headed recovery of consciousness and perhaps early homereadiness.

Recently, conc ern has mounted about periopera-tive awareness due to inadequate delivery of i.v . anaesthe-sia. 39 Anaesthetic techniques based on ultra-short offsethypnotics will be especially v ulnerable to interruptions indrug delivery and offer the alarming prospect of a patientinadvertently going rapidly from the anaesthetized state tofull wa efulne ss at an inappropriate time.In addition, ultra-short-acting drugs offer a pricin g chal-lenge to the pharmaceutical industry: if a reasonable priceis achieved fo r a single bolus injection, then maintenanceby infusion becomes hugely expensive . Alternatively, if sucha compound is priced so that maintenance is affordable,t hen an induction dose will be something of a bargain! Oneapproach to containing drug costs for i.v. anaesthesia is touse a cheap agent for induction and for the maintenanceof anaesthesia and then to switch to a more expensive short-acting a gent towards the end of surgery in the hope of achieving rapid recovery without excessive cost. This tech-nique has been demonstrated for the opioid component o f i.v. anaesthesia by sequential use of alfentanil (infused formost of the anaes thetic) and remifentanil (used only forthe last part of the anaesthetic) in neur osurgery. 40 The tech-nique may be applicable to new ultra-short-acting hypnoticsby sequentia l use at the end of a propofol anaesthetic.Further, the antiemetic effect of res idual subanaesthetic con-centrations of propofol might attenuate PONV induced by anovel hypnotic. Using new drugs to tac le new tas s Obvious goals for the development of new hypnotics arecompounds with superior pe rformance compared with mida-zolam and propofol in current clinical applications . Lessobvious is the opportunity to tac le new tas s. By way of illustration, co nsider the clinical development of opioids. Clin-icians choose combinations of h ypnotic and opioid to achievea clinical endpoint with reasonably prompt recovery at theend of anaesthesia. If anaesthesia is provided with a combi-nation of alf entanil and propofol, there are an in nitenumber of possible equipotent drug combi nations. Thus, a50% probability of suppression of response to lower abdomi-nal s urgery, EC 50 , is achieved by a combination of propofol2 m g ml 2 1 with alfentanil 209 ng ml 2 1 or propofol 10 m g ml 2 1 with alfentanil 16 ng ml 2 1 or a range of intermediate combi-nations. 41 In practice, both of the above combinations causeslow awa ening and the optimum mixture for swift recoveryis propofol 3.5 m g ml 2 1

with alfentanil 85 ng ml 2 1 . 41 High-dose opioid anaesthesia with alfentanil offers haemo-dynamic stability but carries a time penalty for recovery of consciousness at the end of surgery. The newer opioid remi-fentanil is rapidly metabolized and eliminated; this allowscli nicians to offer their patients the bene t of intenseopioid anaesthesia without th e penaltyof prolonged respirat-ory depression and delayed recovery 42 something that waspreviously unavailable. Mindful of remifentanil, newhypnotics n eed to be evaluated for the possibility that theymight open new therapeutic opti ons and improve existingones.What might we be able to do with new benzodiazepine receptor agonists that we cannot do already? A drug withfaster onset than midazo lam might simplify titration to clini-cal effect and decrease the ris of inadve rtent over-sedationby repeated dosage with insuf cient interval between con-secuti ve doses. Midazolam sedation has been combinedwith umazenil reversal in short pro cedures 43 and afterextended infusion on intensive care. 44 In addition, the sameapproach has been used for surgical anaesthesia. 45 46 Never-theless, the technique has never been widely used, perhapsre ecting concerns about excitation and cardiovascularresponse after umazenil administration and th e possibilityof resedation. 47 Perhaps, a truly short-acting benzodiazepineagonist, or one with a faster onset than midazolam, mightallow benzodiazepine anaesthesia to be revisited.At this po int, it may be appropriate to consider whetherbenzodiazepines can produce anaest hesia at all. Typically,even large doses of benzodiazepines depress the BISonly to values of 4060 and the compounds do not easilyproduce brain electrical silence (BIS 0). When theauditory-evo ed potential (AEP) is recorded during progress-ive anae sthesia with inhalation agents or propofol, thesecond negative wave n b is delayed (increased latency) andreduced in size (decreased amplitude). 48 49 In contrast,patients anaesthetized with unitrazepam and fentanylshowed minimal chan ges in the AEP, despite being appar-ently unconscious. 50 Perhaps, patients anaesthetized with abenzodiazepine/opioid combination are in s ome way awarebut amnesic because of the interference by benzodiazepineswith the formation of new memories? Certainly, whenanaesthesia was maintained with a combin ation of midazo-lam and alfentanil, and consciousness monitored by the iso-lated forearm technique, 72% of 32 patients responded withpurposeful movements to ver bal commands during surgery,but none had spontaneous, unprompted postoperativere call for the event. 51 The response to auditory commandsimplies functioning auditory and motor pathways and suf -cient cortical function to interpret the command anddevelop an appropria te movement. If the new benzo-diazepine receptor agonists are used to induce and maintainanaesthesia, then this issue needs to be considered.In the past, we evalu ated new hypnotics by surrogateendpoints such as time to eye opening and dischar ge fromrecovery. Subsequently, the focus of perioperative researchshifted to pat ient satisfaction, 52

PONV, and discharge homewith attempts to use health economics to offset increase ddrug acquisition costs against decreased hospital stay. 53 Recently, we started loo ing at major outcomes includingcardiovascular morbidity , other major complications, and30 day mortality. 54 55 As we approach the second decade of the twenty- rstcentury, several new issues are emerging.Preliminary data suggest that anaesthetics may be neuro-protective, 56 effect (or not) preconditioning, 57 alter cellBJA Sneyd and Rigby-Jones 252 b y g u e s t on N o v e m b e r 1 0 ,2 0 1 1 h t t p : / / b j a . oxf or d j o ur n a l s . or g / D o wnl o a d e d f r om mediated immunity 58 and cell proliferation, 59 and perhapscause neurotoxicity in the developing infant brain. 60 Cur-rently, researchers are wor ing to clarify these preliminarydata and identif y how we should adjust our practice toexploit the bene cial effects and moderate o r avoid theharmful ones. New i.v. agents must be positioned in thiscomplex conte xt. For a new i.v. hypnotic to be successful, itwill not be suf cient for it to be quic and clean, cliniciansand their patients, and commissioners of healthcare andl ocal budget holders will expect clarity about the place of any new agents agains t this body of emerging anaestheticscience.This is an exciting time for anaesthe tic drug developmentwith a plethora of new hypnotics under development. Few of t hem will survive the rigours of commercialization in a cost-constrained environm ent and to be successful, compoundswill need to address the broadening agenda se t out above. Con ict of interest PropofolDiprivanno current con icts. J.R.S. wor ed for ICIpharmaceuticals over 18 yr ago and has 18 months of contri-butions in the AstraZeneca pension fund. Propof ol-RMnotmentioned but a competitor. J.R.S. and A.E.R.-J. have pub-lished on this and J.R.S. has consulted for LaboPharm.RemifentanilJ.R.S. did contract research f or its manufacturer years ago and lectured (paid) on remifentanil study days las t year (2009). CNS7056J.R.S. consulted for CeNes until 2 yrago. No involvement in the human studies. JM-1232 ( 2 )/MR04A3J.R.S. consulted for Maruishi in 2008/9 and led clini-cal investigations of the compound. A.E.R.-J. did contractedcomputer modelling for Maruishi. AZD304 3/THRX-918661J.R.S. has given some paid advice to AstraZeneca in 2010.MOC-etomida te, MTS-etomidate, PF0713, Fospropofol, andSedasys w no con icts for any of these. References 1 Scott RP, Saunders DA, Norman J. Propofol: clinical strategies forpreventing t he pain of injection. Anaesthesia 1988; 43 : 49242 Rau J, Roizen MF, Doenic e AW, OConnor MF, Strohschneider U.Propofol in an emulsion of long- and medium-chain triglycerides:the effect on pain. Anesth Analg

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