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LABORATORY ANIMAL MEDICINE AND SCIENCE - SERIES II

LABORATORY ANIMALS:Rodent Anesthesia & Analgesia

V-9054

Kathleen A. Murray, DVM, MS

Director, Technical Operations

Charles River Laboratories, Inc.Wilmington, Massachusetts

Cinthia Pekow, DVM

Chief, Veterinary Medical Unit, Research

Veterans Affairs Puget Sound Health Care System

Seattle, Washington

Gary L. Borkowski, DVM, DACLAM

Attending Veterinarian & Associate Director

Pharmacia Corporation

St. Louis, Missouri

The Laboratory Animal Medicine and Science - Series II has been developed by the AutotutorialCommittee of the American College of Laboratory Animal Medicine (ACLAM): C.W. McPherson,

DVM, Chair; J.E. Harkness, DVM; J.F. Harwell, Jr., DVM; J.M. Linn, DVM; A.F. Moreland, DVM,

G.L. Van Hoosier, Jr., DVM; L. Dahm, M.S.

Laboratory Animal Medicine and Science Series II

is produced by the

Health Sciences Center for Educational Resources

University of Washington


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2 LABORATORY ANIMAL MEDICINE AND SCIENCE - SERIES II

University of Washington

Health Sciences Center for Educational Resources

Box 357161, Seattle, WA 98195 -7161 206/685-1157

Copyright 2000

by the University of Washington Health Sciences Center forEducational Resources and the American College of Laboratory

Animal Medicine

All rights reserved.

Printed in the United States of America.


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V-9054 Lab Animal Medicine: Rodent Anesthesia & Analgesia 3

PRIMARY AUDIENCE Veterinarians, investigators, and research technicians.

SECONDARY AUDIENCE Veterinary students, laboratory animal care technicians.

GOAL To provide guidelines for a comprehensive rodent anesthesia

and analgesia program.

OBJECTIVES When you complete this program, you should be able to:

1. Explain the unique challenges in rodent anesthesia.

2. List the criteria used to select an appropriate anesthetic.

3. List characteristics of individual animals that affect anesthetic

choice.

4. Describe the advantages and disadvantages of injectableadministration of anesthesia.

5. Describe the advantages and disadvantages of inhalant

administration of anesthesia.


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1. Series Laboratory Animal Medicine and Science Series II

2. Title Rodent Anesthesia & Analgesia

3. Objectives When you complete this program, you should be able to:

1. Explain the unique challenges in rodent anesthesia.

2. List the criteria used to select an appropriate anesthetic.

3. List characteristics of individual animals that affect anesthetic

choice.

4. Describe the advantages and disadvantages of injectable


5. Describe the advantages and disadvantages of inhalant


4. Introduction Rodent anesthesia offers unique challenges that are infrequently

encountered in any other veterinary setting. Among the unique

challenges in rodent anesthesia is that often surgery is done on morethan one animal at a time in an "assembly-line" or "herd" fashion. To

accommodate the simultaneous anesthesia of multiple animals, it is

useful to have an anesthetic solution available that can be

administered based on body weight and that is fairly tolerant of 5, 10,

or 20 g weight differences among the patients. This allows parenteral

administration of anesthesia on a milliliter per kilogram basis with

premixed dilutions or combinations of drugs.

5. Unique Factors There are many anesthetic drugs that have been developed for use in

humans or in other animals. Extrapolation of dosages for rodents is

sometimes difficult. On the other hand, some anesthetic agents are

used only in rodents, but there is very little physiologic, toxicologic, or

pathologic information in the literature about their efficacy. In addition,

the various species and strains of rodents may show differing

sensitivity, efficacy, and duration with various anesthetics. Monitoring

physiologic parameters during anesthesia in rodents is infrequent or

minimal at best, and because of their small size, it is difficult to use

criteria like muscle relaxation and jaw tone to determine the depth of

anesthesia, as one does in other species.

6. Criteria for selecting anesthesia

When trying to determine the most appropriate anesthetic for use on rodents, several

criteria should be considered:First, what is the purpose of the anesthesia?

The purpose will directly influence the duration of anesthesia--whether for short termrestraint in order to perform a physical exam or radiograph or for long-term generalanesthesia for a complicated protocol.


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Second, what is the type of experiment or procedure?

Is this a survival procedure or a non-survival procedure? With a survival procedure, it isimportant that the anesthesia has minimal adverse effects, thereby minimizing its influenceon the data being collected. For example, for a respiratory study, opioids which are known to

cause respiratory depression should be avoided.

Third, is a postoperative analgesia required?

Some anesthetics provide better postoperative analgesia than others. Consider also if theappropriate equipment is available. For example, inhalation anesthetics require equipment toadminister and an adequate method of scavenging the waste gas so personnel are protectedfrom exposure. In addition, consider both the skill and experience of the anesthetist, becausethe margin of safety varies among different types of anesthetics. In general, more technicalskill is required to administer inhalants compared with injectables. Regulation of the agentshould be taken into account since some anesthetics are controlled substances and require aDEA license for purchase.

The final criteria to consider are the costs of the agent and the delivery equipment.

7. Patient characteristics

Characteristics of the individual patient that need to be considered when selecting anesthetics

include:

Species and strain

Age, size, and sex

Physical condition

Temperament

Health (preexisting diseases)

Previous administration of other drugs

Be aware of the health status and physical condition of the patient. Of special importance is any

history of previous administration of other drugs or other disease state, which may influence the

enzyme systems that metabolize the anesthetic.

8. Physical restraint

Anesthetic induction requires some form of physical

restraint. The duration of restraint will vary with the

type of anesthetic agent being administered as well as

the route of administration. While there are a variety of

restraint devices available, it generally requires more

time to place the animal into the restraint device than

to gently hold the animal during the initial inductionphase. The important point to remember is that manual

restraint should be brief, in order to minimize stress to

the animal. When using inhalant anesthetics, the use of

an induction chamber may decrease stress, depending

on the species.

Also take a look at handling and restraint in V-9042 Rats

& Mice: Care and Management, V- 9029 Hamsters: Care

and Management, and other rodent programs.


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METHODS OF DELIVERY

9. Methods of Delivery

This section discusses methods of anesthetic delivery and applicable

equipment. In general, anesthesia is administered to rodents by either

the parenteral route or the inhalation route.

Parenteral route Inhalation route

intraperitoneal (IP)

intramuscular (IM)

intravenous (IV)

subcutaneous (SC)

open drop delivery

precision vaporizer

10. Disadvantages of Injectables

The disadvantages to using injectable anesthetics:

Once a given dose is administered, the anesthetic cannot be

changed. The duration of anesthetic effect is patient-dependent.

There is individual variability for a given dose.

Some injectable agents are irritating and measures need to be

taken to minimize this effect

11. Dilutions Prior to administering injectable anesthetics, consider the drugvolume, the site, and any irritant properties of the drug. Becauseconcentrated agents are delivered to very small animals, the actualdrug volume may be quite small. Many agents can be diluted withphysiologic saline to at least a one to one solution (1:1) and, in somecases, one to ten (1:10).

Dilutions

decrease the chance of overdosing,

facilitate drug absorption,

minimize irritation, and

increase the accuracy of volume measurement by making sure

that a significant percentage of the compound is not left within the

"dead space" of needle and syringe.

If a very large volume of drug needs to be administered, divide the

dosage among sites or use more than one route if appropriate.


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12. IM Route

IM injections should be administered in a large

muscle mass, and the two most common sites used

in rodents are the thigh muscles and the epaxial

muscles located along the spine. Small gaugeneedles, 26 to 30 gauge, are generally

recommended. Large volume doses can be

administered in several IM sites and dilutions are

recommended if a compound may have irritating

properties.

IM injections in rodents may be problematic,

particularly given the small muscle mass of these

animals. Muscle damage may occur from the needle

if the animal struggles during the injection, or the

injected substance itself may cause damage due to

the volume or tissue reaction.

13. IP Route

The intraperitoneal route is probably the most

common for administering injectable agents in

rodents. The technique is relatively easy to master,

and many anesthetics which create irritation when

given IM or subcutaneously (SC) do not cause

lesions or clinical evidence of pain when given IP. In

addition, many of the published drug dosages in the

literature are formulated for IP delivery. This photo

shows the proper site for IP injections in the lower

left abdominal quadrant with the animal's head in a

down position which allows gravity to move

abdominal viscera away from the injection site (drug

volumes in needles are for demonstration purposes

only). Depending on the size of the animal, a 20 to

23 gauge needle is recommended. It is also

important that the needle is long enough to span the

thickness of the abdominal wall and actually

penetrate into the abdominal space.


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14. IV Route

Intravenous administration of anesthetics is not

commonly used in rodents, because access to

peripheral vessels is limited, and the techniques are

difficult. In rats, mice, and gerbils, the lateral tailvein is the peripheral vessel most easily accessed.

To facilitate access, the vein can be vasodilated by

heating, for example, in warm water. In guinea pigs

and hamsters, the ear vein, dorsal metatarsal vein,

and the pubic or penile vein are the only accessible

peripheral vessels. In general though, these require

marked restraint and are not practical for induction

of anesthesia. However, they could be used to

administer compounds in a previously anesthetized

animal.

15. Recommendations for IV administration

There are some general recommendation for IV administration of

anesthetic agents in rodents because the vessels involved are very

small.

These include:

using small gauge needles and small gauge catheters (26 to 30

gauge),

injecting materials slowly and

stabilizing the needle or catheter once it is in place.

After an injection is completed, digital pressure is used to aid in

hemostasis. These recommendations are vital to decrease potentially

painful sequelae and to preserve vessels if the animal is part of a

chronic study.

16. Inhalant anesthetics- advantages

Inhalation anesthesia involves delivery of a volatile anesthetic agent to

the patient via the respiratory tract.

Advantages of using inhalants:

Increased control over depth as well as duration of anesthesia.

Increased safety and survivability.

Minimal metabolism, biotransformation and excretion compared with

injectables, which is desirable in a toxicology studies. Animals generally wake up faster from inhalant administration requiring

less patient support during the postoperative recovery phase.


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17. Inhalant anesthetics- disadvantages

Most of the disadvantages associated with inhalants

involve the required technical skills and the expense of

specialty equipment. In addition, an appropriate

scavenging system is needed to protect personnel and

to comply with OSHA regulations and requirements.

18. Open Drop-bell jar

There are two methods of inhalation anesthesia: open drop and

precision vaporizer. A transparent bell jar is used in an open drop

delivery system with the anesthetic gas placed on cotton balls or

sterile gauze at the bottom of the jar and covered with a wire screen

mesh. The mesh separates animals from contact with the anestheticand prevents irritation, and the transparency allows easy

observation of the animals. The open drop system does not permit

control over the concentration of anesthetic within the jar, therefore

only gases with low vapor pressure such as methoxyflurane should

be used. The jar must be placed in a well ventilated fume hood

whenever it is opened to protect personnel from exposure to the

anesthetic gas.

19. Vaporizer

If gases with high vapor pressure are used, for

example halothane or isoflurane, a calibrated vaporizer

must be used to control the concentration of

anesthetic. A rodent is placed in an induction chamber

connected to the vaporizer. Once the animal is

anesthetized, it can be removed from the chamber and

maintained on anesthetic gas for the remainder of the

procedure. Maintenance is most commonly done by

means of a face mask. Face or head masks are

commercially available, but are also easily made froma funnel or the proximal end of a 20, 50, or 60 cc

syringe barrel depending on the size of the rodent.


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20. Endotracheal intubation

Use of a facemask is probably the most common

means of delivering anesthetic gas to rodents;

however, it is possible to use endotracheal intubation.

In rodents, endotracheal intubation is most easily

accomplished by direct visualization of pharyngealand laryngeal structures. This can be accomplished

by using a pediatric laryngoscope with a Wisconsin

size 0 blade, filed down to make it narrower, and a

fiberoptic light or penlight for a light source. Another

option is to use a functioning otoscope which serves

as both a light source and a speculum and has the

added advantage of magnification. Endotracheal

tubes can be fabricated using intravenous over-the-

needle catheters. Catheter sizes range from 14 to 20

gauge depending on the size of the rodent being

intubated, and the tip should be blunted to prevent

trauma.

Respirators specifically designed for ventilation of

rodents are available.

21. Inhalation setup with scavenging system

An appropriate scavenging system is a crucial

part of administering inhalation anesthetics to

rodents.

A calibrated vaporizer feeds anesthetic gas into

an inhalation chamber. Attached to the opposite

side of the inhalation chamber is a facemask, and

beside the facemask is a vacuum-scavenge unit.

Another option is a carbon-filter gas scavenge

canister.

22. Parallel tube scavenging

An alternative scavenging system is to tape two

parallel tubes on either side of a funnel facemask. Thetubes are connected to a vacuum system and a

rodent's nose is placed in the cone. Any escaping

gases would be suctioned away by the parallel tubes

and protect the surgeon and other personnel in the

area from exposure to the anesthetic.


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INJECTABLE ANESTHETIC AGENTS

23. Scavenging options

In summary, it is necessary to provide adequate

scavenging of the volatile gases when using

inhalation anesthesia. The options addressed inthis program include use of a fume hood,

anesthesia machine scavenging, counter sweeps,

and parallel face mask suction.

24. Hypothermia

Hypothermia has been described as an adequate anesthetic for short procedures in neonatal

rodents. The neonate is encased in a latex sleeve and immersed up to the shoulders in an ice-water slurry for 3 to 4 minutes. After the procedure, the neonate is rewarmed in an incubator at

about 33 degrees. (Dannemann and Mandrell)

25. Injectable anesthetic agents

There are numerous injectable anesthetics available for use in rodents. Some of the more

popular agents include:

pentobarbital

ketamine

tribromoethanol

26. Pentobarbital

Pentobarbital is a barbiturate and, historically, the most commonly used anesthetic in rodents. An

advantage of pentobarbital is that, at recommended doses, it causes minimal cardiovascular

depression. It is also relatively long acting and can provide approximately 45 minutes of surgical

anesthesia.

There are, however, disadvantages to the use of pentobarbital. Pentobarbital

is a potent inducer of the hepatic microsomal enzyme system.

causes pronounced respiratory depression as well as hypothermia, particularly when

repeated doses are given.

has prolonged anesthetic recovery which may be accompanied by excitement.

is a controlled substance, which requires a DEA license for purchase and appropriate

record keeping and storage. is a poor analgesic in many species and can cause high mortality in hamsters and gerbils

because the margin of safety is narrow in these species.

Even thought the list of disadvantages appears long, by being aware of them, one can

successfully use this drug in rodent anesthesia


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27. Tribromoethanol

In most rodents, tribromoethanol produces good surgical anesthesia, with good skeletal muscle

relaxation and only a moderate degree of respiratory depression. It is relatively inexpensive and

not a controlled agent.

The major disadvantage of tribromoethanol is a potential for causing peritonitis. When exposed to

either light or temperatures >40C, tribromoethanol degrades into two byproducts: hydrobromicacid and dibromoacetaldehyde. Both of these compounds are highly irritating when administered

IP and result in peritonitis and visceral adhesions which may be fatal.

If prepared correctly, stored at appropriate temperatures, and kept in light-resistant bottles,

tribromoethanol can be used successfully (Kohn).

28. Urethane

Urethane produces long lasting anesthesia with rapid onset following IP administration. It has

minimal effects on the cardiovascular and respiratory systems. Urethane provides good analgesia

as well as excellent muscle relaxation.

Disadvantages to using urethane:

At high doses, hypotension, hypothermia, bradycardia, and metabolic acidosis are seen.

It is absorbed through the skin and, following topical administration to rodents, can

produce sedation and ataxia.

It is a proven carcinogen and mutagen in rodents.

If urethane is selected as an anesthetic, personnel must take precautions to adequately protect

themselves while mixing a urethane solution. Proper protection should include a double set of

gloves, face mask, and mixing under chemical fume hood. Urethane is not recommended for

survival procedures.

29. Chloral hydrate

Chloral hydrate is a hypnotic and a sedative that, at a

high dose (in the range of 450 ml/kg), gives excellent

analgesia.

Unfortunately, along with this excellent analgesia at

high dose, there is uncompensated metabolic acidosis,

hypotension, and bradycardia, as well as severe

hypothermia. In order to get good analgesia, the dose

is such that there is a very narrow margin of safety with

a dangerously deep plane of anesthesia and a

potential for significant mortality. The abdominal

viscera of this rat demonstrates the distension of

adynamic ileus, a sequela to a high concentration

injection of chloral hydrate administered IP. Chloral

hydrate also has the potential for causing peritonitis,

however, with dilute concentrations, this complication

can be avoided.


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30. Alpha chloralose Alpha chloralose is another agent that is a hypnotic and a sedative.

Historically it has been popularized for its lack of baroreceptor

depression which produces a stable, physiologically awake animal that

is immobilized and appears anesthetized.

A disadvantage of alpha chloralose is that it produces a slow onset ofsedation rather than a surgical plane of anesthesia. This sedation is

characterized by myoclonia, hyperacusia, persistent muscle tone,

convulsion, mild hypothermia, and acidosis. Thus, this drug is probably

a hypnotic rather than a true anesthetic and has unproved analgesic

potency in rodents.

Commonly this agent is used in the second phase of a two-phase

procedure. In the first phase, an initial surgery is performed with a

potent short-acting anesthetic. In the second phase, alpha chloralose

is used to maintain long term immobilization for nonstimulating or

nonpainful procedures.

31. Ketamine hydrochloride

Ketamine hydrochloride, a dissociative anesthetic, disrupts pain

transmission and suppresses spinal cord activity with some action at

opioid receptors. Visceral pain is not abolished with dissociative

anesthetics, and there is poor muscle relaxation and analgesia.

Ketamine is a poor anesthetic when used alone, but is more often

combined with other agents. When combined with other drugs, it is

usually administered IP.

Ketamine is acidic, can be irritating, and cause muscle necrosis when

administrated IM. Ketamine-induced nerve damage can cause self-

mutilation in rodents.Ketamine is a controlled substance. Store in a locked cabinet and

maintain a log of its use.

32. Ketamine + xylazine

Drugs often used in combination with ketamine are xylazine,

acepromazine, and diazepam. The ketamine/xylazine combination

offers superior analgesic activity and is the combination most

frequently used. Advantages of ketamine/xylazine include rapid

induction with a relatively long duration (60 to 90 min.) of anesthesia

plus good analgesia. Upon initial administration, there is transient

respiratory and cardiovascular depression. There is also excellent

muscle relaxation, and both the induction and recovery phase aresmooth. In general, ketamine/xylazine is administered IP in most

rodents.

The ketamine/xylazine combination, particularly at high doses, can

cause significant hypothermia and appropriate measures should be

taken to minimize this disadvantage. This combination can also

increase intraocular pressure,

result in hyperglycemia due to an increase in hepatic glucose

production and a decrease in insulin,


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and also decrease gastrointestinal motility.

33. Yohimbine

Yohimbine is a central alpha-2 adrenergic receptor antagonist that can

be used to reverse central nervous system (CNS) depression,

sedation, bradycardia, and respiratory depression caused by xylazine.

It works within 1-3 minutes when administered IV and within 10minutes when administered IP. Adverse effects of yohimbine are

excitement and seizures. Yohimbine is used to allow animals to

recover more quickly from the anesthetic combination of

ketamine/xylazine. However, in some cases this may not be desirable,

and it may be better to let the animals have a slow, gentle recovery.

34. Ketamine + diazepam

Ketamine/diazepam has rapid onset with about 45 to 60 minutes

duration of anesthesia. Ketamine/diazepam causes the least

respiratory and cardiovascular depression of all ketamine tranquilizer

combinations.The disadvantages of using ketamine/diazepam are

some muscle rigidity and hyperacusia at low dosages,

poor analgesia compared to ketamine/xylazine, and

a chance for significant hypothermia.

Ketamine/diazepam is selected for studies that require the least

respiratory and cardiovascular depression.

35. Tiletamine + zolazepam

A drug combination consisting of tiletamine, a dissociative anesthetic,

and zolazepam provides anesthesia suitable for restraint, blood

sampling, or minor manipulative procedures; however, it provides very

poor analgesia. At high enough doses to provide sufficient surgicalanesthesia, there are problems with prolonged recovery, severe

hypothermia, and hyperacusia. Tiletamine/zolazepam is generally not

recommended for use in rodents for surgical anesthesia.

36. Fentanyl + fluanisone

The combination of fentanyl and fluanisone is a neuroleptanalgesic.

This combination provides reliable surgical anesthesia and analgesia

with good muscle relaxation. Non-purposeful limb movements are

inhibited.

Disadvantages of the fentanyl/fluanisone combination are:

mild to moderate respiratory and cardiovascular depression,

hypothermia, and

difficult to obtain in the United States, though this combination drug

is a very popular general rodent anesthesia in Europe.

Midazolam, which is often combined with fentanyl/fluanisone, is water

soluble, non-irritating, and short acting, and provides additional

analgesia.


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37. Propofol

Propofol is an hypnotic agent administered IV. Typically rodents are

initially anesthetized with another agent, and long term anesthesia is

maintained by IV propofol infusion. It is considered a poor analgesic, but

offers the advantage of rapid recovery.

A disadvantage of propofol is that it requires IV infusion, limiting its use inguinea pigs, hamsters, and gerbils.

38. Local anesthetics

Local acting anesthetics, such as lidocaine, or longer-acting bupivicaine,

may be infiltrated into tissues as an adjunct to general anesthesia. Long

acting local anesthetics may reduce postoperative pain perception,

reducing need for general analgesics. Typically, a small volume of local

anesthetic is infiltrated into a tissue in the area where an incision will be

made (preemptive) or has been made.

INHALATION ANESTHETIC AGENTS

39. Inhalant agents

The following discussion covers inhalant anesthetic agents which include:

halothane

isoflurane

methoxyflurane

carbon dioxide

40. Halothane

Halothane is readily available, a potent anesthetic, and not flammable or

explosive. It has more rapid induction and recovery compared to ether

(generally discouraged as an explosive hazard) and methoxyflurane.

Some disadvantages are that halothane:

reduces cardiac output.

causes peripheral vasodilation leading to hypotension or low blood

pressure.

is a dose-dependent respiratory depressant.

Halothane requires some hepatic metabolism in order to be excreted and

has been shown to be hepatotoxic to guinea pigs with repeated use.

Halothane must be scavenged as it can cause epinephrine-related

cardiac arrhythmias.

41. Isoflurane Isoflurane is nonflammable and nonexplosive. Comparedto halothane, isoflurane causes

less depression of cardiopulmonary function.

less sensitization of the heart to catecholamine (beta-adrenoceptor

agonist) release.

less profound respiratory depressant effect.

Note that isoflurane reduces renal blood flow, glomerular filtration rate

and urinary flow. It is not a significant hepatotoxin. Isoflurane's

metabolism to organic and inorganic flourides is less than any other

halogenated agent available, so if a minimally metabolized anesthetic is


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needed, isoflurane is the choice. Both induction and recovery from

isoflurane are rapid.

42. Methoxyflurane Methoxyflurane has recently become unavailable in the United States,

but is covered here since it is still available elsewhere. Methoxyflurane is

nonflammable, nonexplosive, and a potent analgesic. Low vaporpressuremakes it the only agent suitable for the open drop method. A

disadvantage of methoxyflurane, compared to other inhalents, is a

relatively slow induction phase that can result in a modest respiratory

and cardiovascular depression. Perhaps the biggest disadvantage is that

metabolization leads to flouride ion release which is nephrotoxic. An

appropriate scavaging system must be in place to protect personnel.

43. Carbon dioxide The utility and humane acceptability of CO2 and O2 combination as an

anesthetic is an area of contention. This combination is used for

extremely short term procedures.

Some studies have found that low concentrations (50% CO2) lead to

prolonged induction and severe and frequent adverse effects that includenasal bleeding, excessive salivation, seizures, and even death. Humans,

when asked to voluntarily breath 50% CO2, rated the experience as

unpleasant.

High CO2 concentrations (100%) produce rapid anesthesia with few

adverse effects, but when humans were asked to breathe 100% CO2,

they reported that this experience was extremely painful. A

recommendation is to provide CO2 in the ratio of 70% CO2 to 30% O2 for

anesthesia, as a compromise of humane acceptability and practicality

(Kohn).

MONITORING

44. Anesthetic depth

Throughout the course of anesthesia, animals should be observed for

pink mucous membrane color, a general indication of aqequate

oxygenation. Respiratory rate should remain even. Movement or change

in respiratory rate or depth in response to manipulation may indicate

insufficient depth of anesthesia. Confirm the animal's lack of response to

stimulation, such as withdrawal from a paw pinch, every 15 minutes or so

throughout a surgical procedure.

Pulse oximetry can be used as an objective measure of oxygen

saturation and pulse rate. Several units are available that can be used

with rodents such as rats. However, small size and lack of a tail in some

species limit sites for sensor application.


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ANALGESIA

45. Assessment of pain

Pain in rodents is most commonly assessed on the basis of subjective

measures and observations combined with professional judgment.

Clinical assessments of pain include behavioral changes such asimmobility, unkempt appearance, lack of appetite, abnormal vocalization,

and abnormal posture.

Animals experiencing pain may appear

unresponsive

lethargic

anxious

apprehensive

hypersensitive

aggressive

Any single measure is not pathognomonic for pain. Porphyrin tear

staining may be noted in rats. Animals may chew on themselves or pullhair.

Physiologic signs such as pupil dilatation, fluctuations in blood pressure,

increased heart rate, respiratory rate, and body temperature may be

more difficult to routinely assess. Implanted telemetry devices are used

in some situations to provide objective data on some of these

parameters. Changes in weight can be readily measured.

When pain or distress is suspected, humane considerations dictate that

relief be provided to an animal.

46. Herd analgesia

Rather than assessing individual animals for signs of discomfort,

investigators mayprospectively design an analgesic protocolwhich will

make postoperative analgesic therapy available to each study

participant. The strategies involve recognizing and eliminating pain in

groups of rodents, rather like a herd approach to analgesia. In this

approach, the pain intensity of a given research procedure, based upon

known discomfort levels in larger companion animal species or humans,

should be considered. The prediction of pain intensity is often based on

the type of procedure and the location of the lesion. (Kohn)

47. Salicylates Acetylsalicylic acid (aspirin) and sodium salicylate are

used to relieve only mild to moderate pain; they do not relieve deep-seated visceral pain or sharp intense pain. Aspirin is not routinely

administered to rodents because of the difficulty in dissolving the drug in

water or other oral solutions.


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48. Morphine-sulfate

Morphine-sulfate is a potent narcotic analgesic. It is a controlled

drug and must be stored in a locked cabinet and a log of use

maintained. Investigators need to be aware that animals will

develop tolerance to morphine with chronic administration.

Morphine has a short duration of action and must be re-

administered at frequent intervals usually of less than 4 hours.Morphine can induce respiratory depression and sedation.

49. Meperidine

Meperidine is a narcotic sedative and analgesic that is less

potent than morphine. It can be used as a postoperative

analgesic and its respiratory depressant effects are similar to

morphine. An advantage is the effects can be reversed by an

antagonist. Effects of meperidine are short lived, usually about 4

hours.

Like morphine, meperidine is a controlled drug. Since it is not as

potent as morphine, there is no particular advantage to using itinstead of morphine when a potent, short-acting analgesic is

indicated.

50. Buprenorphine

Buprenorphine is an opioid with prolonged duration of

action, ranging from 6 to 12 hours. High dosages can

negate the analgesic effect, and complications from

repeat high dosage include hematuria and GI bleeding.

(This photo shows hemorrhage in the bladder of a rat

given repeat high dose buprenorphine.) At lower doses

buprenorphine is an effective analgesic in rodents.

(Liles, Flecknell, Roughan, and Cruz-Madorran)

51. Other analgesics

Use of other analgesics has been described. Analgesics with less utility

in rodents include pentazocine, butorphanol, flunixin meglumine, and

nalbuphine.

Pentazocine lactate is a nonnarcotic analgesic used in postsurgicalcare. The respiratory depressant effects of pentazocine areconsidered less than those of meperidine, but unfortunately, it doesnot work well in rats.

Butorphanol tartrate is a synthetic analgesic with narcoticagonist/antagonist properties. In humans, it is three to five timesmore potent than morphine. Unfortunately, it lacks potency inrodents.

Flunixin meglumine is an agent that is used commonly in humansand dogs. It is a potent non-narcotic, nonsteroidal analgesic agentwith anti-inflammatory and antipyretic activity. Again, it is not usefulin rodents-often resulting in a hyperexcitable animal.


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Nalbuphine is a mixed synthetic narcotic agonist/antagonistanalgesic related to oxymorphone and naloxone. However, its veryshort duration time of minutes in rodents makes it useless in rodentanalgesia.

52. Analgesics -preemptive

Preemptive analgesia is the administration of analgesic agents prior to or

at the time of anesthesia, before any tissue-damaging procedures, such

as incisions, have been started. Preempting pain signals in this way have

been shown, in humans, to decrease levels of postoperative pain and

need for analgesia. Preemptive administration of analgesics such as

buprenorphine has also been shown to decrease the amount of

isoflurane gas anesthetic needed to maintain a surgical plane of

anesthesia in rats (Criado).

53. Analgesics -oral

There is no assurance that oral formulations of analgesics, regardless of

flavor or formulation chosen, will be voluntarily ingested by a given

rodent in sufficient quantity to provide effective analgesia. However,

administration of oral buprenorphine mixed with flavored gelatin has

been described as an effective analgesic in rats. The rats are

preconditioned to take flavored gelatin as a treat. (Flecknell, Roughan and

Stewart)

For doses, refer to the Formulary for laboratory animals (Hawk and Leary),

Anesthesia and analgesia in laboratory animals (Kohn, Wixson, White and

Benson), orResearch animal anesthesia, analgesia and surgery(Smith

and Swindle).

54. Supportive care

Intra- and post-surgical supportive care includes

ocular lubrication, topical antibiotics, nutritional

considerations, and minimizing heat loss.

Rodents typically are not fasted or water restricted

prior to anesthesia, as is done with larger species.

Typical postoperative nutritional support can

include supplemental fluids to maintain fluid

volume.

One may also provide

warmed 5% dextrose, given SC

gelatin or agar diets, as well as fruit or

vegetables or peanut butter.

Use of fresh fruit or vegetables may be restricted in some facilities.

Ocular lubrication during the entire anesthetic episode, as well as into

the postoperative phase is recommended Antibiotics should be used

when appropriate, including the use of topical antibiotics along implant


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exit sites. Antibiotic use should not be a routine antidote for poor intra-

operative sterile technique.

Care should be taken to minimize heat loss to the environment. This can

be done by using a heated OR table, heat blankets, heat lamps, drapes,

and minimizing organ exposure from body cavities. While animals are

recovering from anesthesia, rodents may huddle with cage-mates forwarmth. However, anesthetized rodents should not be caged with awake

animals. Return each animal to group housing only when confidant the

animal is able to move about and defend itself.

The V-9055 Rodent Surgery program contains a thorough discussion of

supportive care.

54. ACLAM Credits

The Laboratory Animal Medicine and Science _ Series II

has been developed under the following committee for the

American College of Laboratory Animal Medicine

C. W. McPherson, DVM, ChairJ. E. Harkness, DVM

J. F. Harwell, Jr., DVM

J. M. Linn, DVM

A. F. Moreland, DVM

G. L. Van Hoosier, Jr., DVM

L. Dahm, MS.

59. HSCER Credits

Produced by the

Health Sciences Center for Educational Resources,

University of Washington,

Seattle WA 98195

2000


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References

American Veterinary Medical Association. 1993. Report of the AVMA panel on euthanasia. J.

Am. Vet. Med. Assoc. 202(2):229-249.

Canadian Council on Animal Care. 1993. Guide to the care and use of experimental animals,

vol. 1. Canadian Council on Animal Care, Ottawa, Ontario. [http://www.ccac.ca/]

Criado, A. B., A. Gomez de Segura, F. J. Tendillo, and F. Marisco. 2000. Reduction of

isoflurane MAC with buprenorphine and morphine in rats. Lab. Anim., 34: 252-259.

Danneman, P. and Mandrell, T. 1997. Evaluation of Five Agents/Methods for Anesthesia of

Neonatal Rats. Laboratory Animal Science, August (47) 4.

Flecknell, P. 1996. Laboratory animal anesthesia, 2nd ed. Academic Press, Inc., San Diego.

Flecknell, P. A., J. Roughan, and R. Stewart. 1999. Use of oral buprenorphine ("Buprenorphine

jello") for post-operative analgesia in rats - a clinical trial. Lab. Anim. 33, 169-174.

Hawk, C., and S. Leary. 1999. Formulary for laboratory animals, 2nd ed. Iowa State UniversityPress, Ames.

Jenkins, W. L. 1989. Pharmacologic aspects of analgesic drugs in animals: an overview. J. Am.

Vet. Med. Assoc. 191(10):1231-1240.

Kohn, D., S. Wixson, W. White, and C. Benson. 1997. Anesthesia and analgesia in laboratory

animals. ACLAM, Academic Press, New York.

Liles, J. H., P. A. Flecknell, J. V. Roughan, and I. Cruz-Madorran. 1998. Influence of oral

buprenorphine, oral naltrexone or morphine on the effects of laparotomy in the rat. Lab. Anim. 32,

149-161.

National Institutes of Health. 1996. Guide for the care and use of laboratory animals, p.48. NIH

publication No. 86-23. National Institutes of Health, Bethesda, Md.

Smith, A., and M. Swindle. 1994. Research animal anesthesia, analgesia and surgery.

Scientists Center for Animal Welfare, Greenbelt, Md.

U.S. Department of Agriculture. 1966. Animal Welfare Act, (P.L. 89-544). Amended 1970 (PL

91-579); 1976 (PL 94-279); 1985 (PL 99-198). Animal and Plant Health Inspection Service, U.S.

Department of Agriculture, Hyattsville, Md.

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Indicações ACLAM para anestesia