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Anaesthesia and perioperative care

Paul Flecknell and Hannah OrrUniversity of Newcastle upon Tyne

p.a.flecknell@ncl.ac.ukh.e.orr@ncl.ac.uk

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Introduction.............................................................................................................. 4

Definitions................................................................................................................ 5

Selecting an anaesthetic regimen............................................................................. 6

Pre-anaesthetic preparations.................................................................................... 7

Pre-anaesthetic medication..........................................................................................................7

Special considerations with individual species.......................................................................8Small rodents.........................................................................................................................................8Rabbits....................................................................................................................................................8Cats.........................................................................................................................................................8Dogs.......................................................................................................................................................8Pigs.........................................................................................................................................................9Sheep......................................................................................................................................................9Non-human primates.............................................................................................................................9Birds.....................................................................................................................................................10

Commonly used pre-anaesthetic agents................................................................................11Phenothiazines.....................................................................................................................................11Benzodiazepines..................................................................................................................................11Alpha 2 adrenoreceptor agonists.........................................................................................................11Opioids (morphine-like drugs)............................................................................................................11Ketamine (a dissociative anaesthetic).................................................................................................12

Anaesthetics.….…………………………………………………………………….. 13

i: Injectable anaesthetics.......................................................................................................13a: Neuroleptanalgesic combinations...................................................................................................13b: Ketamine..........................................................................................................................................13c: Barbiturates......................................................................................................................................14d: Propofol............................................................................................................................................14e: Alphaxalone/alphadolone................................................................................................................15

ii: Inhalational agents..............................................................................................................16

Choice of anaesthetic.............................................................................................. 19

Rodents and Rabbits ...............................................................................................................19

Larger mammals......................................................................................................................20

Animal welfare problems with injectable agents....................................................21

Animal welfare problems with inhalational anaesthetics....................................... 21

Safety problems with anaesthetics..........................................................................22

Interactions between anaesthetics and research protocols..................................... 23

Anaesthetic management - Preventing problems and coping with emergencies..... 24

Respiratory function................................................................................................................25Endotracheal intubation.......................................................................................................................26

Circulatory function................................................................................................................27

Monitoring depth of anaesthesia............................................................................................29

Post-operative Care................................................................................................ 30

Pain relief ..................................................................................................................................31

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Analgesic use in laboratory animals ...................................................................................................32Drugs available ....................................................................................................................................32

Further reading:.....................................................................................................36

Tables.....................................................................................................................37

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Introduction

General anaesthesia was first demonstrated in animals in the 16th century, but 300 yearselapsed before it was introduced into medical and veterinary clinical practice. Since then,major advances in anaesthetic techniques and in the anaesthetic agents available, havebeen made. Many of these developments were made using laboratory animals, so a widerange of anaesthetic techniques can readily be extrapolated from man to animals.

Current views on the use of animals in research give considerable emphasis to theadoption of the 3 Rs of Reduction, Replacement and Refinement – concepts firstdescribed by Russell and Burch in the late 1960s. Updating our anaesthetic methodologyto use the most appropriate techniques can represent an important “refinement” of ourresearch. Russell and Burch’s definition states that “refinement” involves reducing to aminimum any pain or distress caused to those animals that are used in research. If ananimal is anaesthetized, and so is unconscious throughout the procedure, then surely thismust be a clear example of refinement? As with many aspects of our use of animals inresearch, the situation is not so clear cut. Appropriate use of anaesthesia can make animportant contribution to refinement, but we must be aware of some potential problems,and these are discussed later in these notes. It is also important to keep abreast of newdevelopments in anaesthetic practice, and apply these when they can improve on oldermethodology. A number of specific areas are reviewed in these notes, and illustrated onthe accompanying video clips. I hope some of these will be of relevance to yourparticular area of work.

The techniques illustrated on the CD that accompanies these notes (and on others in theseries) are provided as examples of suitable anaesthetic methodology. The techniquesshown aim to illustrate general principles of anaesthesia and highlight some key areas ofgood practice. It is not our intention to imply that these are the only appropriatetechniques for the species concerned. A wide range of other methods is available, andsome of these will be more suitable in particular circumstances and for particularresearch projects.

The video clips on the CD illustrate typical responses of various animal species to somedifferent anaesthetic agents. Other CDs in the collection include examples in differentspecies. Occasionally, unpredictable effects may be encountered, but careful planning,and availability of emergency drugs and equipment can help cope with such problems.More detailed guidance can be found in the reading list provided at the end of thesenotes. The interactive version of the notes included on the CD contains additionalmaterial.

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Definitions

Anaesthesia is defined as a state of controllable, reversible insensibility in whichsensory perception and motor responses are both markedly depressed. This state can beeither General anaesthesia - when animals lose consciousness, or Local anaesthesia,when the loss of sensory and motor function is confined to a specific region, for exampleone limb.

Analgesia is the temporary abolition or diminution of pain perception.

Sedatives produce drowsiness and appear to reduce fear and apprehension in animals.

Tranquillisers produce a calming effect without causing sedation, and at high doses theyproduce ataxia (unsteady, uncoordinated movement) and depression, but animals areeasily roused. There is considerable overlap in the action of many agents, and differentanimal species often respond differently.

The term Muscle relaxant is usually used to describe neuromuscular blocking agents,which produce paralysis of the skeletal muscles.

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Aims of anaesthesia

Anaesthesia aims to:

• Eliminate pain so that surgical and diagnostic procedures can be carried outhumanely (in addition to preventing distress, and movement in response tosurgical stimuli, elimination of pain also reduces the risk of shock).

• Immobilize the animal so that procedures can be carried out safely.• Produce relaxation of skeletal muscles to reduce or eliminate reflex responses

and muscle spasm.

Selecting an anaesthetic regimen

Anaesthesia can be produced by:

• Injectable anaesthetics (eg propofol)• Inhalational anaesthetics (these can be gases, such as nitrous oxide, or volatile

liquids, eg isoflurane, which are vaporized before delivery to the animal)• Local anaesthetics (eg lidocaine).

Anaesthetic techniques are often selected from just one of these groups, but it is oftenbeneficial to use two or more techniques in combination, for example isoflurane byinhalation to produce loss of consciousness and some muscle relaxation, and ananalgesic such as pethidine, to block the perception of pain. This approach is called“balanced anaesthesia”. Although it might appear at first to be an unnecessarycomplication, by reducing the dose of the individual agents used, it reduces theirundesirable side-effects (such as hypotension - a reduction in arterial blood pressure),and can also result in more rapid recovery.

A number of factors will influence the choice of a particular technique, and theseinclude:

• The species of animal – different species respond in different ways to specificanaesthetic agents

• The depth and duration of anaesthesia required – anaesthetics vary both in theirduration of action and the depth of anaesthesia they produce

• The availability of equipment such as anaesthetic machines• The experience and skills of the staff involved• The potential interactions between the anaesthetic protocol and the particular

research project. This can be a major factor when selecting anaesthetics for use inlaboratory animals, and is discussed in more detail below.

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Pre-anaesthetic preparations

Before anaesthetising an animal check:

• All equipment that will be needed is in working order and readily available• That any personnel involved are familiar with its operation and have been briefed

on their role in the procedure• That the animals that are to be anaesthetised have been examined for signs of ill-

health, their behaviour and temperament assessed, and body weights recorded.Some basic biological data are listed in Tables 1a and 1b.

Non-human primates, dogs, cats and ferrets may vomit on induction of anaesthesia, orduring recovery, so it is advisable to withhold food for 12-16 hours, and water for 3-4hours before induction of anaesthesia. Small rodents and rabbits do not vomit so there isgenerally no need to withhold food or water prior to anaesthesia. Withholding food fromsmall rodents for prolonged periods can be detrimental as it can predispose tohypoglycaemia, and in rabbits and guinea pigs withholding food can lead to thedevelopment of gastrointestinal disorders in the post-operative period. Problems aremost unlikely to be encountered when allowing free access to both food and water untilimmediately prior to anaesthesia in both rodents and rabbits. In guinea pigs, smallquantities of food are often found in the mouth, but this is not due to regurgitation ofstomach contents.

Pre-anaesthetic medication

It may be helpful to include pre-anaesthetic medication as part of the anaestheticprotocol. The advantages of this are:

• Use of sedatives and tranquillisers can reduce aggression and fear or apprehension.

• Use of analgesics can reduce pain and provide “pre-emptive analgesia” (see below)

• Atropine or glycopyrollate can be given to reduce bronchial and salivary secretions,and to protect the heart from vagal inhibition caused by some surgical procedures (egmanipulation of the viscera). It is advisable to use glycopyrollate in rabbits, as atropineis often relatively ineffective in this species.

• Use of sedatives, tranquillisers and analgesics can reduce the amount of anaestheticneeded to produce desired level of anaesthesia

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Special considerations with individual species

Small rodents

Since anaesthetic induction is usually achieved using either volatile anaestheticsadministered in an anaesthetic chamber, or intraperitoneal or subcutaneous injection ofan anaesthetic agent (or mixture of agents), pre-anaesthetic agents are rarely used.When only immobilisation is required, rather than anaesthesia, high doses of some ofthese agents may be effective, but often low doses of anaesthetic combinations (egketamine/medetomidine) are more useful.

Rabbits

Rabbits are easily stressed when handled and restrained, so use of sedatives ortranquillisers can have significant benefits. Administration of the drug before removalfrom the animal’s home cage or pen is advisable. Suitable agents includefentanyl/fluanisone (“Hypnorm”), medetomidine, acepromazine, diazepam andmidazolam.

Cats

Cats should be well-socialised, and so easy to restrain for intravenous administration ofanaesthetic agents. They may resent insertion of over-the-needle catheters, and maystruggle in response to venepuncture. This can be avoided by using local anaestheticcream (EMLA, Astra-Zeneca). This mixture of lignocaine and prilocaine produces fullskin thickness anaesthesia, but requires 45min-1h contact time, and needs to be coveredwith a dressing. Its advantage is that it prevents sensation during venepuncture. Analternative approach is to administer a sedative such as medetomidine. This agentproduces vomiting in a high proportion of cats, followed by light to heavy sedationdepending upon the dose used. As mentioned earlier, its effects can be reversed usingatipamezole.

Dogs

Early socialisation of laboratory bred dogs is important, as they will then be easy tohandle and restrain for injection of anaesthetics. Like cats, they may resent insertionof over-the-needle catheters, and may struggle in response to venepuncture. Use ofEMLA cream can prevent discomfort during venepuncture or catheter placement.Alternatively, a range of different sedatives can be administered as pre-anaestheticmedication, including medetomidine, acepromazine and acepromazine/buprenorphine.

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Pigs

Laboratory bred pigs (usually mini-pigs) should have been socialised to be accustomedto human contact. They can usually be readily trained to accept some degree of restraint,enabling intramuscular injection of a sedative combination to immobilise them. If trainedto accept restraint in a sling, then the ear can be anaesthetised with EMLA cream, and acatheter placed for intravenous induction of anaesthesia. Many pigs, particularly thosereared under farm conditions, may be apprehensive and difficult to approach. Suchanimals should be immobilised or heavily sedated using one of the agents listed in tables3a and 3b. Drug administration is easier if a long (3-4cm) needle is attached usinganaesthetic extension tubing to a syringe, so that after placing the needle in the pig, thedrug can be injected without the need for physical restraint of the animal.

Sheep

The temperament of sheep varies very considerably, depending upon the degree ofhuman contact they have experienced. Some may be extremely apprehensive anddifficult to approach, others more tractable. In most cases, however, it is preferable toadminister a sedative to avoid causing distress when restraining the animal for inductionof anaesthesia. Although alpha2 agonists such as medetomidine are extremely effectivein sheep, they produce profound hypoxia, even at low doses, and so should be used withgreat care in this species. Other suitable agents include midazolam and diazepam.

Non-human primates

The use of pre-anaesthetic medication in primates is often essential because of concernsfor the safety of the staff involved. For example, ketamine, a dissociative anaesthetic, isfrequently administered to immobilize an animal so that it can then be handled safely.Administration of the drug may be facilitated by use of a cage design that allows theanimal to be confined for injection. As an alternative to the dissociative anaesthetics,sedatives and tranquillisers can also be used in non-human primates, but these are notalways effective in preventing aggression. Medetomidine, an alpha2 agonist, has beenused successfully in a wide range of laboratory species to produce heavy sedation andimmobilization. It must be used with great care in non-human primates as its sedativeeffects are less predictable, and some animals may suddenly become alert and may bitetheir handlers. When combined with ketamine, it has effects similar to ketamine/xylazinein combination. Animals are immobilized, and a medium plane of anaesthesia isproduced. The advantage of this agent is that it can be reversed using a specificantagonist, atipamezole. Although the effects of ketamine still remain, recovery isgenerally rapid.

The use of ketamine in marmosets has been associated with muscle damage. This isprobably related to the low pH of ketamine (3-4), and its injection into the relativelysmall muscle mass of marmosets. Similar effects have been seen in small rodents. Forthis reason, pre-medication with alphaxalone/alphadolone is preferable. Despite therelatively large volume of injectate, no muscle damage has been associated with its use.An advantage of this agent is that additional drug can be given intravenously to deepenanaesthesia.

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Birds

Many species of birds, especially wild caught individuals, are easily stressed by handlingand restraint, so use of sedatives can minimise the stress associated with induction ofanaesthesia. However, in many circumstances rapid recovery, with a minimal period ofataxia is desirable, so that the risk of injury, for example following wing-flapping inrecovery, is minimised. For this reason, induction of anaesthesia with isoflurane orsevoflurane using a face-mask, or in an anaesthetic chamber, with no pre-anaestheticmedication, is often considered the method of choice.

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Commonly used pre-anaesthetic agents

Suggested dose rates for different species are listed in Tables 3a and 3b

Phenothiazines

Phenothiazines such as acepromazine can be used to sedate most mammals. Althoughthey provide sedation they do not normally immobilise the animal. Phenothiazinesdepress blood pressure, and potentiate the effect of other anaesthetic agents.

Benzodiazepines

Both diazepam and midazolam have marked sedative effects in rodents and rabbits, buttheir effects in dogs and cats are less predictable. In sheep and pigs they produce goodsedation. They can be administered by a variety of routes (see Tables 3a and 3b) and areoften used in combination with other agents to produce balanced anaesthesia. Thesedative properties, although pronounced, are not usually sufficient to completelyimmobilise an animal for minor procedures such as radiography.

Alpha 2 adrenoreceptor agonists

Xylazine and medetomidine can both be used to produce sedation with some analgesia ina wide range of different species. At higher dose rates the effects can be sufficient toimmobilise some animals. In rabbits, cats and dogs, medetomidine can be used toprovide sedation and restraint for radiography. Sheep are also heavily sedated, but thesedrugs can cause pronounced hypoxia, so should be used with great care in this species.In species that vomit, medetomidine often triggers this reflex. In most species, other sideeffects including hyperglycaemia, diuresis, and respiratory and cardiovascular systemdepression occur. A major advantage of these sedatives is that their action can bereversed by administration of specific antagonists such as yohimbine and atipamezole.Atipamezole is preferable since it has fewer non-specific side effects. It can be given bythe subcutaneous, intraperitoneal, intramuscular or intravenous routes. Absorptionfollowing subcutaneous injection is rapid, generally acting within 5 to 10 minutes. Doserates of 0.5-1.0mg/kg are required, depending upon the dose of medetomidine that hasbeen administered

Opioids (morphine-like drugs)

The use of these agents in the pre-anaesthetic period to provide pre-emptive analgesia isdiscussed later. Opioids are frequently used in combination with sedative agents toprovide chemical restraint and analgesia for minor procedures such as suturingsuperficial wounds and draining abscesses. A number of commercial preparations,which combine a potent opioid with a sedative or tranquilliser, are available, such as

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“Hypnorm” (Janssen) (fentanyl and fluanisone) in Europe, and “Innovar Vet” (fentanyland droperidol) in the USA. It is also possible to produce other useful combinations. Forexample, a mixture of acepromazine and butorphanol is useful when blood samplingrabbits as it provides some sedation, analgesia, and dilates the ear veins. Buprenorphinecombined with acepromazine provides excellent restraint for procedures such asradiography in dogs. Dose rates for these combinations are included in tables 3a and 3b.

Ketamine (a dissociative anaesthetic)

Ketamine is often used to provide chemical restraint in several species. As mentionedabove, it is widely used in old-world primates, and produces immobility and someanalgesia. It has the advantage that even at light levels of sedation, the bite reflex is lost.Ketamine is usually administered intramuscularly, but it can also be given by mouth ifintramuscular injection is not possible. It is most effective if applied to the mucousmembranes of the mouth, once in the stomach it undergoes some first-pass livermetabolism, and both onset of action and peak effect are markedly reduced compared toadministration by injection (4-10 times the i/m dose is required). It can, however, beinjected into foods such as bananas, to sedate animals that have escaped from theircages.

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Anaesthetics

i: Injectable anaesthetics

A number of commonly used anaesthetic regimens are described briefly below.

a: Neuroleptanalgesic combinations

Fentanyl/fluanisone (“Hypnorm”, Janssen), when administered alone, produces sedationand sufficient analgesia for superficial surgery in most small mammals (Table 3a). Thedegree of muscle relaxation is generally poor, and the high doses needed for more majorsurgery produce marked respiratory depression. Combining this regimen with abenzodiazepine (midazolam or diazepam) produces surgical anaesthesia with onlymoderate respiratory depression. The combination has the advantage that it can bepartially reversed with a mixed opioid agonist/antagonist such as butorphanol or a partialagonist such as buprenorphine. This reverses the respiratory depression caused by thefentanyl, but maintains post-operative analgesia. The benzodiazepine antagonistflumazenil can be used to further speed recovery, but repeated doses are needed to avoidresedation.

In small rodents, a mixture of midazolam and “Hypnorm” can be given as a singleintraperitoneal injection. In rabbits it is preferable to give the “Hypnorm” first, byintramuscular injection. The midazolam or diazepam can then be administeredintravenously to effect as described above.

Fentanyl/droperidol (“Innovar Vet”) when used alone produces effects similar to“Hypnorm” but with a greater tendency to produce limb rigidity. In combination withmidazolam its effects are unpredictable and it is best used alone to provide immobility,sedation and analgesia for minor procedures.

Although the use of neuroleptanalgesics has been reported in non-human primates, theyare not widely used because of problems with respiratory depression.

b: Ketamine

Ketamine, when used alone, does not produce surgical anaesthesia in most animalspecies. In cats and non-human primates, sufficient analgesia for minor surgicalprocedures can be produced, but it is better combined with other agents such asacepromazine, midazolam or diazepam. When used in this way, ketamine produces lightto moderate surgical anaesthesia in many species (see Tables 4a and 4b). In smallrodents the effects of these combinations are less predictable than in larger species, andusually only light planes of anaesthesia, insufficient even for minor surgery, areproduced. In contrast, administration of ketamine in combination with medetomidine orxylazine results in surgical anaesthesia in most mammals and many species of birds. Itseffects are slightly less uniform in guinea pigs, and some individuals may not becomesufficiently deeply anaesthetised for major surgery. In these circumstances, it is

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preferable to deepen anaesthesia using an inhalational agent, or to provide additionalanalgesia using local anaesthesia.

Ketamine combined with medetomidine or xylazine also has less predictable results inpigs, and the combination should be evaluated in the particular strain used. In allspecies, anaesthesia can be partially reversed by administration of atipamezole.

c: Barbiturates

Pentobarbitone has been used for many years to produce anaesthesia in small rodentsand rabbits. It has a narrow margin of safety, the anaesthetic dose being close to thelethal dose in many animals. It is best used in low doses to provide light planes ofanaesthesia, with inhalational agents used to deepen anaesthesia if required. In the rabbit,even careful administration of a diluted solution (6mg/ml) intravenously is hazardous,and respiratory arrest may occur before surgical planes of anaesthesia are attained.Pentobarbitone, administered by intravenous injection, is less hazardous in dogs, cats,and other larger species. Recovery can be prolonged however, and surgical anaesthesia isaccompanied by marked respiratory and cardiovascular depression, so in mostcircumstances it is better to replace it with alternative techniques.

Thiopentone, methohexitone and thiamylal can all be used to produce short periods ofanaesthesia when administered intravenously. In rabbits and larger species this can beuseful both for short surgical procedures, and to allow endotracheal intubation followedby maintenance with volatile agents.

d: Propofol

When administered intravenously, propofol produces short periods of surgicalanaesthesia in most species, and additional doses can be given to prolong the period ofanaesthesia, without unduly prolonging recovery. In rabbits, it can provide sufficientdepth of anaesthesia for intubation, but respiratory arrest usually occurs before the onsetof surgical anaesthesia. Although it can be used safely in sheep, this species requiresunusually high dose rates for induction and maintenance of anaesthesia.

Propofol can cause transient apnoea if given rapidly, but this has not been found to be aclinically significant problem by the author. Some hypotension can occur following itsadministration, but this is not generally a concern in healthy individuals. Mean arterialblood pressure is often better maintained than with inhalational agents. The dose ofpropofol required to maintain anaesthesia can be reduced by concurrent administrationof opioids. This balanced anaesthetic technique can be used to provide prolonged periodsof anaesthesia, with a relatively mild degree of cardiovascular depression. Respiratorydepression is often marked, however, so it is strongly advised that animals aremechanically ventilated. A number of short acting mu agonist opioids can be used, suchas fentanyl, alfentanil and sufentanil. At the end of the period of anaesthesia, respiratorydepression caused by the opioid can be reversed by administration of a mixed agonist-antagonist opioid such as nalbuphine, butorphanol or buprenorphine.

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e: Alphaxalone/alphadolone

In most species, intravenous administration produces surgical anaesthesia, which can beprolonged with additional doses. In rabbits, effects similar to propofol result afterintravenous injection, with respiratory arrest occurring before surgical anaesthesia isattained. Sufficient depth of anaesthesia for intubation can be produced. In the dog, thesolubilising agent in the commercial preparation (Chremophor) causes histamine releasewith associated hypotension and peripheral oedema, so it should not be used in thisspecies. In cats, histamine release may occur in some individuals, resulting in oedema ofthe paws, ears and muzzle, but there is rarely a significant effect on blood pressure.When given by deep intramuscular injection, alphaxalone/alphadolone produces lightanaesthesia, and this route is useful in cats and new world primates. After administrationof an initial dose intramuscularly, additional drug is given intravenously to inducesurgical anaesthesia. Anaesthesia can then be maintained by further doses or bycontinuous infusion of the agent. In other species, the high volumes of drug requiredmake intramuscular administration impracticable – for example the dose required toproduce anaesthesia in a 1kg guinea is 3.3ml.

Both alphaxalone/alphadolone and propofol are relatively non-cumulative, unlike thebarbiturates, so that recovery following prolonged anaesthesia is relatively rapid. Theshort duration of action of these agents (approximately 10 minutes after a single dose)means that the depth of anaesthesia can be adjusted easily by changing drug infusionrates.

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ii: Inhalational agents

Inhalational agents can be used to provide safe and effective anaesthesia in virtually alllaboratory species. A number of different anaesthetic agents are available – ether,halothane, isoflurane, desflurane, sevoflurane and nitrous oxide.

Ether was first synthesised in the 16th century, and its use for surgical anaesthesia inman was first reported in the 19th century. It was used in animals at around the sametime, and has remained a standard anaesthetic in domestic and laboratory animals untilrecently. The irritant nature of its vapour has long been recognised, but the significanceof this in relation to animal welfare was outweighed in some institutes by the relativesafety and low cost of ether. Ether can also be delivered using very simple apparatus.Although ether has been considered a safe anaesthetic, in that it is difficult to overdosean animal, the risks of explosion or fire associated with its use have been of growingconcern, and have led many research units to severely restrict its use. It is clear fromrecent studies that ether is aversive to laboratory species, and its use should bediscontinued unless clear scientific justification can be provided for specific researchprojects. Initially, methoxyflurane was used as an alternative to ether, since it too couldbe delivered using simple apparatus. Recently this agent has become unavailable inmany countries, and there has been growing interest in the other volatile anaesthetics:halothane, enflurane, isoflurane, desflurane and sevoflurane.

Halothane has, of course, been widely used in laboratory animals for many years, andisoflurane has been rapidly gaining in popularity. In laboratory animal units, the mainfactor limiting more widespread use of these agents in small rodents has been the need touse a calibrated vaporiser to deliver the anaesthetic. In addition to the costs associatedwith purchase of an anaesthetic machine, health and safety considerations required theuse of apparatus to remove waste anaesthetic gases. As the importance of well-controlledanaesthesia has become more widely appreciated, use of these volatile agents has grown.Isoflurane, in particular, has attracted much interest since it undergoes virtually nometabolism (<0.5%) and is eliminated almost entirely by exhalation from the lungs. Thisreduces the likelihood of interaction with drug metabolism and other studies, both duringanaesthesia, and afterwards. Isoflurane also has the advantage of providing rapidinduction and recovery, and this has been believed to be an advantage, especially insmall rodents in which there is a particular continued risk of hypothermia in the recoveryperiod. Two newer agents, desflurane and sevoflurane, offer even greater advantages inrelation to speed of recovery, and differ slightly in their effects on the animal’s bodysystems. The varying influences on, for example, the cardiovascular and respiratorysystems, may be of significance in particular research projects, and it is useful to consultsome of the recent comparative reviews of these agents in order to determine the mostappropriate choice for a particular project. In terms of speed of induction and recovery,induction times are relatively rapid in small rodents with all of these agents, howeverrecovery after medium duration anaesthesia (1 hour) differs significantly.

A further advantage of these newer agents in man was their greater acceptance bypatients. Sevoflurane in particular has been recommended for use in children. Althoughall of the agents appear well tolerated in most laboratory species, we have noted marked

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breath holding and struggling during halothane, isoflurane or sevoflurane induction inrabbits. Slow induction with desflurane was better tolerated, although some breathholding still occurred. This behaviour indicates that rabbits find inhalation of theseagents aversive, and the severe apnoea that occurs may represent a significant hazardduring induction of anaesthesia. It is therefore preferable to avoid this by inducinganaesthesia using injectable agents.

Nitrous Oxide

Nitrous oxide is a vapour at room temperature and is supplied in cylinders at about a 750p.s.i. At this pressure, it is a liquid. For this reason, it is not possible to determine howmuch nitrous oxide remains in a cylinder by looking at the pressure gauge, as the gaugewill read full as long as there is liquid nitrous oxide remaining. To determine how muchliquid remains in the cylinder, its weight must be compared with the weight of an emptycylinder.

Nitrous oxide is not a very potent anaesthetic in animals (it has a MAC of around 200%in most species, compared to about 100% in man). It can be used to reduce theconcentration of other anaesthetics needed, but only be a relatively small amount. Forexample, using 60% nitrous oxide reduces the concentration of halothane needed forsurgical anaesthesia from around 1.5-1.8% to 1.2-1.4%. It therefore has limited value forroutine anaesthesia of small laboratory mammals, but is useful in some circumstances:

• When using a face mask to induce anaesthesia in larger animals, adding nitrousoxide can speed induction when using another volatile anaesthetic.

• When maintaining long periods (> 24h) of light anaesthesia (eg forneurophysiological studies) it allows a reduction of the volatile anaestheticconcentration and also reduces the inspired concentration of oxygen sopreventing oxygen toxicity.

Using volatile anaesthetics in small rodents

When inducing anaesthesia with volatile agents in small animals, it is often convenientto use an anaesthetic chamber. With all agents, animals first become slightly ataxic(wobbly), may then go through a period of involuntary excitement, then lose theirrighting reflex and become immobile. With the newer agents, induction can be veryrapid, so that animals pass almost immediately from a state of full alertness to completeunconsciousness. This can be achieved without using dangerously high concentrations ofanaesthetic, providing the concentration of anaesthetic agent in the chamber is raisedrapidly. Simply calculate the volume of the chamber (usually about 5-10 litres) and aimto fill the chamber in less than a minute by using flow rates of 5-10 litres/minute.Always fill the chamber from the bottom, and remove excess gas at the top, as theseanaesthetic vapours are all denser than air. The volatile anaesthetic must be vaporised ina specially manufactured vaporiser. Attempts to induce anaesthesia in an anaestheticchamber in which liquid anaesthetic is placed on a gauze pad is extremely dangeroussince high concentrations (>20%) of anaesthetic vapour are produced.

Following induction of anaesthesia the animal can be removed from the chamber andbrief (<30secs) procedures carried out. It is usually more convenient to maintain

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anaesthesia by placing the animal on a facemask. Suitable masks can either be purchasedcommercially or constructed from plastic syringes. As with larger species it is importantthat waste anaesthetic gases are scavenged effectively and this is most easily achieved byusing purpose made commercial apparatus.

Use of volatile anaesthetics in larger animals

Although it is possible to induce anaesthesia with volatile anaesthetics, the animal mayresent being restrained and having a face-mask placed over its nose. For this reason,anaesthesia is often induced with injectable agents and then maintained using the volatileagent.

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Choice of anaesthetic

Rodents and Rabbits

The majority of injectable and inhalational agents available can be used in smallmammals, but practical constraints such as the difficulties of intravenous induction maylimit the use of some agents (eg propofol). Local anaesthesia is used less frequently insmall mammals than dogs and cats because of the difficulties of physical restraint.However, even in these small animals it is practicable to use local anaesthetic techniquesto provide additional analgesia in conjunction with low doses of injectable anaestheticsor low concentrations of inhalants.

The difficulty of administering anaesthetics by the intravenous route in smallermammals has some important practical implications:

• When anaesthetics are given intravenously, the dose can generally be adjusted toprovide the desired effect in a particular individual. Allowance can easily bemade for individual and breed or strain variation, and over- or under-dosing iseasy to avoid.

• When administering anaesthetics by the intramuscular, intraperitoneal orsubcutaneous routes, a calculated dose is given, and there is no opportunity toadjust it to the individual’s requirements. Large variations in response (up to150% difference in sleep times) related to genetic background, age and sex haveall been documented in small rodents.

• When giving injectable anaesthetics i/m, s/c or i/p, select an anaesthetic regimenwith a wide safety margin, and if possible, one that is completely or partiallyreversible.

A second consequence of administration by these routes is that relatively large doses ofdrug are given, and recovery times tend to be prolonged. In small mammals, this isundesirable because of:

• The risks of hypothermia during recovery• The problems associated with prolonged respiratory depression• The potential metabolic effects of several hours unconsciousness or sedation.

Once again, then, use of a reversible anaesthetic regimen can be advantageous.

Although they have these potential disadvantages, injectable anaesthetic regimensremain popular in small rodents because administration using the subcutaneous,intramuscular or intraperitoneal route is relatively simple. The same general approach isadopted in all species. For intraperitoneal injection, it is easier if an assistant restrains theanimal, and the anaesthetist can then extend one hind limb and inject into the middle ofthe right posterior quadrant of the abdomen. This minimises the risk of inadvertentpuncture of the bladder, which lies in the midline just anterior to the pelvic brim.Injecting into the right side of the abdomen avoids the caecum, which is large and thinwalled in all rodents, and so may reduce the risk of injecting into the gastrointestinal

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tract. Intramuscular injections can be made into the quadriceps, with the animalrestrained by an assistant in a similar manner. The anaesthetist immobilises the limb andthe muscle, and injects into the middle of the muscle mass. Subcutaneous injections aremade into the scruff (rat, mouse, hamster, gerbil, guinea-pig).

Inhalational anaesthetics, however, may be considered even easier to administer,especially when an anaesthetic chamber is used. Although a calibrated vaporiser must beused for modern anaesthetic agents, the anaesthetic apparatus required need not becomplex or expensive.

Larger mammals

Use of intravenous induction agents can result in smooth, rapid, stress free induction,provided the animal can be restrained effectively, and that the injection is carried outwith the required degree of skill. A wide range of anaesthetic agents can be usedsuccessfully, and intravenous administration allows careful control of the depth ofanaesthesia that is produced. If animals resent the physical restraint needed forintravenous injection, then a sedative can be administered (see “pre-anaesthetic”medication above). As mentioned earlier, in some species catheters can be placed inconscious animals without causing any discomfort by using EMLA cream. Dependingupon the species, the cephalic vein in the foreleg (dog, cat, sheep, non-human primate),the ear vein (rabbit, pig, sheep) the saphenous vein (dog, non-human primate) and thetail vein (marmoset) are easily visible and placement of an “over-the-needle” catheter isrelatively straightforward. It is advisable to do this even if anaesthesia with volatileagents is planned, as the catheter will enable fluid therapy to be administered, and alsoallow emergency drugs to be given rapidly if anaesthetic complications develop.

Alternatively, after induction of anaesthesia with an injectable agent, anaesthesia can bemaintained using an inhalational agent. Whichever technique is used, it is important toensure the animal’s airway remains unobstructed, and it may be advisable to intubate theanimal (see below).

When anaesthetising large and small animals, a significant advantage of usinginhalational agents is that they are delivered in oxygen. This helps prevent hypoxiadeveloping as a consequence of the respiratory depression caused by most anaesthetics.Administration of oxygen to animals anaesthetised with injectable anaesthetics is oftenoverlooked, but is strongly recommended.

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Animal welfare problems with injectable agents

Although intravenous induction is smooth, rapid, and generally stress-free, local adversereactions to intravenous injections can result from inadvertent perivascularadministration (eg thiopentone). Although a recognised complication in man,thrombophlebitis following administration of the propylene glycol formulation ofdiazepam appears not to have been recognised in animals. An adverse response noted inman is slight pain on intravenous injection of propofol. This response has been noted ina small percentage of dogs receiving the agent. As mentioned earlier, the transient paincaused by venepuncture can be easily prevented by use of local anaesthetic cream (egEMLA, Astra).

In small animals, such as rodents, intravenous injection may be consideredimpracticable, so anaesthetics may be given by the intraperitoneal, subcutaneous orintramuscular routes. When administered by this route, some agents can cause tissuedamage, for example ketamine and fentanyl/droperidol. Others can cause longer termadverse effects, for example chloral hydrate can cause ileus 7 to 14 days afteranaesthesia and improperly prepared or poorly stored tribromoethanol can causegastrointestinal disturbances. More recently, it has been reported that tribromoethanolcan cause low grade peritoneal irritation, even when correctly prepared and stored. Thisreport was questioned, but the authors maintained their original conclusions, which wasthat this drug should be replaced with alternative regimens (the paper and letters areavailable at www.lal.org.uk). In view of the widespread use of tribromoethanol intransgenic mice, this issue needs to be resolved - aside from disagreement as tomethodology, the study simply identifies pathology, but as yet there has been noassessment of whether these lesions cause pain or discomfort.

Animal welfare problems with inhalational anaesthetics

The main problem with administering inhalant anaesthetics to larger animals is the firmphysical restraint needed. This in itself may be resented by the animal, but also may berequired because the animal finds the inhalational agent aversive. Rabbits seemparticularly distressed by exposure to inhalants, but dogs, cats and other species mayresent facemask induction with halothane or isoflurane. Sevoflurane appears to havesignificant advantages in some species, perhaps due to the significantly faster speed ofinduction of anaesthesia. In birds, sevoflurane and isoflurane have significant advantagescompared to halothane, since the faster induction and recovery reduces the risk of injury.Ether should not be used unless there is a convincing scientific reason for its selection,since it is unpleasant to inhale and presents a risk of explosion.

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Safety problems with anaesthetics

Many injectable anaesthetics are controlled drugs in the UK. Although the immediaterisks associated with accidental self-injection are small, they must be handled carefully,and stored securely. Anaesthetics that are not used should be properly disposed of -usually via a sink accompanied with copious quantities of water. Careful records shouldbe maintained of the quantities used, and this may be a legal requirement for some drugs.In the UK, anaesthetics must be obtained through the establishment’s named veterinarysurgeon, as with other Prescription Only Medicines (POMs).

Inhalational anaesthetics other than ether cause few immediate safety problems, althoughif a bottle of anaesthetic is spilt, dangerously high concentrations of vapour can beproduced. The safety issue of greatest concern, however, is long-term exposure of staffto low concentrations of anaesthetic vapour. To reduce this exposure:

• Use an effective gas-scavenging system whenever practicable• During induction using a face-mask, use a close-fitting mask, and try to reducing

any struggling by the animal so that the mask does not become displaced• Avoid sitting close to the animal’s head during recovery, as it will continue to

exhale anaesthetic for a considerable time• Always work in a well-ventilated room• Fill anaesthetic vaporisers using a “key-filling” system.

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Interactions between anaesthetics and research protocols

As discussed earlier, determining potential interactions between a particular anaestheticand a specific research protocol is difficult, however the following general guidance canbe given:

1) What specific pharmacological properties of the anaesthetic are likely to be relevant?Reasonably detailed reviews of the activities of specific agents are readily availablein standard anaesthetic (veterinary and medical) texts. Unfortunately these usuallyfocus on actions that have clinical importance - eg effects on cardiac output,respiratory function etc.

2) To establish more subtle interactions, carry out a literature search. Check that youhave the correct names of the active principles, but also run a search on the tradename (eg "Hypnorm" as well as "fentanyl" and "fluanisone "). If possible, find outthe code number used for the drug when it was in development (usually cited in theearly publications) and run a search on that (eg ICI 35 868 became "Propofol"). If asearch for work in the specific species of interest is not helpful, try using "animal" orrat, mouse or rodent, since much development work will have been undertaken inthese species.

3) Review articles can be a useful source of early references and may provide citationsthat do not appear on a Medline search. Carry out the search on the anaesthetic drug,then select some recent reviews and check their reference list.

4) Try approaching the search from an alternative angle - look for "anaesthesia" (andanaesthesia) and the system of interest. You can then perform searches on thecitations this strategy produces.

5) Having determined that there could be interactions, don't forget to place them in theoverall context of the research protocol. Remember, unless you are very careful,almost ALL anaesthetics will:

• Depress respiration - producing hypoxia, hypercapnia and acidosis• Depress the cardiovascular system - reducing cardiac output, changing organ

blood flow• Depress thermoregulation mechanisms - causing hypothermia, and consequent

changes in metabolism, and cardiovascular function

If you are also undertaking surgical procedures, then the effects of surgical stress arealmost unavoidable, and have profound and long-lasting effects on the animal'smetabolism and endocrine system.

Finally, if you have identified an interaction of a particular animal model and ananaesthetic (or analgesic) agent, then consider publishing the information (for examplein "Laboratory Animals").

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Anaesthetic management - Preventing problems and coping withemergencies

Even during brief periods of anaesthesia, it is important to give attention to supportingthe animal’s vital body functions:

• Onset of surgical anaesthesia usually results in the loss of all protective airwayreflexes, and the animal should be placed in a position with its head and neckextended, to help ensure its airway remains clear and unobstructed.

• Provide oxygen by facemask to prevent the animal becoming hypoxic.

• Anaesthetised animals lose their protective blink reflexes, and the eyes should beprotected both from physical damage and from drying. Ophthalmic ointment canbe placed in the eyes, or the lids can be taped closed with micropore tape.

Careful monitoring of the patient is important to allow early detection and correction ofany problems that may arise. In all species, respiratory and cardiovascular functions areof primary importance, but in small rodents in particular, maintenance of bodytemperature is of critical importance:

• Small mammals have a higher surface area to body weight ratio than largerspecies such as the dog, and so lose heat more rapidly, for example significantfalls in body temperature (5-10 degrees C) can occur in mice within 15 minutesof induction of anaesthesia.

• Most anaesthetics depress thermoregulation, and this effect, coupled with use ofcold fluids, shaving and preparation of the surgical site and use of coldanaesthetic gases can rapidly result in severe hypothermia.

To avoid problems:

• Monitor body temperature using an electronic thermometer

• Small mammals should be placed on a heating pad, and if necessary covered ininsulating material (eg bubble packing or aluminium foil or space blanket)

• Avoid using excessive amounts of skin disinfectants, minimize the area of furshaved at the site of surgery, and avoid unnecessary exposure of the abdominalviscera

• Warm all fluids to body temperature before administration.

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Respiratory function

Observing the movements of the chest can be used to monitor the pattern and depth ofrespiration, although this becomes difficult once surgical drapes have been placed. If areservoir bag is present on the anaesthetic circuit used, then this can be observed toassess the rate and depth of respiration. In many circumstances it is helpful to use anelectronic respiratory monitor, but in small rodents the small size of the animal, and itsrapid respiratory rate, can make some monitors ineffective.

Although both the pattern and rate of respiration change during anaesthesia, this variesgreatly depending upon the anaesthetic regimen used. Becoming familiar with one ortwo regularly used regimens allows changes to be interpreted more reliably. In general,once anaesthesia has been induced, respiratory rate reduces markedly, especially inanimals such as rabbits that show tachypnoea prior to induction of anaesthesia. Typicalrespiratory rates during anaesthesia are 50-100 breaths per minutes for small rodents, 30-60 breaths per minute for rabbits, and 10-30 breaths per minute for larger species. Areduction to less than 50% of the estimated normal respiratory rate (see Tables 1a and1b) should give cause for concern. It is more usual to see gradual changes in rate, ratherthan a sudden reduction, so keeping an anaesthetic record is helpful when assessing thestate of the animal during anaesthesia.

Pulse oximeters can be used to monitor both the adequacy of oxygenation, and also theheart rate, but not all instruments function in small rodents. The high heart rates mayexceed the upper limits of the monitor, and the low signal strength may not be detected.A monitor with an upper limit of at least 350 bpm is needed for rodents and rabbits andit is useful to have a range of different probe designs. A reliable signal can usually beobtained from across the hind foot in small rodents, or across a toe in larger rabbits, butthe tail, tongue and ear are also useful in some individuals.

Capnographs, which measure the concentration of carbon dioxide in expired air, areextremely useful for monitoring respiration. When an animal is breathing normally, theend-tidal carbon dioxide is between 5 and 6%. Although these instruments can be usedto monitor respiratory function in small mammals, mainstream capnographs (which areplaced in the anaesthetic breathing circuit close to the animal) introduce too muchequipment dead space and so cannot be used in small mammals. Side-streamcapnographs (which extract gas out of the anaesthetic circuit to be analysed) can be used,but the volume of gas sampled may be very large in relation to the animal’s tidalvolume, so the measurements made may not be very accurate.If respiratory depression occurs, it must be monitored carefully, and if severe depression(<40% of estimated resting rate, see Tables 1a and 1b) or arrest occurs, it must be treatedpromptly. If severe hypoxia occurs, and is uncorrected, this can lead to cardiac failure.

• Administer oxygen if this is not already being done – it is advisable to provideoxygen immediately following induction of anaesthesia with injectableanaesthetics, since all of the agents used produce some degree of respiratorydepression.

• Assist ventilation - if an endotracheal tube is in place, this is easy to achieve (seebelow), if not, assist ventilation by manually compressing the thorax, and

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providing oxygen by facemask. Attempts to ventilate the lungs using a facemaskare often relatively ineffective. In small rodents such as the rat, ventilation can beassisted temporarily by positioning the animal with its head and neck inextension, and placing the barrel of a plastic syringe over the nose. Gentlyblowing down the tube will usually enable the lungs to be inflated.

• Administer a respiratory stimulant such as doxapram (10mg/kg, i/v, s/c, i/p orsub-lingual).

Endotracheal intubation

Assisting ventilation is considerably easier if the animal has been intubated, and this isan easy technique to master in the dog, cat, pig, non-human primate, sheep and rabbit.

Detailed descriptions of endotracheal intubation are given in standard anaesthetic texts.In general, intubation is made easier if an appropriately sized laryngoscope blade isobtained, so that the larynx can be visualised clearly. In species in which theoropharyngeal opening is relatively small (eg the rabbit), it is often easier to use anintroducer to straighten the endotracheal tube and guide it into the larynx. A similartechnique can be employed using an otoscope to visualise the larynx. An introducer ispassed down the speculum into the trachea, the otoscope is removed and theendotracheal tube passed over the introducer and into the trachea. The introducer is thenremoved and the tube tied in place. An introducer is also helpful when intubating non-human primates, as although visualisation of the larynx is easy to achieve (using aMacintosh or Wisconsin laryngoscope blade), the larynx is relatively mobile, makinginsertion of an endotracheal tube difficult in smaller primates.

In all species it is advisable to administer 100% oxygen for 1-2 minutes beforeattempting intubation, as this will usually maintain arterial oxygen saturation whilstintubation is performed. Insertion of the tube should always be carried out gently. Ifdifficulty is encountered, the tube can be withdrawn, repositioned and a further attemptmade. When learning the technique, it is helpful to monitor the animal with a pulseoximeter during this process, so that attempts can be discontinued and oxygenadministered if the animal becomes hypoxic (oxygen saturation <80%).

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Circulatory function

To minimise the risk of circulatory failure, the cardiovascular system should bemonitored during anaesthesia. Heart rate and rhythm can be monitored in most species,and in larger animals this can be done either by palpating a peripheral pulse, or by use ofan oesophageal stethoscope. The small size of rodents and rabbits, and their rapid heartrate, can make it difficult to monitor heart rate and rhythm. Ausculation of the chest wallis possible in rabbits and guinea pigs. Although it is not usually possible to palpate thepulse in the periphery in small rodents, the heartbeat can be detected by palpating thechest wall in all species. However, since the heart rate often exceeds 250 bpm in many ofthese animals, it is not possible to count the heart rate accurately. Problems can also arisewhen an ECG is used, as many instruments have an upper heart rate limit of 250 or 300beats per minute, and may also be unable to detect the low amplitude signals generatedin small rodents.

The adequacy of the peripheral circulation can be assessed using the capillary refill time.The mucus membranes on the inside of the lip are blanched by pressing with a finger,and the refill time assessed when pressure is removed. The colour of the membranesshould return to normal in less than a second. The small size of rodents usually preventsuse of capillary refill time as an assessment of peripheral perfusion, although it ispossible to assess this in rabbits. Assessment of the colour of the mucus membranes canalso give some indication of problems associated with blood loss, cyanosis, and poorperipheral perfusion. In addition to inspecting the gingiva, the colour of light reflected inthe eyes is also helpful in detecting cyanosis, or pallor due to blood loss in albinoanimals.

Total blood volume is approximately 70ml/kg of bodyweight in most mammals and lossof more than 15% can lead to signs of circulatory failure. In small mammals, thesevolumes will be very small - for example a 100g hamster will have a total bloodvolume of only 7ml, so loss of 1ml of blood can be serious. It is therefore criticallyimportant to monitor blood loss, and this is most easily done by careful weighing of theswabs used during surgery, together with assessing other losses at the surgical site.

Methods for supporting the circulation or treating cardiac arrest are similar in mostspecies, but correct use of these techniques requires considerable experience. It is alwayspreferable to try to anticipate impending problems, and try to prevent them. For example,if some blood loss is likely, then setting up an intravenous infusion of fluid is advisable.Initially a balanced electrolyte solution should be given, at a rate of approximately 5-10ml/kg/h, and if blood loss occurs, whole blood or plasma volume expanders (eg“Haemaccel”) can be given.

Whole blood should be collected from a donor animal and immediately mixed with acid-citrate-dextrose (ACD), at a rate of 1 part ACD to 4 parts blood. Blood from mostspecies can be stored at 4 degrees C for several days until required. Cross matching ofblood is advisable, but in an emergency, an initial transfusion can usually be given safelyusing blood from another animal of the same species.

If intravenous administration of fluids is considered impractical or technically toodemanding (eg in small rodents), then some circulatory support can be provided by

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administering intraperitoneal or subcutaneous electrolyte solutions. This is ineffective incases of severe haemorrhage, but is of value in providing fluid supplementation post-operatively. Intraperitoneal administration will result in more rapid absorption of fluidthan subcutaneous administration.

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Monitoring depth of anaesthesia

Before commencing a surgical or other painful procedure, it is essential to ensure thatthe animal is at an appropriate depth of anaesthesia. The most reliable method is toassess the pedal withdrawal reflex. In rodents the tail pinch response can also beassessed. The tail pinch response is usually lost at light to medium planes of anaesthesia,and this is followed by loss of the pedal withdrawal response at medium to deep planesof anaesthesia. Most surgical procedures can be carried out when the pedal withdrawalreflex is absent or barely detectable. In rabbits and guinea pigs, the ear pinch reflex is anadditional useful measure of anaesthetic depth.

The use of ocular reflexes is useful in the dog, cat, pig and sheep. With most anaestheticregimens, eye gradually rotates downwards as anaesthesia deepens, and the blink reflexwhen the eyelids are gently brushed is also lost. At very deep planes of anaesthesia, theeye rotates back up and becomes fixed centrally. In rodents, the position of the eyeremains fixed, and the blink reflex may still be present at surgical planes of anaesthesia.In rabbits, there is also considerable variation in loss of ocular reflexes, however at deepplanes of anaesthesia the eye may rotate and protrude. Since cardiac arrest may occurshortly after reaching such a deep plane of anaesthesia, this appearance requiresimmediate supportive measures.

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Post-operative Care

Recovery should be smooth, without excitement, or prolonged recumbency, and shouldbe pain free. Since all animals will require some degree of special attention in the post-operative period, it is preferable to provide a separate recovery area. This not onlyenables more appropriate environmental conditions to be maintained but also encouragesindividual attention and special nursing.

• The ambient temperature should be warmer than the animal’s usual housing,since its thermoregulation may be impaired during recovery from anaesthesia. Asa general guide, a temperature of 30-35°C should be provided until the animalhas regained consciousness. A temperature of 35°C should then be maintainedfor neonatal animals, 25-30°C for small rodents, and 25°C for larger animals.The temperature can gradually be reduced to the normal range for the species asthe animal regains normal activity. This is easiest to achieve by using a purposemade incubator or recovery pen.

• Provide suitable bedding. Sawdust and shavings are generally unsuitable, as theycan clog or abrade the animal’s eyes, nose and mouth. It is preferable to usetoweling or “Drybed” (synthetic sheepskin bedding).

• The recovery area should be quiet, with subdued lighting, but light levels shouldbe adjustable to allow clinical assessment of the animal.

• The degree of nursing attention provided in the recovery period should betailored to suit the species concerned, since some respond positively to humancontact, whereas others may find this attention stressful. Some handling isinevitable during the recovery period, and any stressful responses can beminimised by familiarisation of the animal to the staff during the pre-operativeacclimatisation period.

• Some of the laboratory species used will be prey species, and their predators maybe housed in the same specialist recovery area – ensure this does not occur, andtake care to clean thoroughly any incubators that may have been used previouslyto house predators.

Fluid therapy should be considered a routine requirement following surgical procedures.Many animals reduce their fluid intake post-operatively, and the consequent dehydrationmay contribute to post-operative distress, and increase morbidity and mortality. Thenormal fluid requirements of mammals are 40-80ml/kg/24h, and if the voluntary intakeis inadequate, fluids can be supplemented either by hand feeding, or by subcutaneous,intraperitoneal, or intravenous administration.

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Pain relief

It is particularly important that good post-operative analgesia is provided, both foranimal welfare reasons and because pain can cause inappetence and prolong the effectsof surgery. Whenever possible, attempts should be made to assess the degree of pain thatis being experienced by the animal. This will enable selection of an appropriateanalgesic, and ensure it is administered at an appropriate, effective dose, for a sufficientperiod.

Pain assessment in animals is not always easy, but most veterinarians, technicians andresearch workers who are relatively familiar with the normal behaviour of an animal canrecognise changes in behaviour in the post-operative period that may be related to pain.In some species, the changes in behaviour that occur may be very subtle, so that signsassociated with pain may be overlooked. There are also some other problems: severalspecies of small mammal are nocturnal and so may not be active when observed duringnormal working hours. They may also remain immobile in the presence of an observer asthey may regard them as a threat. This behaviour can limit our attempts to use behaviourand changes in posture to assess pain. It is important that we overcome these difficultiesso that pain can be prevented or controlled effectively in all species.

A number of pain scoring schemes are being developed, and these may become usefulfor routine use in laboratory animals. At present, however, they are not particularlyreliable. Nevertheless, it is very helpful to develop a scoring sheet for use followingspecific surgical procedures, and for all of those involved in the care of the animal to beinvolved in developing the scoring sheet and the means of managing post-operative pain.Whether a scoring system is used or not, pain assessment will be facilitated by:

• A good knowledge of the normal behaviours of the particular species of animal beingassessed.

• A knowledge and comparison of the individual animal’s behaviour before and after theonset of pain (eg pre and post-operatively)

• The use of palpation or manipulation of the affected area and assessment of theresponses obtained.

• Examination of the level of function of the affected area eg leg use following injury orlimb surgery, together with a knowledge of any mechanical interference with function.

• The use of analgesic regimens or dose rates that have been shown to be effective incontrolled clinical studies, and evaluation of the change in behaviour this brings about.

• A knowledge of the non-specific effects of any analgesic, anaesthetic or other drugsthat have been administered.

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Analgesic use in laboratory animals

When formulating an analgesic regimen for a particular animal, several factors need tobe considered:

• What is the likely severity of pain, and what is its anticipated duration?

• Which drug or drugs should be administered, and at what dose rates?

• Are there any special factors that will influence the choice of analgesic, forexample the species of animal, any pre-existing medical condition, or anyparticular features of the current condition and the type of pain?

• What facilities are available for management of the animal? What level ofnursing care and monitoring of the animal is available? Can staff attendthroughout a 24 hour period? Are there facilities for continuous infusion ofanalgesics?

Drugs available

Opioids

The opioid or morphine-like drugs provide effective analgesia for moderate to severepost-operative pain in most species. They vary in their duration of action, in theirreceptor activity (mu, delta or kappa), and in whether they have full agonist, partialagonist, or antagonist properties at specific receptors. They cause respiratory depression,but this is rarely of clinical significance in animals, except when very potent analgesics(eg fentanyl) are administered at high dose rates during anaesthesia. They also haveeffects on a variety of other body systems, for example they can slow gut transit times,and they can have marked effects on behaviour. These effects vary considerably indifferent species.

NSAIDs

Non-steroidal anti-inflammatory drugs have analgesic, antipyretic and anti-inflammatoryactions. They act primarily by decreasing the release of prostaglandins and thromboxaneA2. They are effective analgesics for mild to moderate pain, and are often sufficient toprovide post-operative analgesia even when used alone. Several of these agents haverelatively long durations of actions in some species (eg carprofen, 24 hours in dogs andmeloxicam, 3 days in cattle), and this is of considerable advantage when they are usedfor pain relief.

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Side effects include gastrointestinal irritation, interference with platelet function, andnephrotoxicity in animals with reduced renal blood flow. These side effects are rarely ofclinical significance in laboratory species when the drugs are used for a relatively shortperiod for post-operative pain relief. Because of the risks of renal toxicity shouldhypotension occur during anaesthesia, only carprofen should be administeredpreoperatively.

Local anaesthetics

Local anaesthetics block transmission of nerve impulses in nerve fibres, so completeanalgesia can be provided (sufficient for surgery). They can be infiltrated aroundsurgical wounds to provide postoperative analgesia and they can also be used to producespecific nerve blocks. In larger species, they can be administered epidurally orintrathecally to produce regional analgesia and anaesthesia.

High dose rates can cause cardiovascular disturbances and CNS effects such asconvulsions. The safety of these agents is similar in most mammals but in rodents it isrelatively easy to inadvertently overdose the animal because of their small size. Providedcare is taken to calculate the dose accurately, local anaesthetics such as lidocaine andbupivacaine can be used safely in rodents and rabbits. It is important to note that theduration of action of some local anaesthetics may be shorter in rodents than in largerspecies such as dogs. As mentioned earlier, one use of local anaesthetics that isparticularly effective in rabbits is the application of topical agents (e.g. EMLA cream,Astra-Zeneca) to provide analgesia for venepuncture or placement of “over-the-needle”catheters.

Some general guidance can be given for the use of analgesics in the majority oflaboratory species:

• When major surgery is undertaken, an opioid analgesic, such as buprenorphine,should be given.

• When possible, combine the use of opioids with administration of a non-steroidalanti-inflammatory drug (NSAID) such as carprofen, meloxicam or ketoprofen,since this may provide more effective pain relief.

• Infiltration of the surgical site with a long acting local anaesthetic such asbupivacaine can also be a useful adjunct to the use of systemic analgesics.

Less extensive procedures may require only administration of a potent NSAID.Following an initial dose at the time of surgery an additional dose of an NSAID can begiven by mouth 16-24 hours later. In most circumstances, provision of analgesia for 24-48 hours appears sufficient.

It is generally recommended that analgesics should be administered pre-operatively, asthis provides more effective pain relief, and also may reduce the dose of anaestheticrequired. Experience in small rodents and rabbits has shown that use of buprenorphine in

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this way enables the concentration of isoflurane or halothane needed for surgicalanaesthesia to be reduced by 0.25-0.5%.

Care should be taken if pre-emptive analgesic administration is combined with the use ofinjectable anaesthetics administered by the intraperitoneal or intramuscular routes. Asdiscussed earlier, in these circumstances it is not possible to adjust the dose ofanaesthetic to meet individual requirements, and there is little data available on thepotentiating effects of opioids. Until such information is available, it is probably better toadminister the agent post-operatively. When using neuroleptanalgesics, the opioidcomponent will provide analgesia, and this can conveniently be partially reversed withbuprenorphine or butorphanol. If the latter opioid is used, although it provides betterreversal, it has a short duration of action, so either additional doses should be given, or itshould be combined with a potent NSAID.

There may be some concerns regarding use of analgesic drugs in laboratory animals:

• “Alleviation of post-operative pain will result in the animal injuring itself” –

Provided that surgery has been carried out competently, administration of analgesics,which allow resumption of normal activity, rarely results in problems associated with theremoval of pain’s protective function. Claims that analgesic administration results inskin suture removal are unsubstantiated, and contrary to findings in our laboratory. Incertain circumstances, for example after major orthopaedic surgery, additional measuresto protect and support the operative site may be required, but this is preferable toallowing an animal to experience unrelieved pain. All that is required in thesecircumstances is to temporarily reduce the animal’s cage or pen size, or to provideadditional external fixation or support for the wound. It must be emphasised that thesemeasures are very rarely necessary, and in our institute, administration of analgesics tolaboratory animals after a wide variety of surgical procedures has not resulted in anyadverse clinical effects.

• “Analgesic drugs have undesirable side-effects such as respiratory depression “. –

The side effects of opioids in animals are generally less marked than in humans andshould rarely be of clinical significance unless very high dose rates of pure mu agonistsare used.

• “We don’t know the appropriate dose rates and dosage regimens” –

This is primarily a problem of poor dissemination of existing information. Virtuallyevery available analgesic drug has undergone extensive testing in animals. Dose ratesare therefore available for a range of drugs in many common laboratory species. It isoccasionally difficult to extrapolate available dose rates from one species to another andto translate dose rates that are effective in experimental analgesiometry into dose ratesthat are appropriate for clinical use. Nevertheless, in most instances a reasonable guideas to a suitable, and safe, dose rate can be obtained (see tables 6 and 7).

• “Pain relieving drugs might adversely affect the results of an experiment” This is asimilar problem to that discussed earlier in relation to anaesthetics and their interactionswith a research protocol. Although there will be occasions when the use of one or other

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type of analgesic is contra-indicated, it is extremely unlikely that there will be nosuitable analgesic that could be administered. More usually, the reluctance to administeranalgesics is based upon the misconceived idea that the use of any additional medicationin an experimental animal is undesirable. The influence of analgesic administration in aresearch protocol should be considered in the context of the overall response of theanimal to anaesthesia and surgery. The responses to surgical stress may overshadow anypossible adverse interactions associated with analgesic administration. An additionalconsideration is that many arrangements for intra-operative care fail to control variablessuch as body temperature, respiratory function and blood pressure. It seems illogical toassume that changes in the function of the cardiovascular or respiratory systems areunimportant, but that administration of an analgesic will be of overriding significance. Itshould be considered an ethical responsibility of a research worker to provide areasoned, scientific justification if analgesic drugs are to be withheld. It is alsoimportant to realise that the presence of pain can produce a range of undesirablephysiological changes, which may radically alter the rate of recovery from surgicalprocedures. In animals, post-surgical pain can reduce food and water consumption,interfere with normal respiration (for example after thoracotomy), and reduce a wholerange of “self-maintenance” behaviours. The immobility caused by pain can lead tomuscle spasm, can cause atrophy of areas, and can slow healing. Prolonged immobilitycan also cause pressure sores, urine-scalding, faeces soiling and can greatly complicateanimal care routines.

• Legal constraints can restrict the administration of analgesics. In many countries, theuse of the majority of opioids is controlled by legislation (eg the Misuse of Drugs Act inthe UK). Complying with this legislation often requires careful record keeping of thepurchase, storage and dispensing of opioids and may restrict the persons who are able todispense and administer these substances. In some countries the degree of recordkeeping required can act as a strong disincentive. Legislative control, together withgenuine safety concerns may also limit the dispensing of this class of analgesics for useby investigators or technicians. These constraints should not result in a failure to provideeffective pain relief.

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Further reading:

These notes are largely based on material from the following sources, and these shouldbe consulted for more detailed information:

“Pain Management in Animals” eds Flecknell, P.A. and Waterman-Pearson, A.E.,Harcourt International, 2000.

“Laboratory Animal Anaesthesia” Flecknell, P.A., Academic Press, 1995

“BSAVA Manual of Small Animal Anaesthesia” eds Seymour, C. and Gleed, R., pubBSAVA, 1998

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Tables

Table 1a Biological data for small laboratory mammalsTable 1b Biological data for larger laboratory mammalsTable 2 Volumes for fluid replacement in small animalsTable 3a Pre-anaesthetic agents for use in small laboratory animalsTable 3b Pre-anaesthetic agents for use in larger laboratory animalsTable 4a Anaesthetic agents for use in small laboratory animalsTable 4b Anaesthetic agents for use in larger laboratory animalsTable 5 Properties of inhalational anaestheticsTable 6 Analgesic drugs for use in laboratory animals (Opioids)Table 7 Analgesic drugs for use in laboratory animals (NSAIDs)

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Table 1a Biological data for small mammals

Gerbil GuineaPig

Hamster Mouse Rabbit Rat

Adult bodyweight (g)

85 -150 700 - 1200 85 - 150 25 – 40g 2000 -6000

300 - 500

Respiratoryrate (bpm)

90 50-140 80-135 80-200 40-60 70-115

Heart rate(bpm)

260-300 150-250 250-500 350-600 135-325 250-350

Averageadult bloodvolume (ml)(65-70ml/kg)

9 60 9 2.5 250 30

PCV (%) 41-52 37-48 36-55 36-49 36-48 38-50Bloodglucose(mmol/l)

3-7 4.5-6 3-8 3.5-9 4-8 3-8

TotalProtein(g/dl)

4.3-12.5 4.6-6.2 5.9-6.5 3.5-7.2 5.4-7.5 5.6-7/6

BUN (mg/dl) 17-27 9-32 10-25 12-28 17.0-23.5

6-23

ALT (IU) ? 25-59 12-36 74-232 35-38 17.5-30

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Table 1b Biological data for larger laboratory mammals

Dog Cat Pig Sheep Primate(Rhesus)

Primate(Marmoset)

Adult bodyweight (kg)

15-20 3-5 40-200 60-80 8-12 0.5

Respiratoryrate (bpm)

25 26 12-18 20 35 -

Heart rate(bpm)

100 150 75 150 225

Average adultblood volume(ml) (65-70ml/kg)

1000ml 280ml 7000 4900 700 35

PCV (%) 29-55 38-57 32-50 27-45 36-49 42.7 + 11.2Blood glucose(mmol/l)

3.61-6.55

3.89-6.11

4.72-8.33 2.78-4.44 3.89±0.57 9.55±2.3

Total Protein(g/dl)

5.4-7.1 5.4-7.8 7.9-8.9 5.7-9.1 6.6-8.0 7.2 + 0.8

BUN (mmol/l) 7.14-19.99

14.28-21.42

7.41-21.42

5.71-14.28

12.07-14.85

22 + 7

ALT (U/L) 21-102 6-83 31-58 30±4) 27-42 55 + 17

Table 2 Volumes of fluid for administration to small mammals. Volumes aresuggested rates for adult animals. All fluids should be warmed to body temperaturebefore administration. With all species, intravenous fluid administration, at rates of 5-10% of blood volume in 60 minutes, can be used to support circulatory function duringanaesthesia (blood volume is approximately 70ml/kg body weight).

Subcutaneous IntraperitonealGerbil 1-2ml 2-3mlGuinea Pig 10-20ml 20mlHamster 3ml 3mlMouse 1-2ml 2mlRabbit 50ml 30-50mlRat 5ml 5ml

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Table 3a Pre-anaesthetic agents for use in small mammals

Drug Species Dose rate EffectRat, Guinea Pig 2.5mg/kg i/p or

s/cMouse, Hamster,Gerbil

3-5mg/kg i/p ors/c

Sedation, but still activeAcepromazine

Rabbit 1mg/kg s/c ori/m

Sedated – often immobilised

Acepromazine +Butorphanol

Rabbit 1mg/kg plus1mg/kg s/c

Sedation, often immobilised,some analgesia

Atropine Mouse, Hamster,Gerbil, Rat, GuineaPig

40micrograms/kgs/c or i/m

Reduced bronchial and salivarysecretions, inhibits vagalresponses, ineffective in manyrabbits

Mouse, Hamster,Gerbil, Guinea Pig

5mg/kg i/p

Rat 2.5mg/kg i/p

Diazepam

Rabbit 1-2mg/kg i/m

Sedation

Glycopyrrolate Rabbit 0.01mg/kg i/v0.1mg/kg s/c

Reduced bronchial and salivarysecretions, inhibits vagalresponses

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Table 3a Pre-anaesthetic agents for use in small mammals (part 2)

Drug Species Dose rate EffectMouse, Hamster,Gerbil, Rat, GuineaPig

0.5ml/kg s/c or i/pHypnorm(fentanyl/fluanisone)

Rabbit 0.3-0.5ml/kg s/c ori/m

Sedation and analgesia – oftensufficiently immobilised forminor surgical procedures

Mouse, Hamster,Rat

30-100micrograms/kg s/c ori/p

Medetomidine

Rabbit 100-500 microgramss/c or i/p

Sedation and some analgesia,immobilised at higher dose rates

Mouse, Hamster,Gerbil, Guinea Pig

5mg/kg i/p

Rat 2.5mg/kg i/p

Midazolam

Rabbit 1-2mg/kg i/m

Sedation

Mouse, Hamster,Rat

5mg/kg s/c or i/mXylazine

Rabbit 2.5mg/kg s/c or i/m

Sedation and some analgesia,immobilised at higher dose rates

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Table 3b Pre-anaesthetic agents for use in larger mammals

Drug Species Dose rate EffectDog, Ferret 0.1-0.2 mg/kg i/mCat, Sheep 0.05-0.1mg/kg i/m

or s/c

Light-moderate sedationAcepromazine

Pig 0.2 mg/kg i/m SedationCat 0.05mg/kg plus

0.01mg/kg i/mAcepromazine +Buprenorphine

Dog 0.07mg/kg plus0.01mg/kg i/m

Sedation, often immobilised,some analgesia

Alphaxalone/alphadolone Marmoset 12-18mg/kg Heavy sedation, immobilisationAtropine Cat, Dog, Pig,

Primates,Ferrets

50 micrograms/kgs/c or i/m

Reduced bronchial and salivarysecretions, inhibits vagalresponses, ineffective in manyrabbits

Azaperone Pig 5mg/kg i/m Deep sedation, no analgesiaFerret 2mg/kg i/mPig 1-2mg/kg i/m

Diazepam

Sheep 1-2mg/kg i/m

Sedation

Drug Species Dose rate EffectHypnorm(fentanyl/fluanisone)

Dog 0.1-0.2ml/kg s/c or i/p Sedation and analgesia

Cat, Old WorldPrimates

5-20mg/kg i/m Moderate-Heavy sedation, someanalgesia

Ferret 20-30mg/kg i/m Immobilisation, some analgesiaPig 10-15mg/kg i/m Sedation, immobilisation

Ketamine

Sheep 20mg/kg i/m Sedation, immobilisation, someanalgesia

Ketamine +midazolam

Pig 10mg/kg plus 1mg/kgi/m

Deep sedation and immobilisation

Cat, Dog 10-80 micrograms/kgs/c or i/p

Medetomidine

Ferret 100-200micrograms/kg s/c

Sedation and some analgesia,immobilised at higher dose rates

Xylazine Cat, Dog 1-2mg/kg s/c or i/m Sedation and some analgesia,immobilised at higher dose rates

Pig 1mg/kg i/mMidazolamSheep 0.5mg/kg i/m

Sedation

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Table 4a Anaesthetic and related drugs for use in small mammals. Note thatconsiderable between-strain variation occurs, so that these dose rates should only betaken as a general guide.

Anaesthetic andrelated agents

Gerbil Guinea Pig Hamster

Atipamezole 1mg/kg s/c, i/m, i/p,i/v

1mg/kg s/c, i/m, i/p,i/v

1mg/kg s/c, i/m, i/p,i/v

Doxapram 5-10mg/kg i/m, s/c i/vFentanyl/fluanisoneand diazepam

0.3ml/kg i/m+5mg/kg i/p

1.0ml/kg i/m+2.5mg/kg i/p

1ml/kg i/m+5mg/kg i/p

Fentanyl/fluanisoneand midazolam*

8ml/kg i/p 8ml/kg i/p 4ml/kg i/p

Ketamine+medetomidine

- 40mg/kg+0.5mg/kg i/p

100mg/kg+0.25mg/kg i/p

Ketamine +xylazine

- 40mg/kg + 5mg/kgi/p

100-200mg/kg +10mg/kg i/p

Pentobarbitone 60-80mg/kg i/p 37mg/kg i/p 50-90mg/kg i/p

Anaesthetic andrelated agents

Mouse Rabbit Rat

atipamezole 1mg/kg s/c, i/m, i/p,i/v

1mg/kg s/c, i/m, i/p,i/v

1mg/kg s/c, i/m, i/p,i/v

Doxapram 5-10mg/kg i/m, s/c i/vFentanyl/fluanisoneand diazepam

0.3ml/kg i/m+5mg/kg i/p

0.3ml/kg i/m+2mg/kg I/p or i/v

0.3ml/kg i/m+2.5mg/kg i/p

Fentanyl/fluanisoneand midazolam*

10ml/kg i/p 0.3ml/kg i/m+2mg/kg I/p or i/v

2.7ml/kg i/p

Ketamine+medetomidine

75mg/kg +1mg/kgi/p

15mg/kg+0.25mg/kg i/m

75mg/kg+0.5mg/kg i/p

Ketamine +xylazine

80-100mg/kg +10mg/kg i/p

35mg/kg + 5mg/kgi/p

75mg/kg +10mg/kg i/p

Pentobarbitone 40-50mg/kg i/p 30-45mg/kg i/v 40-50mg/kg i/p

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Table 4b Anaesthetic and related drugs for use in larger mammals. Note thatconsiderable between-strain variation occurs, so that these dose rates should only betaken as a general guide.

Anaesthetic andrelated agents

Cat Dog Ferret

Alphaxalone/alphadolone 9-12mg/kg i/v DO NOT USE 8-12mg/kg i/vKetamine/medetomidine 7mg/kg +

80micrograms/kgi/m

2.5-7.5mg/kg +40micrograms/kgi/m

8mg/kg +100micrograms/kgi/m

Pentobarbitone 20-30mg/kg i/v 20-30mg/kg i/v 25-30mg/kg i/vPropofol 5-8mg/kg i/v 5-7.5mg/kg i/v -Thiopentone 10-15mg/kg i/v 10-20mg/kg i/v -Chloralose (non-recoveryonly)

60mg/kg i/v 80mg/kg i/v -

Urethane (non-recoveryonly)

750mg/kg i/v 1000mg/kg i/v 1500mg/kg i/v

Anaesthetic andrelated agents

Pig Primate Sheep

Alphaxalone/alphadolone 6mg/kg i/m then2mg/kg i/v

10-12mg/kg i/v 2-3mg/kg i/v

Ketamine/medetomidine 10mg/kg +80micrograms/kgi/m (variable effects)

- 1mg/kg +25micrograms/kgi/m (Producessever hypoxia)

Pentobarbitone 20-30mg/kg i/v 25-35mg/kg i/v 30mg/kg i/vPropofol 2.5-3.5mg/kg i/v

(afterketamine/midazolampremed)

7.5-12.5mg/kgi/v

4-5mg/kg i/v

Thiopentone 6-9mg/kg i/v (afterketamine pre-med)

15-20mg/kg i/v 10-15mg/kg i/v

Urethane (non-recoveryonly)

- - 1000mg/kg i/v

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Table 6 Opioid (morphine-like drugs) for use in laboratory animals. Note that these areonly suggestions based on clinical experience and the limited published data that areavailable. Dose rates should be adjusted depending upon the clinical response of theanimal. Data adapted from Flecknell and Waterman-Pearson, 2000.

Drug Species and frequency of dosing Dose rateRat (6-12h), Guinea Pig (?) 0.05mg/kg s/c

Mouse (6-12h), Hamster, (?) Gerbil (?) 0.1mg/kg i/p or s/cRabbit (6-12h) 0.01-0.05mg/kg i/v or s/cCat (6-12h), Sheep (4h), Primates (?6-12h) 0.005-0.01mg/kg i/m, s/c

or i/v

Buprenorphine

Dog, Pig (6-12h) 0.005-0.02mg/kg i/m, s/cor i/v

Rat, Guinea pig (1-2h) 2mg/kg s/c

Rabbit (1-2h) 0.1-0.5mg/kg s/c

Cat, Dog (3-4h) 0.2-0.4mg/kg s/c

Butorphanol

Primates (3-4h) 0.01mg/kg i/m, i/v

Drug Species and frequency of dosing Dose rate

Mouse, Hamster, Gerbil, Rat, Guinea Pig (?4h) 2-5mg/kg i/p or i/m

Cat (4h) 0.1mg/kg i/m

Dog (4h) 0.5-5mg/kg i/m

Pig (4h?), Primate (?4h) 0.2-1mg/kg i/m

Morphine

Sheep (4h?) 0.2-0.5mg/kg i/m,

Rat, mouse, guinea pig (?2-3h) 10-20mg/kg s/c or i/mRabbit (2-3h) 10mg/kg s/c or i/mCat (2h) 2-10mg/kg i/m or i/vDog (2-3h) 5-10mg/kg i/m or i/v

Pethidine

Pig (4h), Sheep (2h) 2mg/kg i/m or i/v

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Table 7 NSAID (Non-steroidal anti-inflammatory drugs) for use in laboratory animals.Note that these are only suggestions based on clinical experience and the limitedpublished data that are available. Dose rates should be adjusted depending upon theclinical response of the animal. Data adapted from Flecknell and Waterman-Pearson,2000.

Drug Species and frequency of dosing Dose rateRat (12-24h), Mouse (?) 5mg/kg s/c or per os

Guinea pig 2.5mg/kg s/c uidRabbit (6-12h) 1.5mg/kg per os, 4mg/kg

s/cCat (once), Dog, daily 4mg/kg s/c or i/vPig (daily) 2-4mg/kg s/c or i/v

Carprofen

Sheep (daily) 1.5-2mg/kg s/c or i/vRat, Guinea pig (1-2h) 2mg/kg s/c

Rabbit (1-2h) 0.1-0.5mg/kg s/c

Cat (once), Dog (12h) 1mg/kg i/v or i/m

Pig (daily) 1mg/kg i/v or s/c oncedaily

Flunixin

Sheep (daily) 2mg/kg i/v or s/c oncedaily

Drug Species and frequency of dosing Dose rate

Rat (?12-24h) 5mg/kg i/m

Rabbit (daily) 3mg/kg i/m

Cat , Dog (daily ,up to 3 days)) 2mg/kg s/c

Ketoprofen

Pig (once) 3mg/kg s/c

Rat (?daily) 1.0mg/kg s/c or per osRabbit (daily) 0.2mg/kg s/c

Meloxicam

Dog (once), Cat (once) 0.2mg/kg s/c