be used to determine the appropriate target concentration of one of the gases based on the concentration of the other. However, this has been challenged. When interactions of inhaled anaesthetics, with positive motor response from noxious stimuli, were studied in experimental animals involving nitrous oxide, some deviation from additivity were found (DiFazio et al, 1972; Clarke et al, 1978; Cole et al, 1990). Small deviations from additivity were also found with the hypnotic component of anaesthesia in mice: interactions between sulphur hexafluoride-nitrous oxide and argon-nitrous oxide combinations. Sulphur hexafluoride-argon combination has been found to be infra-additive (Clarke et al, 1978). It is of interest that the deviations from additivity with combinations of inhalational agents were always towards some degree of antagonism.

Nitrous oxide-inhalational agents The addition of nitrous oxide to the potent inhalational anaesthetics is undoubtedly the most widely used interaction in anaesthesia. An inspired concentration of 60-70% nitrous oxide is commonly used. Nitrous oxide is

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Figure 1. Relationship between the alfentanil plasma concentrations (with 66% nitrous oxide) and their effects for three specific events of short duration (intubation, skin incision and skin closure). The diagrams at the upper part show the alfentanil plasma concentrations of every patient associated with (downward deflection) or without (upward deflection) a response to each of these three stimuli. The plasma concentration-effect curves for these stimuli (lower part) were defined from the quantal data shown in the upper diagrams using logistic regression. Reproduced from Ausems et al (1986, Anesthesiology 65: 362-373) with permission.

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considered to reduce the MAC value of volatile agents in a simple additive manner (Quasha et al, 1980). The advantages of this combination are that while the anaesthetic effects are additive, the toxic effects (e.g. myocardial depression) are not. The rapid elimination of nitrous oxide and the secondgas effect can also speed awakening. Rampil et al (1991) studied the MAC reduction of desflurane by nitrous oxide in healthy adult patients in two age groups, 18-30 and 31-65. Nitrous oxide reduced the MAC of desflurane from 7.25 to 4% in the younger age group, and from 6.0 to 2.8% in the older age group. This reduction of about 3% corresponds to MAC reductions of 45-53% which is compatible with an additive effect of nitrous oxide in adults. Katoh and Ikeda (1987) determined the MAC of sevoflurane in 100% oxygen or 67% nitrous oxide in 33% oxygen. They found that 67% nitrous oxide reduced the MAC value of sevoflurane from 1.71 to 0.66%, which is in agreement with additive effect (assuming the MAC of nitrous oxide is approximately 110%). With the rapid increase in the use of intravenous drugs, and the combination of these drugs with inhalational agents to achieve the anaesthetic state, the degree of drug interactions are increasingly complex, and cannot be easily predicted by their pharmacokinetic and pharmacodynamic actions.

DRUG INTERACTIONS: I N T R A V E N O U S - I N H A L A T I O N A L AGENTS

Opioid-inhalational agents To establish the interaction between volatile anaesthetics and opioids, the reduction in MAC of the volatile agents by opioids can be characterized. The first of these series of interaction studies was reported by Sebel et al (1992) who studied the fentanyl-desflurane combination. These authors investigated doses of fentanyl of 0.3 and 0.6 gg/kg in a group of healthy patients. Twenty five minutes after a single injection, fentanyl plasma concentrations were 0.78 + 0.53 and 1.72 +0.76 ng/ml in the two groups. At these concentrations fentanyl reduced the MAC of desflurane by 58 and 67%, respectively. Hence, there appears to be a ceiling effect, and little was gained by doubling the dose of fentanyl. The time from discontinuing desflurane administration to eye opening was 5-6 minutes, regardless of the dose of fentanyl given 2 hours earlier. This study, however, did not attempt to equilibrate the opioid concentrations between plasma and effect site. In order to characterize drug interactions more accurately, it is important that both the volatile anaesthetic and the opioid are maintained at stable concentrations and have equilibrated with their effect site. For the volatile anaesthetic, this is readily achieved using a calibrated vaporizer. For the opioid, CACI (computer-assisted continuous infusion) or similar targetcontrolled delivery devices are used to maintain constant opioid concentration (Glass et al, 1994). Subsequent interaction studies between opioid and volatile agents have been performed with these devices to maintain steady-state effect-site concentrations. The Cp50 of fentanyl required to

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prevent somatic response has been defined as 3.26 ng in the presence of 70% nitrous oxide while its Cp50-BAR was 4.2 ng under similar condition (Glass et al, 1993a). The steady-state concentrations of various intravenous anaesthetic drugs when combined with nitrous oxide for pre-defined effects are listed in Table 1. Table 1. Steady-state concentrations for pre-defined effects*.

Drug

IC50 (+-SD)

Alfentanil (ng/ml) Fentanyl (ng/ml) Sufentanil (ng/ml) Remifentanil (ng/ml) Thiopentone (~tg/ml) Propofol (I.tg/ml)

520+ 123 6.9 + 1.9 0.68+0.31 14.7 17.9

Cp50 incision or painful stimulus (-+SD) 241 + 16 4.2 (0.3-0.4) (3-4) 39.8+3.3 15.8

Cp50 LOC (+SD)

12 15.6+1.1 3.4

Cp50 Spont Vent (+SD) 226 + 10 (3-4) (0.3-0.4) (2-3)

50% Reduction in isoflurane MAC MEAC 50 1.67 0.145 1.37

10 0.7 0.04 (0.6)

IC50: the steady-state serum concentration in equilibration with the effect compartment that causes a 50% slowing of the maximal EEG. Cp50 skin incision: the steady-state plasma concentration in equilibration with the effect compartment that will prevent a somatic or autonomic response in 50% of patients in combination with 66% N20. Cp50 LOC: the steady-state plasma concentration in equilibration with the effect compartment which provides absence of a response to a verbal command in 50% of patients. Cp50 Spont Vent: the steady-state plasma concentration in equilibration with the effect compartment that is associated with adequate spontaneous ventilation in 50% of patients. MEAC: the minimum effective plasma concentration providing post-operative analgesia. Values in parentheses are estimated by scaling to the alfentanil Cp50. * Reproduced from Glass et al (1994, Intravenous drug delivery systems. In Miller RD (ed.) Anesthesia, vol 1, 4th edn, pp 389-416. New York: Churchill Livingstone) with permission.

McEwan and colleagues reported the interactions between the two most widely used agents in modern day practice, isoflurane and fentanyl (McEwan et al, 1993). As shown in Figure 2, fentanyl 1 ng/ml resulted in a 39% MAC reduction of isoflurane. Increasing the fentanyl plasma concentration to 3 ng/ml resulted in a further MAC reduction to 63%. However, further increases in fentanyl concentration (greater than 3 ng/ml) produced a limited reduction in MAC. A 50% MAC reduction of isoflurane was produced by 1.67 ng/ml fentanyl (McEwan et al, 1993). This can be achieved by a fentanyl loading dose of 4 gg/kg followed by 0.03 gg/kg/minute (1.75gg/kg/hour). These data suggest that a substantial reduction in isoflurane requirements (40~60%) can be achieved at low (1-3ng/ml) plasma concentrations of fentanyl (Figure 2). In addition, there is little to be gained by increasing the plasma concentration of fentanyl greater than 3--4 ng/ml as plasma concentrations above 2 ng/ml have been shown to be associated with significant respiratory depression (McClain and Hug, 1980). This study also demonstrated that, beyond 5 ng/ml, a plateau or ceiling effect is seen with a maximum MAC reduction of approximately 80%. Thus, in clinical practice, the maximum MAC reduction of isoflurane was at concentrations around 0.3%. This concentration is very close to the MAC awake (minimum alveolar concentrations at return to consciousness) for isoflurane.

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Similar findings were shown with sufentanil; 0.1-0.5 ng/ml resulted in a substantial reduction of the MAC of isoflurane (Brunner et al, 1994). Increasing the plasma concentrations of sufentanil beyond 0.5 ng/ml results in only minimal further reduction in isoflurane requirements (Figure 3). A sufentanil plasma concentration of 0.15 ng/ml can be achieved with a manual infusion consisting of an initial loading dose of 0.15 ~tg/kg followed by an infusion of 0.003 ktg/kg/minute. A 0.5 ~g/kg loading dose followed by a continuous infusion of 0.008 p~g/kg/minute would achieve a sufentanil plasma concentration of 0.5 ng/ml (Table 2). Manual infusion schemes of other intravenous drugs for anaesthesia and sedation are also shown. Alfentanil (Figure 4) (Westmoreland et al, 1994) and remifentanil (Figure 5) (Lang et al, 1996) produce similar reductions in the MAC of isoflurane, with an initial steep reduction at lower concentrations and a plateau effect at higher concentrations. Remifentanil is a new esterase metabolized opioid that has an extremely short context-sensitive half-time (3-5 minutes) (Egan et al, 1993; Glass et al, 1993b; Westmoreland et al, 1993). As remifentanil has such a brief context-sensitive decrement time, it was possible to administer remifentanil to extremely high concentrations. Again, even with these very high concentrations (>30 ng/ml), a ceiling effect was still observed at an isoflurane concentration of 0.2-0.3% (Figure 5). The effect of fentanyl on MAC reduction of sevoflurane was recently reported by Katoh and Ikeda (1997). Similar to the MAC reduction with isoflurane and desflurane, fentanyl produces an initial steep decrease in the MAC of sevoflurane followed by a plateau with minimal further reduction

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Table 2. Manual infusion schemes when combined with 66% nitrous oxide*. Anaesthesia Drug Alfentanil Fentanyl Sufentanil Methohexital Ketamine Propofol Midazolam

Loading dose (~tg/kg) 50-150 5-15 1-2 1000-2000 1000-2000 1000-2000 50-150

Maintenance infusion (~g/kg/minute) 0.5-3 0.03-0.1 0.006-0.02 50-150 10-50 80-150 0.25-1.0

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Maintenance infusion (~tg/kg/minute)

10-25 1.5-3 0,15-0.3 500-1000 500-1000 250-1000 20-100

0.25-1 0.01-0.03 0.002-0.007 10-50 10-20 10-50 0.25-1

Following the loading dose an initially high infusion rate to account for re-distribution should be used and then titrated to the lowest infusion rate that will maintain adequate anaesthesia or sedation. For sedation the loading dose is given over 5 to 10 minutes and is adjusted according to the patient's response. For anaesthesia, midazolam must be administered combined with an opiate. * Reproduced from Glass et al (1994, Intravenous drug delivery systems. In Miller RD (ed.) Anesthesia, vol. 1, 4th edn, pp 389-416. New York: Churchill Livingstone) with permission.

in the MAC of sevoflurane at fentanyl concentrations greater than 3 ng/ml. Doubling the plasma concentration from 3 ng/ml to 6 ng/ml produces a further reduction of only 11% in MAC. A 50% reduction in MAC was produced by 1.8 ng/ml fentanyl, which was close to the concentration of fentanyl that produced a similar MAC reduction of isoflurane (1.7 ng/ml) and desflurane. In this same study the authors also defined the reduction of sevoflurane MAC awake by increasing concentrations of fentanyl. They demonstrated that the MAC awake of sevoflurane does decrease with

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increasing fentanyl concentration but far less than the MAC for skin incision. Fentanyl at 1.5-2 ng/ml provided a 50% MAC reduction, with a low risk of post-operative respiratory depression and requires only a decrease in sevoflurane from 0.8% to 0.45% for 95% of patients to be awake (Figure 6). The concentrations of opioids producing a 50% reduction of the MAC of volatile anaesthetics also provides a means of determining equipotency (in the concentration domain) between the various opioids (Table 3). 3.5 3.0 ~- 2.5 0

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Table 3. The relative potencies of the potent ~t specific opioid agonists based on their ability to reduce the MAC of isoflurane by 50%.

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Plasma concentration (ng/ml) resulting in 50% MAC reduction of isoflurane

Calculated potency relative to fentanyl based on 50%

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* The 50% MAC reduction of isoflurane by alfentanil was determined following induction of anaesthesia with thiopental and thus underestimates the alfentanil concentration. t Remifentanil was measured as the whole blood concentration. ~: The potency in parentheses is that calculated for alfentanil when corrected for the presence of thiopental.

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o~2-Agonists-inhalational agents Clonidine has been widely used in veterinary anaesthesia. It has been estimated that 7 million animals receive clonidine as a sedative-analgesic or anaesthetic adjunctive agent each year. The use of clonidine in humans has not been as popular but has experienced a resurgence of interest recently. In clinical practice today, the use of clonidine has been limited to pre-operative adjunctive medication, rather than as the sole anaesthetic used in veterinary medicine, o~-Agonists have also been found to reduce anaesthetic and analgesic drug doses in both normotensive and hypertensive patients undergoing non-cardiovascular surgery. Ghignone et al (1988) found that patients pre-treated with 5 gg/kg of clonidine needed 40% less isoflurane and nearly 75% less fentanyl supplementation than a matched control group. In another study, elderly patients having ophthalmic surgery required 50% less fentanyl and 30% less isoflurane (Ghignone et al, 1986). The effects of transdermal clonidine have been investigated. In a placebo controlled study involving patients undergoing lower abdominal surgery two doses of clonidine were administered to achieve perioperative plasma clonidine levels of 1.0 or 1.5 ng/ml. Both clonidine-treated groups were more sedated at the time of arrival in the operating room, had lower volatile anaesthetic requirements to achieve haemodynamic endpoints, had greater intra-operative haemodynamic stability, and more rapid emergence from anaesthesia. Patients in the highdose clonidine-treated group also required significantly less morphine by Patient Controlled Analgesia (PCA) (Segal et al, 1991). Recently, dexmedetomidine has been shown to possess highly selective t~2-agonist properties (Jaakola et al, 1991). Its therapeutic value is especially evident in the post-surgical period (emergence and recovery phases) with improved haemodynamic and metabolic stability resulting from its sympatholytic effect, improved patient comfort with less shivering, antagonized opioid-related muscle rigidity, decreased nausea and vomiting, and less requirement for opiates with decreased respiratory depression (Weinger et al, 1989; Aantaa et al, 1991; Aho et al, 1991, 1992; Jaakola et al, 1992; Aho et al, 1993; Scheinin et al, 1993; Jaakola, 1994). Dexmedetomidine has been shown to reduce peri-operative dose requirements for intravenous as well as inhalational agents. Aantaa et al found that plasma dexmedetomidine concentrations of 0.3 and 0.6ng/ml were associated with a 35% and 47% reduction of the MAC of isoflurane respectively.

Benzodiazepine-inhalational agents Despite the wide clinical applications of benzodiazepines as premedication and during the intra-operative phase, formal studies investigating the interactions between benzodiazepines and volatile anaesthetics have been few. Diazepam (0.2mg/kg) given intravenously 15 to 30 minutes before surgical incision decreases halothane MAC by 34%. However, twice the amount of that dose (0.4 mg/kg) apparently does not further reduce

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anaesthetic requirement (Perisho et al, 1971). This suggests that there is a ceiling effect in the interactions between benzodiazepines and volatile anaesthetics. Melvin et al (1982) studied the interactions of four doses of midazolam (0.15, 0.3, 0.45 and 0.6 mg/kg) with halothane and showed a linear decrease in MAC of halothane with increasing doses of midazolam. They demonstrated that midazolam 0.6 mg/kg (four times the induction dose), given 35-45 minutes before incision, does not decrease the MAC of halothane as much as does 0.2mg/kg diazepam given 15-30 minutes before incision, even though midazolam is 1.5 to 2 times more potent. This is probably due to the short half-life of midazolam (2 versus 25 hours for diazepam). Glosten et al (1990) studied two doses of midazolam (0.025 and 0.05 mg/kg) given prior to anaesthesia in ASA I and II adult patients. The MAC of desflurane was reduced from 6 to 4.7% by the 0.05 mg/kg group while recovery from anaesthesia did not differ.

Ketamine-inhalational agents While there are many studies investigating the interactions between ketamine and other intravenous anaesthetic agents, there have been few investigating ketamine with inhalational agents. White et al (1975) administered three doses of ketamine, 10, 20 and 50 gg/kg, intramuscularly in rats during halothane anaesthetic. The MAC of halothane was reduced in a dose-dependent manner as much as 56% 1-2 hours and as much as 14% 5-6 hours after injection of the highest dose of ketamine. The half-life of ketamine in plasma and brain was longer in the presence of halothane than when ketamine was given alone. Hence, ketamine is not a 'short-acting' agent, and subanaesthetic doses of ketamine resulted in depression of MAC of halothane for as long as 6 hours.

Neuromuscular blockers-inhalational agents In general, inhalational anaesthetics potentiate the action of neuromuscular blocking drugs. They cause a decrease in twitch height, T4/T1 ratio, peak tetanic contraction, and the ability to sustain tetanus in the presence of nondepolarizing relaxants (Kennedy and Galindo, 1975; Ali and Savarese, 1976; Hughes, 1979; McIndewar and Marshall, 1981; Delisle et al, 1982; Rupp et al, 1984; Caldwell et al, 1991). For example, the addition of isoflurane or enflurane enhanced the degree of mivacurium-induced blockade by 25-30% (Shanks et al, 1989; Powers et al, 1992) despite mivacurium's lack of dependence on organ elimination. Augmentation of neuromuscular blockade by volatile agents, however, is not uniform. While isoflurane and enflurane tend to enhance neuromuscular blockade, halothane exhibited little or no potentiation in adults (From et al, 1990) and children (Goudsouzian et al, 1989). It is difficult to reconcile the lack of potentiation by halothane and not enflurane, isoflurane and desflurane. Factors that are important include the dose of the volatile agents studied, methods of administration (single bolus or continuous infusion), duration

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of infusion, age (Whittaker, 1980; Maddineni et al, 1994) and gender (Maddineni et al, 1994). Gan et al (1996) found that desflurane and isoflurane potentiate mivacurium to a similar degree. The effects of inhalational agents on the degree of potentiation of neuromuscular blocking drug are related in the following fashion: diethyl ether (Waud and Waud, 1975) > enflurane (Waud and Waud, 1975; Ali and Savarese, 1976; Delisle et al, 1982) > isoflurane (Waud and Waud, 1975; Ali and Savarese, 1976) = desflurane (Caldwell et al, 1991; Gan et al, 1996) > halothane (Goudsouzian et al, 1989; From et al, 1990). Nitrous oxide causes a slight increase in neuromuscular blockade within 5-10 minutes (Fiset et al, 1991). The effects of inhalational agents are greater for longacting muscle relaxants and when administered in a prolonged infusion (Stanski et al, 1979; Rupp et al, 1984; Swen et al, 1985, 1989). Inhalational agents cause a delay in reversal, especially if they are continued after the administration of the reversal agents (Delisle et al, 1982; Gencarelli et al, 1982; Dernovoi et al, 1987; Gyermek, 1988). IMPLICATION OF DRUG INTERACTION IN THE RECOVERY PHASE

Recovery from general anaesthesia is dependent on a number of factors. While recovery from an inhalational agent depends on the speed of washout (ventilation), recovery from intravenous agents is more complex. Our understanding of the pharmacokinetic processes that determine the recovery from intravenous drug effect has recently been more clearly defined (Sharer and Varvel, 1991; Hughes et al, 1992). The concentration of a drug in the plasma and the biophase is dependent on those processes adding drug to the body and the disposition of drug within the body. When the administration of drug to the body is terminated, the concentration of the drug in the plasma (and biophase) will decrease due to both the irreversible elimination of drug from the body and the re-distribution of drug from the plasma to peripheral tissues. Conventional wisdom has been that the elimination half-life of the drug represents the measure of how rapidly recovery from drug occurs. The elimination half-life represents the terminal clearance of the drug and does not incorporate any re-distribution of drug and, thus, clearly does not provide any quantitative measure of how long it will take for the drug to decrease by 50%. To provide an estimation of the time for recovery to occur with intravenous anaesthetics, the concept of 'context-sensitive half-time' has been proposed and represents the time required for the plasma concentration of a drug to decrease by 50% (for an infusion designed to maintain a constant concentration) for any given duration of the infusion (Hughes et al, 1992). The context-sensitive halftimes for the opioids is shown in Figure 7. It will be noted from the figure that the 'context-sensitive half-time' can vary markedly according to the duration of the infusion, with the longer the duration of the infusion the longer the time required for a 50% decrease. The actual percentage decrease required at the termination of the procedure to provide awakening

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and adequate spontaneous ventilation varies according to the dose of opioid administered during the anaesthetic. For example, if fentanyl is administered to a concentration of 2 ng/ml (2 ~g/kg/hour), then only a 30% decrease will be required for adequate spontaneous ventilation. In a similar vein, simulations demonstrate that the time for, for example, 25, 50 or 75% decrease in plasma drug concentration is not linear (i.e. a 25% decrease may:take 5 minutes, a 50% decrease 20 minutes and a 75% decrease 120 minutes). -~ 100 ... Fentanyl

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Infusion duration (minutes) Figure 7. A simulation of the time necessary to achieve a 50% decrease in drug concentration in the blood (or plasma) after variable-length intravenous infusions of remifentanil, fentanyl, alfentanil and sufentanil. The simulation for remifentanil was done using the NONMEM three-compartment model parameters. Reproduced from Westmoreland et al (1993, Anesthesiology 79: 893-903) with permission.

The volatile anaesthetic should provide an absolute minimal end tidal concentration equivalent to its MAC awake value (e.g. for isoflurane a minimal concentration of 0.4%). If the patient demonstrates signs of inadequate anaesthesia it is preferable to increase the volatile anaesthetic, as increasing this has less of an effect on prolonging wake-up time than increasing the opioid. Remifentanil, as previously stated, has an extremely short context-sensitive half-time of only 3-5 minutes and a contextsensitive 80% decrement time of 10-15 minutes irrespective of the duration of the infusion (Figure 7). This offset is quicker than with most of the volatile anaesthetics; thus, with remifentanil, the reverse is true. It is preferable to administer remifentanil to high opioid concentrations of 8-12 ng/ml (0.25-0.4 p.g/kg/minute) with just sufficient hypnotic to ensure an unconscious patient. Also, if the patient responds, recovery time is less prolonged by increasing the remifentanil than by increasing the volatile anaesthetic. However, it must be reiterated that, although for recovery it is preferable to increase the opioid; the primary goal is to ensure that the patient is not conscious and this is achieved only with the volatile anaesthetic. Of interest is the recent introduction and FDA approval of the

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bispectral monitor. The bispectral index has been shown to provide a.very strong correlation between increasing sedation and loss of consciousness (Glass et al, 1997) and, thus, may help clinicians titrate the volatile anaesthetic to maintain adequate anaesthesia and allow for the most rapid recovery. BIS index has proven to be a useful clinical tool in achieving these aims (Gan et al, 1997). In surgery in which immediate recovery is not required (e.g. most cardiac procedures where post-operative ventilation is planned) and where surgical stimulation is profound, it is probably preferable to administer the opioid to its ceiling effect, thereby ablating any stress response to surgery. In studies in which remifentanil was administered at infusion rates of 1 gg/kg/minute, epinephrine and norepinephrine (markers of the stress response) were unchanged or decreased from baseline at sternotomy. Thus, for cardiac anaesthesia to minimize the stress response and yet provide fast-track recovery, it is preferable to use a combination of volatile anaesthetic and opioid rather than a pure high-dose opioid technique. In this instance, the opioid should be administered at a dose that will be just at the ceiling effect of the opioid. CONCLUSION Anaesthesia appears to consist of at least two components--analgesia and loss of consciousness. This is commonly achieved with the administration of a combination of intravenous (benzodiazepines and opioids) and inhalational agents. The interaction of volatile anaesthetics and opioids in providing anaesthesia is complex, but consistent. In addition, as two or more drugs are being used to provide anaesthesia, recovery to an awake state is dependent on these drugs. Thus, to provide adequate anaesthesia and appropriate recovery, it is important to incorporate the pharmacodynamic interaction that occurs between these drugs as well as their relative offset.

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