British Journal of Anaesthesia 105 (3): 24654 (2010) Advance Access publication 21 July 2010 . doi:10.

1093/bja/aeq190

REVIEW ARTICLES

New drugs and technologies, intravenous anaesthesia is on the move (again)

J. R. Sneyd and A. E. Rigby-Jones *
Anaesthesia Research Group, Peninsula Medical School, University of Plymouth, The John Bull Building, Research Way, Tamar Science Park, Plymouth PL6 8BU, UK * Corresponding author. E-mail: robert.sneyd@pms.ac.uk

Key points
Current i.v. anaesthetic agents have some limitations. New agents based on benzodiazepine, etomidate, and propofol structures are being developed. Some are reaching the stage of clinical trials. Improved methods of drug delivery are also being developed.

Summary. Although well established in clinical practice, both propofol and midazolam have limitations. New hypnotics with different and potentially superior pharmacokinetics and pharmacodynamics are under development. These include the benzodiazepine receptor agonists CNS7056 and JM-1232 (2), the etomidate-based methoxycarbonyl-etomidate and carboetomidate, the propofol-related structures PF0713 and fospropofol, and THRX918661/AZD3043. The basic pharmacology and the initial anaesthesia studies for each of these agents are reviewed. Several of the agents (CNS7056, THRX-918661/AZD3043, and fospropofol) have reached the stage of clinical trials. To be successful, novel compounds need to establish clear clinical advantages over existing agents and where possible the new agents are discussed in this context. Computer-controlled drug administration offers the ability to automatically implement infusion schemes too complex for manual use and the possibility of linking patient monitoring to administration to enhance patient safety. Keywords: anaesthetic techniques, i.v.; anaesthetics i.v., propofol; hypnotics benzodiazepine, midazolam; model, pharmacodynamic; model, pharmacokinetic

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Current clinical practice in i.v. anaesthesia and sedation is focused around two compounds, midazolam and propofol. Both are widely used and available as generic preparations and are therefore well understood and inexpensive. Why then look for new compounds? The answer is that both have limitations. Propofol causes pain on injection which can be attenuated by co-administration of lidocaine1 and by formulation in medium chain rather than long chain triglyceride.2 Propofol also supports bacterial growth3 and causes haemodynamic depression which may be problematic for compromised patients if dosing is inappropriate. Lipid accumulation during infusion has been associated with serious syndromes in both paediatric and adult practice.4 5 In addition, propofol occasionally causes excitation.6 Midazolam has a slow onset of action, that is, time-to-peak effect, with the consequence that patients need to be dosed by titration over several minutes (Fig. 1). Further, over-rapid titration may lead to inadvertent overdosing. Midazolam has an active metabolite, a1-hydroxymidazolam.7 8 Both propofol and midazolam have relatively steep dose response curves meaning that dosing for anything other than maximum effect requires careful titration (Fig. 2).

New benzodiazepine receptor agonists

CNS7056
CNS7056 is a new esterase-hydrolysed benzodiazepine9 with rapid onset, short duration of action, and a fast recovery prole in animal models (Fig. 3). To date, it has been tested in volunteers and, to a limited degree, in patients. When 1 min infusions of CNS7056 were administered to healthy male volunteers, a dose-related depression of bispectral index (BIS) and a change in the sedation state occurred.10 CNS7056 0.75 mg kg21 reduced the Modied Observers Assessment of Anaesthesia and Sedation (MOAA/S) score11 from 5 (responds readily to name spoken in normal tone) to 1 (does not respond to mild prodding or shaking). The sedative effect was of short duration with recovery within 10 min compared with 40 min for midazolam 0.075 mg kg21, which was used as an active control producing equivalent depression of consciousness. Early patient studies are in short diagnostic procedures. In a randomized, double-blind, study of 100 patients undergoing upper gastrointestinal endoscopy, the procedure was completed without assisted ventilation or supplementary sedation in 32%, 56%, and 64% of patients receiving CNS7056 0.1, 0.15, and 0.2 mg kg21, respectively, compared with 44% of patients receiving midazolam 0.075 mg kg21.12

& The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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10 000 9000 8000 Propofol (ng ml1) 7000 6000 5000 4000 3000 Propofol plasma concentration Propofol effect-site concentration Midazolam plasma concentration Midazolam effect-site concentration

70 Midazolam (ng ml1) 60 50 40 30 20

depression of BIS and sedation score occurred.14 Both onset and offset times were faster than literature values for midazolam and there was an estimated value of t1/2 Ke0 of 4.2 min [95% condence interval (CI) 3.16.7]. This t1/2 Ke0 value compares with published estimates of 0.95.6 min for midazolam and 1.23.3 min for propofol.14 Early animal work also suggests a possible analgesic effect for this compound;15 however, this has not yet been evaluated in man.

Etomidate derivatives
Etomidate was widely used for induction and occasionally for maintenance of anaesthesia because of its brief duration of action and haemodynamic stability. These benecial characteristics were perceived to outweigh its propensity to cause myoclonus16 and postoperative nausea and vomiting (PONV). The recognition of serious risks caused by etomidate-induced adrenocortical depression17 led to its abandonment as an intensive care unit (ICU) sedative, and recently, it has fallen out of favour as an induction agent for similar reasons, although the importance of these effects after a single dose remains disputed.18 19 A retrospective analysis of data from 176 patients admitted to an ICU after emergency laparotomy showed that in 52 patients, anaesthesia had been induced using etomidate.18 However, there was no association between receiving etomidate and dying in hospital. The risk of developing hypotension at induction or of receiving vasopressor to treat hypotension was lowest with etomidate.18 In contrast, when the use and timing of etomidate administration were evaluated in a substudy of the CORTICUS trial of hydrocortisone in septic shock, the 19% (n96) of ICU patients who had received etomidate were less likely to respond to corticotrophin and more likely to die.20 A randomized controlled trial comparing single-dose etomidate and ketamine in the critically ill found that the percentage of patients with adrenal insufciency was signicantly higher in the etomidate group than in the ketamine group (odds ratio 6.7, 95% CI 3.5 12.7).21 The issue of etomidate and outcome after single bolus doses remains unclear and there are no data to suggest that it is associated with adverse outcome in proper randomized trials. What is now needed is an outcome study in nonseptic patients. Attempts to improve on the clinical pharmacology of etomidate are based on improved understanding of the drugs action at a molecular level and chemical modication of the molecule to allow esterase hydrolysis.22 Etomidate potentiates GABAA receptor activation. GABAA receptors are pentameric with two etomidate-binding sites per GABAA receptor. Methanethiosulphate-etomidate (MTS-etomidate) (Fig. 5) is an etomidate analogue which forms a covalent bond to one of these binding sites but not to the other.23 24 This provides information about the orientation of etomidate within its binding site on the GABAA receptor and identies the residues with which it interacts. The hypnotic properties of MTS-etomidate have been

2000 1000 0 0 20 Time (min)

Fig 1 Simulations of arterial concentration and predicted effectsite concentration after bolus doses of propofol 2 mg kg21 (Diprifusorw model)61 and midazolam 0.05 mg kg21 (Greenblatt model,62 70 kg). Simulations were made using STANPUMP software from www.opentci.org. Note that the time-to-peak effectsite concentration for midazolam (10.4 min) is considerably longer than for propofol (2.4 min).

10 0 40 60

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190 90 80 Midazolam 70 y=225x+241 Propofol 2=0.93 60 R 50 y=274x+46 40 R 2=0.92 30 20 10 0 1.1 0.9 0.7 0.5 0.3 0.1 0.1 0.3 Log dose (mg kg1)

Fig 2 Propofol and midazolam dose response curves for hypnosis (failure to open eyes on command). Both agents have relatively steep dose response curves, implying that a small increase in dose results in a large increase in response. Gamma, the slope of the dose response curve is 2.04 for midazolam and 5.84 for propofol. Data taken from Short and Chui.63

JM-1232 (2)
JM-1232 (2) is a novel isoindoline derivative benzodiazepine receptor site agonist which is chemically different from benzodiazepines (Fig. 4) but acts as a full agonist at the benzodiazepine receptor and is fully reversible by umazenil.13 JM-1232 (2) has been evaluated in man as MR04A3, a 1% aqueous preparation of JM-1232 (2). When volunteers were given 10 and 1 min infusions of MR04A3, a dose-related

% patients hypnotic

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N N N N O Br N (E) N Tissue esterases CNS7056 CNS7054

Sneyd and Rigby-Jones

(S) Br N (E) N

(S)

OH

Fig 3 CNS7056 is a novel benzodiazepine which is rapidly broken down by tissue esterases.

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O S N O S O

H N O JM-1232 () N O N N Cl N N N R(+)MTS-etomidate N Me N

Fig 5 R(+)Methanethiosulfate etomidate, MTS-etomidate.

F Cl Midazolam Diazepam

Fig 4 Structure of JM-1232 (2) (upper), midazolam (lower left), and diazepam (lower right). JM-1232 (2) is (2)-3-[2-(4-methyl1-piperazinyl)-2-oxoethyl]-2-phenyl-3,5,6,7-tetrahydrocyclopenta [ f ]isoindol-1(2H)-one and is not a benzodiazepine. The closed-ring (lipid-soluble) structure of midazolam, as shown, is formed at physiological pH.

demonstrated on tadpoles.24 However, its duration of hypnotic effect and its impact on adrenocorticosteroidogenesis are currently unclear. Because it binds with a covalent bond to the receptor site, MTS-etomidate is not a candidate for

clinical development and should be considered a molecular probe which can be used to interrogate the etomidatebinding site. Methoxycarbonyl-etomidate, also known as MOC-etomidate, is a rapidly metabolized etomidate analogue which only briey depresses adrenocortical function after single administration in rats (Fig. 6).25 Published data comparing the effects of etomidate and MOC-etomidate on adrenocortical function in rats were based on adrenocorticotropic hormone injections 15 min after bolus administration of the anaesthetic agents.25 At this time, MOC-etomidate will have been almost entirely eliminated, whereas etomidate would have been present in signicant concentration. Thus, although adrenocortical function has been shown to recover quickly after single doses of MOC-etomidate, it is likely to be depressed during infusions even if this effect terminates promptly at the end of infusion as the drug is metabolized. Bolus injection of MOC-etomidate induced haemodynamically stable anaesthesia of brief duration in rats.25 Although the degree and duration of arterial pressure reduction induced by MOC-etomidate were less than those seen in

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OH

O + OH

N N

N N

N N

Etomidate

MOC-etomidate

MOC-etomidate carboxylic acid

Methanol Downloaded from http://bja.oxfordjournals.org/ by guest on November 10, 2011

Fig 6 Etomidate, MOC-etomidate, and its inactive metabolite MOC-etomidate carboxylic acid.

animals receiving etomidate or propofol, these data must be interpreted with caution. The duration of hypnosis after bolus injection of etomidate and propofol was very sensitive to the administered dose, whereas the short period of anaesthesia induced by MOC-etomidate is almost dose-independent.25 Etomidate, propofol, and MOC-etomidate produced loss of righting reex in rats with ED50s of 1.0, 4.1, and 5.2 mg kg21, respectively. Thus, MOC-etomidate is less potent than the older agents. Further, given its very brief duration of action, maintaining anaesthesia by infusion of MOC-etomidate will require a substantial mass of drug with subsequent metabolism to carboxylic acid and methanol (Fig. 6). The safety of these metabolites in the amounts likely to accumulate after prolonged infusion of MOC-etomidate is currently unclear. By way of example, we know that after prolonged remifentanil infusion, the arterial concentration of the metabolite remifentanil acid is many times greater than that of the parent drug and this is exaggerated in patients with renal impairment.26 Fortunately, remifentanil acid is well tolerated but the same cannot be automatically assumed for the breakdown products of every new soft22 drug. Although preliminary data describing MOC-etomidate are attractive, its proper evaluation requires human exposure.

Fig 7 Carboetomidate.

Carboetomidate
Carboetomidate (Fig. 7) represents an alternative solution to the problem of adrenocortical suppression by etomidate. Etomidate binds to the P450 enzyme 11-b-hydroxylase and thereby suppresses steroidogenesis. This effect is due to binding of a nitrogen atom in etomidates imidazole ring to haem iron within the 11-b-hydroxylase enzymes active site. Removal of the binding nitrogen atom from etomidate reduced adrenocortical inhibitory potency by three orders of magnitude, whereas the molecule remains anaesthetic.27 Carboetomidate is the lead compound in a class of etomidate

analogues designed not to inhibit adrenocortical function at pharmacologically relevant doses. When tested in human adrenocortical cells, the half maximal concentration for inhibition of cortisol synthesis by carboetomidate and etomidate was 2.6 (SD 1.5) mM and 1.3 (0.2) nM, respectively, a difference of three orders of magnitude.27 Serum corticosterone concentrations in rats given carboetomidate were not signicantly different from those given vehicle alone.27 Carboetomidate is anaesthetic in tadpoles and rats. Hypnotic bolus doses of 14 mg kg21 produced minimal changes in arterial pressure in rats.27 Because carboetomidate should not suppress adrenocortical function during administration, it might be suitable for the maintenance of anaesthesia or sedation.28 MOC-etomidate and carboetomidate represent two distinct approaches to the adrenocortical effects of etomidate. The rapid metabolism of MOC-etomidate may be considered a pharmacokinetic solutionswift esterase metabolism rapidly removes the cause of adrenocortical depression.

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In contrast, carboetomidate offers a pharmacodynamic solutionremoving the nitrogen atom from etomidate massively decreases adrenocortical depression. Both drugs appear to offer the principal advantages of etomidatethey are potent anaesthetic agents with minimal haemodynamic effects. What is unclear is whether the unwelcome effects of etomidatemyoclonus and nausea and vomiting remain unchanged.
OH

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PF0713
OH

Other novel anaesthetic agents

THRX-918661/AZD3043
This allosteric modulator of the GABAA receptor has a very similar structure to that of propanidid (Fig. 8). AZD3043 is hydrolysed by esterases to an inactive metabolite. THRX-918661appeared very attractive when tested in a pig model,29 although concern was expressed that it might actually be too short acting and insufciently potent for human use.30 Subsequent development was delayed by formulation difculties. Now renamed AZD3043, the compound has been tested in man by bolus injection and infusion with four studies registered at www.clinicaltrials.gov, although the data are currently unpublished.

Propofol
Fig 9 PF0713 is (R, R)-2,6-di-sec-butylphenol, a compound very similar to propofol. Both the two and the six groups on the phenol ring are optically active and it is the R, R form that has been evaluated in man.

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PF0713
PF0713, (R, R)-2,6-di-sec-butylphenol, is a compound very similar to propofol but with larger side groups. (R, R)2,6-di-sec-butylphenol is a single diastereomer containing two dened chiral centres of the R-conguration (Fig. 9). PF0713 is a potent GABAA receptor agonist and behaved similarly to propofol in the hippocampal brain slice assay and fully potentiated the muscimol-mediated response at the GABAA receptor.31

N O O THRX-918661/AZD3043

N O O Propanidid

Fig 8 The structure of AZD3043 is similar to that of propanidid.

Interestingly, several similar molecules including 2,6-di-sec-butylphenol were considered during the chemical development of propofol.32 2,6-Di-sec-butylphenol (then known as Compound 31) was formulated in the surfactant Cremophor EL and tested in mice and rabbits. Hypnotic potency was similar to that of propofol (then known as Compound 25) but onset of action was slower and duration of action was longer than propofol.32 Thus, it is clear that the anaesthetic properties of this molecule have been known for some time. What is not clear is whether the original experiments used a racemic mixture or, as recently tested in man, a single enantiomer. Individual enantiomers of molecules often have strikingly different pharmacological properties to racemic mixturesconsider cisatracurium and L-bupivacaine in comparison with the racemates atracurium and bupivacaine. Accordingly, the difference in performance of (presumably racemic) 2,6-di-sec-butylphenol and propofol in small animals may be irrelevant to the as yet untried comparison between PF0713 and propofol in man. Like propofol, PF0713 is minimally soluble in water and has been investigated as a 1% oil in water emulsion. PF0713 induces brief propofol-like anaesthesia without pain on injection.33 The aqueous phase concentration of (R, R)-2,6-di-secbutylphenol in a 1% formulation is 0.38 (0.02) mg ml21, whereas the aqueous phase concentration of propofol in Diprivanw was 4.1 mg ml21.31 This reduction in the aqueous phase concentration may be the explanation for the reported lack of pain on injection. PF0713 is antiemetic in ferrets (an established laboratory model which also demonstrates the antiemetic effect of propofol).31 PF0713 produces similar anaesthesia to propofol in man;33 however, no effect-site model has yet been described and it is possible that its onset and time-to-peak effect may differ from those of

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Sedasysw
Sedasysw (Ethicon Endo Surgery, Inc., Cincinnati, OH, USA) is a new proprietary system developed for automated sedation with propofol in conjunction with comprehensive patient monitoring and sophisticated software. Described as computer-assisted personalized sedation (CAPS), the apparatus monitors ECG, SaO2, exhaled CO2, and patient responsiveness to auditory commands. Subject to satisfactory monitoring values and various safety interlocks, the system administers propofol sedation in accordance with the prescribing information, that is, slow titration in small increments. Operation of the sedation protocol is contingent on patient responsiveness and the absence of apnoea or desaturation. Sedasysw may stop or decrease the rate of propofol administration but cannot increase it. Sedasysw is therefore a hybrid systemmore complex than an open-loop system such as Diprifusorw yet not a true closed-loop anaesthesia system which titrates drug against an effect measure to achieve a hypnotic endpoint. Instead, Sedasysw delivers a xed sedation protocol or a subset of it and reacts to protect patient safety. When used with patients undergoing endoscopy, Sedasysw provided satisfactory sedation without device-related adverse events.35 In Europe, Sedasysw has received a CE mark for routine colonoscopy and screening of the upper gastrointestinal tract and the Canadian regulator, Health Canada, has approved the device for use during routine colonoscopy. Approval has been refused in the USA. It is also unclear to what extent machine supervised propofol sedation will meet clinical needs. One commentator observed that The intent of Sedasysw is to permit practitioners to use propofol at the low end of the sedation continuum. Although we have little doubt that this is useful, practitioners expecting the performance of anaesthetistadministered propofol may be disappointed.36 Certainly, Diprifusorw and Sedasysw represent impressive examples of integration of computer technology and clinical pharmacology and we can expect to see further such cross boundary devices in the future.

propofol. Although, in man, recovery from bolus injections appears satisfactory, its performance during and after infusion requires further investigation.

Fospropofol
Fospropofol is a phosphate pro-drug for propofol which is converted to propofol within a few minutes of i.v. injection. Inevitably, time-to-peak effect is longer than when propofol is used and recovery is correspondingly slower. These apparent disadvantages are being developed as advantages with US Food and Drug Administration (FDA) approval recently given for moderate sedation. However, an application for the drug to be licensed for more profound sedation has been refused. The FDA required that fospropofol be used only by persons trained in the administration of general anaesthesia and that all patients should be continuously monitored by persons not involved in the conduct of the procedure (see www.fda.gov). These restrictions effectively preclude operatorsedation by non-anaesthetists during endoscopy. Fospropofol does not cause pain on injection and is water soluble. However, it does have some side-effects not described with propofol, specically perineal pain or paraesthesia. Whether the compound is clinically useful will require evaluation in comparative studies and the development of clinician understanding of how to best use a drug which when injected i.v. only works after a signicant delay.

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Using technology to support drug administration

Target-controlled infusion (TCI) of propofol has been adopted worldwide with the exception of the USA. Initial scepticism has given way to general use, aided by the development by pump manufacturers of systems capable of TCI without using expensive proprietary pre-lled Diprivanw syringes. However, the availability of alternative pharmacokinetic models is potentially confusing for clinicians.34 The availability of generic or open TCI also allows infusion of other anaesthetic drugs notably remifentanil. Open TCI systems implement published pharmacokinetic and pharmacodynamic data sets. Although the equipment manufacturers are responsible for the electronic and mechanical systems which deliver drug at the infusion rates dictated by the mathematical models, the choice of model and the question of its appropriateness to the individual patient remain the responsibility of the anaesthetist. Only remifentanil and propofol have been specically licensed for TCI. The Open TCI initiative, www.opentci.org, brings together academics and manufacturers to share data and develop best practice in TCI. Currently available TCI remains strictly open loop, that is, there is no feedback of an effect measure from the patient to the TCI system. Closed-loop anaesthesia has been the subject of considerable research but has not been developed commercially, possible for fear of liability issues and the possibility of litigation.

Outstanding questions
Almost 50 yr ago, Barron and Dundee37 signposted the track for anaesthetic drug discovery by identifying cardiovascular and respiratory depression, accumulation, and slow recovery and also tissue irritation as undesirable characteristics of thiopental. Arguably, short-onset, rapid offset hypnosis with modest haemodynamic perturbation by drugs without active metabolites has already been achieved. Even patients with very severe circulatory compromise may be safely anaesthetized with propofol, provided that the dosage is judiciously adjusted.38 Times change, however, and several new goal criteria are emerging. Is it possible for an i.v. hypnotic to be too short acting? For AZD3043 and MOC-etomidate, esterase hydrolysis offers ultra-fast recovery from anaesthetic drug effect. If translated into humans, this might allow swift and clear-

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headed recovery of consciousness and perhaps early home readiness. Recently, concern has mounted about perioperative awareness due to inadequate delivery of i.v. anaesthesia.39 Anaesthetic techniques based on ultra-short offset hypnotics will be especially vulnerable to interruptions in drug delivery and offer the alarming prospect of a patient inadvertently going rapidly from the anaesthetized state to full wakefulness at an inappropriate time. In addition, ultra-short-acting drugs offer a pricing challenge to the pharmaceutical industry: if a reasonable price is achieved for a single bolus injection, then maintenance by infusion becomes hugely expensive. Alternatively, if such a compound is priced so that maintenance is affordable, then an induction dose will be something of a bargain! One approach to containing drug costs for i.v. anaesthesia is to use a cheap agent for induction and for the maintenance of anaesthesia and then to switch to a more expensive shortacting agent towards the end of surgery in the hope of achieving rapid recovery without excessive cost. This technique has been demonstrated for the opioid component of i.v. anaesthesia by sequential use of alfentanil (infused for most of the anaesthetic) and remifentanil (used only for the last part of the anaesthetic) in neurosurgery.40 The technique may be applicable to new ultra-short-acting hypnotics by sequential use at the end of a propofol anaesthetic. Further, the antiemetic effect of residual subanaesthetic concentrations of propofol might attenuate PONV induced by a novel hypnotic.

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Using new drugs to tackle new tasks

Obvious goals for the development of new hypnotics are compounds with superior performance compared with midazolam and propofol in current clinical applications. Less obvious is the opportunity to tackle new tasks. By way of illustration, consider the clinical development of opioids. Clinicians choose combinations of hypnotic and opioid to achieve a clinical endpoint with reasonably prompt recovery at the end of anaesthesia. If anaesthesia is provided with a combination of alfentanil and propofol, there are an innite number of possible equipotent drug combinations. Thus, a 50% probability of suppression of response to lower abdominal surgery, EC50, is achieved by a combination of propofol 2 mg ml21 with alfentanil 209 ng ml21 or propofol 10 mg ml21 with alfentanil 16 ng ml21 or a range of intermediate combinations.41 In practice, both of the above combinations cause slow awakening and the optimum mixture for swift recovery is propofol 3.5 mg ml21 with alfentanil 85 ng ml21.41 Highdose opioid anaesthesia with alfentanil offers haemodynamic stability but carries a time penalty for recovery of consciousness at the end of surgery. The newer opioid remifentanil is rapidly metabolized and eliminated; this allows clinicians to offer their patients the benet of intense opioid anaesthesia without the penalty of prolonged respiratory depression and delayed recovery42something that was previously unavailable. Mindful of remifentanil, new

hypnotics need to be evaluated for the possibility that they might open new therapeutic options and improve existing ones. What might we be able to do with new benzodiazepine receptor agonists that we cannot do already? A drug with faster onset than midazolam might simplify titration to clinical effect and decrease the risk of inadvertent over-sedation by repeated dosage with insufcient interval between consecutive doses. Midazolam sedation has been combined with umazenil reversal in short procedures43 and after extended infusion on intensive care.44 In addition, the same approach has been used for surgical anaesthesia.45 46 Nevertheless, the technique has never been widely used, perhaps reecting concerns about excitation and cardiovascular response after umazenil administration and the possibility of resedation.47 Perhaps, a truly short-acting benzodiazepine agonist, or one with a faster onset than midazolam, might allow benzodiazepine anaesthesia to be revisited. At this point, it may be appropriate to consider whether benzodiazepines can produce anaesthesia at all. Typically, even large doses of benzodiazepines depress the BIS only to values of 4060 and the compounds do not easily produce brain electrical silence (BIS0). When the auditory-evoked potential (AEP) is recorded during progressive anaesthesia with inhalation agents or propofol, the second negative wave nb is delayed (increased latency) and reduced in size (decreased amplitude).48 49 In contrast, patients anaesthetized with unitrazepam and fentanyl showed minimal changes in the AEP, despite being apparently unconscious.50 Perhaps, patients anaesthetized with a benzodiazepine/opioid combination are in some way aware but amnesic because of the interference by benzodiazepines with the formation of new memories? Certainly, when anaesthesia was maintained with a combination of midazolam and alfentanil, and consciousness monitored by the isolated forearm technique, 72% of 32 patients responded with purposeful movements to verbal commands during surgery, but none had spontaneous, unprompted postoperative recall for the event.51 The response to auditory commands implies functioning auditory and motor pathways and sufcient cortical function to interpret the command and develop an appropriate movement. If the new benzodiazepine receptor agonists are used to induce and maintain anaesthesia, then this issue needs to be considered. In the past, we evaluated new hypnotics by surrogate endpoints such as time to eye opening and discharge from recovery. Subsequently, the focus of perioperative research shifted to patient satisfaction,52 PONV, and discharge home with attempts to use health economics to offset increased drug acquisition costs against decreased hospital stay.53 Recently, we started looking at major outcomes including cardiovascular morbidity, other major complications, and 30 day mortality.54 55 As we approach the second decade of the twenty-rst century, several new issues are emerging. Preliminary data suggest that anaesthetics may be neuroprotective,56 effect (or not) preconditioning,57 alter cell-

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metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis. Br J Anaesth 2002; 89: 428 37 Wiard RP, Feldman PL, Collins H et al. CNS 7056: a novel ultra-short-acting benzodiazepine. Anesthesiology 2007; 107: 60 6 Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A phase I SAD study evaluating the safety, pharmacokinetics and pharmacodynamics of CNS 7056. Anesthesiology 2009: A1603. Available from www.asaabstracts.com Chernik DA, Gillings D, Laine H et al. Validity and reliability of the Observers Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol 1990; 10: 24451 Short acting anaesthetic/sedative CNS 7056 in a Phase IIa study in upper GI endoscopy. Available from www.paion.com (accessed January 5, 2010) Kanamitsu N, Osaki T, Itsuji Y, Yoshimura M, Tsujimoto H, Soga M. Novel water-soluble sedative-hypnotic agents: isoindolin-1-one derivatives. Chem Pharm Bull (Tokyo) 2007; 55: 16828 Rigby-Jones AE, Sneyd JR, Ohkura T, Tominaga H, Cross M. MR04A3 (aqueous 1.0% JM-1232(-)) pharmacokinetics and pharmacodynamics in man. Anesthesiology 2009: A464. Available from www.asaabstracts.com Nishiyama T, Chiba S, Yamada Y. Antinociceptive property of intrathecal and intraperitoneal administration of a novel watersoluble isoindolin-1-one derivative, JM 1232 (-) in rats. Eur J Pharmacol 2008; 596: 56 61 Reddy RV, Moorthy SS, Dierdorf SF, Deitch Rd Jr, Link L. Excitatory effects and electroencephalographic correlation of etomidate, thiopental, methohexital, and propofol. Anesth Analg 1993; 77: 1008 11 Ledingham IMA, Finlay WEI, Watt I et al. Inuence of sedation on mortality in critically ill multiple trauma patients. Lancet 1983; 321: 1270 Ray DC, Hay AW, McKeown DW. Induction drug and outcome of patients admitted to the intensive care unit after emergency laparotomy. Eur J Anaesth 2010; 27: 4815 Bloomeld R, Noble DW. Etomidate and fatal outcomeeven a single bolus dose may be detrimental for some patients. Br J Anaesth 2006; 97: 11617 Cuthbertson BH, Sprung CL, Annane D et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med 2009; 35: 186876 Jabre P, Combes X, Lapostolle F et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet 2009; 374: 293 300 Egan TD. Is anesthesiology going soft?: trends in fragile pharmacology. Anesthesiology 2009; 111: 229 30 Forman SA, Stewart D, Husain S et al. MTS-etomidate selectively reacts with cysteines in the GABA A receptor etomidate binding site. Anesthesiology 2009: A1382. Available from www. asaabstracts.com Stewart DS, Husain SS, Miller KW, Forman SA. MTS-etomidate selectively reacts within the GABAA receptor etomidate binding site. Biophys J 2009; 96: 487a488a Cotten JF, Husain SS, Forman SA et al. Methoxycarbonyletomidate: a novel rapidly metabolized and ultra-short-acting etomidate analogue that does not produce prolonged adrenocortical suppression. Anesthesiology 2009; 111: 240 9 Pitsiu M, Wilmer A, Bodenham A et al. Pharmacokinetics of remifentanil and its major metabolite, remifentanil acid, in ICU patients with renal impairment. Br J Anaesth 2004; 92: 493 503

mediated immunity58 and cell proliferation,59 and perhaps cause neurotoxicity in the developing infant brain.60 Currently, researchers are working to clarify these preliminary data and identify how we should adjust our practice to exploit the benecial effects and moderate or avoid the harmful ones. New i.v. agents must be positioned in this complex context. For a new i.v. hypnotic to be successful, it will not be sufcient for it to be quick and clean, clinicians and their patients, and commissioners of healthcare and local budget holders will expect clarity about the place of any new agents against this body of emerging anaesthetic science. This is an exciting time for anaesthetic drug development with a plethora of new hypnotics under development. Few of them will survive the rigours of commercialization in a costconstrained environment and to be successful, compounds will need to address the broadening agenda set out above.

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Conict of interest
PropofolDiprivanno current conicts. J.R.S. worked for ICI pharmaceuticals over 18 yr ago and has 18 months of contributions in the AstraZeneca pension fund. Propofol-RMnot mentioned but a competitor. J.R.S. and A.E.R.-J. have published on this and J.R.S. has consulted for LaboPharm. RemifentanilJ.R.S. did contract research for its manufacturer years ago and lectured (paid) on remifentanil study days last year (2009). CNS7056J.R.S. consulted for CeNes until 2 yr ago. No involvement in the human studies. JM-1232 (2)/ MR04A3J.R.S. consulted for Maruishi in 2008/9 and led clinical investigations of the compound. A.E.R.-J. did contracted computer modelling for Maruishi. AZD3043/THRX-918661 J.R.S. has given some paid advice to AstraZeneca in 2010. MOC-etomidate, MTS-etomidate, PF0713, Fospropofol, and Sedasyswno conicts for any of these.
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