静脉麻醉最新进展英文版和中文翻译.doc

Recent advances in intravenous anaesthesiaEfforts to develop new hypnotic compounds continue, although several have recently failed indevelopment. Propofol has been reformulated in various presentations with and without preservatives.Pharmacokinetic and pharmacodynamic differences exist between some of thesepreparations, and it is currently unclear whether any have substantial advantages over the originalpresentation. The use of target-controlled infusion (TCI) has been extended to include paediatricanaesthesia and sedation. Application of TCI to remifentanil is now licensed. Linking of electroencephalogram(EEG) monitoring to TCI for closed-loop anaesthesia remains a research tool,although commercial development may follow. The availability of stereoisomer ketamine andimproved understanding of its pharmacology have increased non-anaesthetic use of ketamine asan adjunct analgesic. It may be useful in subhypnotic doses for postsurgical patients with painrefractory to morphine administration.Br J Anaesth 2004; 93: 72536Keywords: anaesthetics i.v., etomidate; anaesthetics i.v., ketamine; anaesthetics i.v., ORG21465;anaesthetics i.v., ORG25435; anaesthetics i.v., propofol; anaesthetics i.v., THRX-918661;analgesics opioid, remifentanilIntravenous anaesthesia (IVA) is now well established inmost areas of anaesthetic provision and is the preferredtechnique for some. This review assesses the present statusof IVA, describes recent and forthcoming developments,and addresses various related controversies and their implications.Intravenous anaesthetics have other uses beyond theinduction and maintenance of anaesthesia, and recent developmentsof relevance to clinicians are also summarized.Material for this review was gathered from literature searching,attendance at meetings and personal communicationwith experts in the field. Priority has been given to developmentssince 2000. The content has been constrained toclinical developments and late-stage animal work with possiblerelevance to man.New drugsAttempts to develop new water-soluble i.v. agents for use inman have not been successful. Two Organon compounds,ORG 21465 and 25435, were both rejected in phase 1 clinicaltrials because of unwanted effects, including excitationand tachycardia, and disappointing pharmacokinetics leadingto slow recovery after prolonged infusion.102 103 106Other novel water-soluble anaesthetics exist which performwell in rodents but which for various reasons have not beentested in man.18 The success of remifentanil and its esterasemetabolism has encouraged other attempts at developingcompounds with very rapid metabolism. THRX-918661, asedativehypnotic agent being developed by Theravance(Theravance, South San Francisco, CA, USA), is an allostericmodulator of the GABAA receptor which is hydrolysedby esterases to an inactive metabolite. In rat and guinea-pigwhole blood the compound is rapidly hydrolysed (t1/2 0.4and 0.1 min respectively). After discontinuing a 3 h continuousi.v. infusion in rats, the parent compound was onlydetectable for 5 min.50 When the compound was administeredto pigs by continuous i.v. infusion, recovery was fasterthan with propofol.34 However, rapid metabolic deactivationcombined with modest potency require that a large mass ofdrug be infused to produce a therapeutic effect (1.5 mg kg_1min_1 to maintain anaesthesia in a pig), and this mightimpede clinical development. If the ultrarapid recoveryfrom THRX-918661 anaesthesia is confirmed in man, thisagent will have a clinical profile distinct from other hypnotics.Whether such abrupt emergence is clinically advantageousis unknown. Certainly, this compound raises thetheoretical question of whether it is possible for an i.v.anaesthetic agent to wear off too quickly. In any case,speed of emergence could presumably be controlled bytapering rather than discontinuing the infusion. The structureof THRX-918661 is described as a commercial secret, but a# The Board of Management and Trustees of the British Journal of Anaesthesia 2004Declaration of interest. Professor Sneyd is an Advisory Board memberfor Organon Inc. and has received research funding from AstraZeneca.recent US patent application51 includes the formula4-(N,N-diethylcarbamoyl)methoxy-3-ethoxyphenylaceticacid propyl ester and a structure (Fig. 1) which appear todescribe the compound.PropofolAfter its launch in 1986, propofol rapidly became the mostcommonly used i.v. anaesthetic agent, with thiopental, ketamineand etomidate reserved for specific indications. Soubiquitous has propofol IVA become that it is simpler tolist its contraindications than to describe the techniques forwhich it is suited.When should propofol not be used? The only absoluteindication to propofol is allergy and this appears to be rare.Although Laxenaire58 59 65 has described several cases ofpropofol allergy, its overall incidence appears to be verylow and the drug is well tolerated by most patients, includingthose allergic to eggs. Alternative induction agents alsocause serious adverse reactions.15Several groups have studied propofol for induction andmaintenance of anaesthesia during Caesarean section; neonatalscores and neurobehavioural measures were inferiorwhen propofol was used in comparison to thiopental andinhalational agents respectively.26 130 Propofol is notlicensed for use in obstetric anaesthesia.Parkinsons disease is a common condition, yet there isremarkably little information to guide anaesthetists onwhich, if any, i.v. agent to use for these patients. A limitednumber of case reports suggest that Parkinsons disease maybe worsened by propofol,75 presumably due to dopaminergiceffects. However, the ability of propofol to diminish orabolish Parkinsonian tremor yet induce myoclonic movementsis hard to understand.5 Clearly, we need to know moreabout these aspects of propofol pharmacology; meanwhile,the drug should be used cautiously in patients with movementdisorders. Excitatory events following propofol administrationare well described if not well understood,101 andthiopental may be a better choice for patients with epilepsywho hold a driving license.105Haemodynamic changes following propofol administrationare well detailed and are generally moderated by areduction in dose and slower administration,78 combinedwith adequate fluid administration. In practice, propofol iscommonly co-administered with other drugs, some of whichhave vagotonic effects, particularly opioids. However,although frequent, bradycardia associated with propofolanaesthesia seldom has serious consequences.47Old drugs in new clothing: propofol revisitedWhilst the original 1 and 2% presentations of propofol insoya oil remain popular, there have been a number ofattempts at reformulation. The basic presentation38 supportsbacterial growth,88 and has been supplemented with EDTA(ethylene diamine tetraacetic acid)42 or sulphite,99 the manufacturersof rival formulations arguing whether sulphitecauses allergic reactions, especially in atopic or asthmaticpatients. When the sulphite and EDTA formulations wereadministered to 40 current, long-term smokers, total respiratorysystem resistance was increased in the patients treatedwith the sulphite-containing formulation. But changes ininflation pressure were not significant,84 suggesting thatsulphite has some effect on the tracheobronchial systemof patientswith reactive airways. However, the clinical significanceof these small changes is unclear.Sulphite supports the peroxidation of lipids in soybean oilemulsions,12 and this may cause the infusion to develop ayellowish discoloration during use.13 The addition of sulphitealso lowers the pH of the propofol formulation and maycompromise the stability of the oil-in-water emulsion, leadingto an increase in the number and size of large-diameterlipid droplets in the ampoule.In Europe, propofol continues to be safely used withoutsupplementary preservatives and it is clear that when thedrug is prepared using a proper aseptic technique and notstored beyond recommended guidelines, then bacterial contaminationis not a clinical issue. Whether the added preservativesare clinically important in standard anaestheticpractice is probably debatable, but different considerationsmay apply for critically ill patients with organ dysfunctionreceiving prolonged propofol infusions.131Propofol in different lipidsThe standard propofol formulation contains 10% soya oilas long-chain triglycerides. Triglyceride concentrationsOOOOO N(Et)2EtCH2CH2CH3Fig 1 THRX-918661 is a short-acting novel i.v. anaesthetic agent whichhas been evaluated in various animal models.16 34 50 Its formula is probably4-(N,N-diethylcarbamoyl)methoxy-3-ethoxyphenylacetic acid propylester. A likely structure is shown.51Sneyd726increase in a proportion of patients after propofol administration.Changing the emulsion in which propofol is presentedmight have favourable effects on the plasmatriglyceride profile. An emulsion containing long- andmedium-chain triglycerides (Propofol-Lipuro_) reducedthe incidence of pain on injection from 14.7 to 2.7% (lidocainewas not given).82 When used to maintain anaesthesiain volunteers, their plasma triglyceride concentrations didnot rise.125 Whether these advantages are of any real clinicalimportance remains to be determined. In critical care,however, things seem to be different. When a similar comparisonbetween standard (long-chain triglyceride) propofoland the long- and medium-chain mixture was made using2% formulations, similar propofol concentrations andequivalent levels of sedation were achieved. But therewas no difference in plasma triglyceride concentrationsbetween the two groups and the recovery time was prolongedin patients receiving the new formulation.113 Thus,the reformulation not only failed to confer any advantage, itactually reduced clinical performance. However, the studywas a small one and differences in patient characteristicsmay also have influenced the outcome.Another propofol-containing emulsion based on mediumchaintriglycerides (AM149 1%) caused pain on injection in93% of subjects as well as thrombophlebitis and seemsunsuitable for further development.77Propofol prodrugPropofol phosphate is a water-soluble propofol prodrugwhich is enzymatically converted to propofol, formaldehydeand inorganic phosphate. The compound produces sedationand anaesthesia in a range of animal species.14 However, theonset of hypnotic effect ranged from a minute to severalminutes and was much slower than for propofol. When thecompound was administered to volunteers as a 10-min infusion,two of the nine subjects reported an unpleasant sensationof burning or tingling in the anal and genital region.Modelling suggested that, after a bolus injection of propofolphosphate, the peak blood propofol concentration wouldoccur more than 5 min later and context-sensitive halftimeswould increase substantially after prolonged infusions.35 The effects of formaldehyde and formate (towhich the formaldehyde is converted) have not yet beenfully investigated in man. Whilst the prodrug approach rendersthe compound water-soluble and may reduce pain oninjection, it is clinically counterintuitive to modify a drug insuch a way as to slow its onset of action when almost theentire focus of anaesthetic drug development has been toachieve the opposite.Water-soluble propofol analoguesA substantial number of water-soluble anaesthetics havebeen prepared with structures derived from that of propofol.4 27 116 These have been tested in rodents as bolus injectionsand in some cases by infusion for closed-loopcomputer-controlled maintenance of anaesthesia. Theselaboratory projects indicate that the potential remains fornew propofol-derived drugs but their commercializationremains uncertain.Non-lipid formulations of propofolCyclodextrins are widely used as solubilizing agents in pharmaceuticalpractice. Cyclodextrins are ring sugar moleculeswhich form guesthost complexes, the guest compound (inthis case propofol) migrating between the hydrophilic centreof the cyclodextrin molecule and the water-soluble phase.This allows compounds which are sparingly soluble in waterto be presented in an injectable format. After injection, theguest (propofol) migrates out of the cyclodextrin into theblood, where it is protein-bound and, in small amounts,dissolves. Adjustment of the size of the cyclodextrin ringand the addition of side-chains allows cyclodextrins to bedeveloped with specific binding characteristics. Propofol hasrecently been evaluated in a cyclodextrin-based formulation(Fig. 2). When administered to isoflurane-anaesthetizedpigs, the pharmacokinetic and pharmacodynamic effectsof conventional and cyclodextrin formulated propofolwere similar and further clinical investigation may be appropriate.32 This study was, however, a small and preliminaryinvestigation and extrapolation of these findings to man isnot appropriate without additional supporting information.Polysorbate 80 is a non-ionic surfactant derived fromsorbitol which is used widely as an additive in foods, pharmaceuticalpreparations and cosmetics as an emulsifier, dispersantor stabilizer. A polysorbate formulation of propofolhas been tested in goats but was associated with haemodynamicinstability and prolonged apnoea.19Fig 2 Sulfobutyl ether-b-cyclodextrin (Captisol), a polyanionic b-cyclodextrinderivative with a sodium sulfonate salt separated from the lipophiliccavity by a butyl ether spacer group. Captisol has been used as a lipid-freevehicle for propofol.32I.V. anaesthesia update727Another aqueous formulation of propofol may exist butdetails are sketchy. The use of a vegetarian formulationof propofol, Cleofol_ (Themis Medicare, Vapi, Gujarat,India), has been described in a patient from the Jaincommunity of India.70 No details of the supposedly aqueousformulation are available, nor are any supporting volunteeror preclinical data.More drug, less fatAttempts have been made to reduce the amount of fat givento patients receiving propofol. Increasing the concentrationof propofol from 10 to 60 mg ml_1 reduced the total amountof fat received by sedated patients in intensive care andwas also associated with lower triglyceride concentrationsthan in patients receiving the standard formulation.57Another version of propofol emulsion has been describedwith the soya oil content reduced to 5%, i.e. half that of theoriginal presentation. When this formulation was given tooutpatients, the pharmacodynamic effects were unchangedbut the incidence of pain on injection was increased from 9%(with the original formulation) to 39%, despite pretreatmentwith lidocaine.108 A summary of the formulations of propofolis given in Table 1.Propofol and pain on injectionAlthough important to patients given propofol, this has beenpartially addressed by the preadministration of lidocaine.97Not withstanding this well-established practice, investigatorscontinue to study alternative and sometimes bizarreways of addressing the problem (Table 2). Medline nowlists many studies on the topic, perhaps reflecting the relativeease with which such investigations can be conducted.Propofol and nausea and vomitingIntravenous anaesthesia with propofol has long been associatedwith a modest reduction in postoperative nausea andvomiting.104 115 Apfel and colleagues8 used a complexmultifactorial crossover design to evaluate in detail the relativecontributions of the hypnotic agent, opioid selection andvarious antiemetics. This study confirmed that replacingan inhaled anaesthetic agent with propofol does reduce postoperativenausea and vomiting (PONV) by roughly thesame amount as a single antiemetic. Further, addition ofone or more antiemetics to a propofol anaesthetic doesreduce PONV.9 Recent consensus guidelines for managingPONV include i.v. anaesthesia with propofol as part of amultimodal strategy to reduce baseline risk in susceptiblepatients.36Propofol pharmacokineticsUnderstanding of the pharmacokinetics and pharmacodynamicsof propofol has improved with a comprehensiveremodelling of pooled data, drawing together informationfrom a number of clinical trials and specific modelling forchildren and the elderly.93 However, the interpretation andapplicability of the data for the elderly has been disputed123and defended.94 The pharmacokinetics of propofol in criticallyill children have also been described in detail.85 Pharmacokineticparameters from four different models aresummarized in Table 3. The major difference between themodels is the size of the central compartment, which affectsthe predicted concentrations achieved by propofol infusions.These differences are illustrated in Figure 3. Differencesbetween models also affect their predictions for the declinein blood propofol concentrations when an infusion isstopped. Context-sensitive half-time is a clinically usefulTable 1 Formulations of propofolCharacteristics Trade name Manufacturer ReferencesPropofol 1% and 2% in 10% soya oil with or without EDTA Diprivan, Disoprivan AstraZeneca 38, 42Propofol 6% in 10% soya oil 57Propofol 1% and 2% in 10% soya oil with or without sodium sulphite Various Various 99Propofol 1% and 2% in 10% long and medium chain triglycerides Propofol Lipuro Braun medical 82, 125A new galenic formulation of propofol AM149 Amrad 77Propofol phosphate Aquavan Guildford Pharmaceuticals 35Propofol polysorbat