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Anesthesia and Analgesia
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Anesthesia and Analgesia
GUIDELINES and REGULATIONS
Guidance on the use of anesthetics, analgesics, and other categories of drugs for the prevention or relief of pain and distress in laboratory animals comes from several documents. Appropriate parts of those documents are listed below.
The U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training states the following: "Proper use of animals, including the avoidance or the minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals." Additionally, "Procedures with animals that may cause more than momentary or light pain or distress should be performed with appropriate sedation, analgesia, or anesthesia. Surgical or other painful procedures should not be performed on unanesthetized animals paralyzed by chemical agents."
The Guide for the Care and Use of Laboratory Animals (1996 ed.) states the following: "The proper use of anesthetics and analgesics in research animals is an ethical and scientific imperative." "In general, unless the contrary is known or established, it should be assumed that procedures that cause pain in humans also cause pain in animals." If a painful procedure must be conducted without the use of an anesthetic, analgesic, or tranquilizer, because such would defeat the purpose of an experiment, the procedure must be approved by the Institutional Animal Care and Use Committee (IACUC). Neuromuscular blocking agents (e.g., succinylcholine, pancuronium) are not anesthetics. They must not be used alone for surgical restraint, although they can be used in "properly ventilated conscious animals for specific types of nonpainful, well-controlled neurophysiologic studies."
Last, but certainly not least, the Animal Welfare Act (Public Law 89-544) as amended, requires that institutional veterinarians provide guidelines regarding the use of tranquilizers, anesthetics, analgesics, and euthanasia agents. In the case of a research facility, the program of adequate veterinary care shall include "the appropriate use of anesthetic, analgesic, or tranquilizing drugs..."
Anesthesia is the act of providing sensation-free relief from pain or pain-producing procedures. Anesthesia must be performed by a person with knowledge of and familiarity with the drugs to be used in the animal species under consideration. It is the responsibility of the Principal Investigator to ensure adherence to proper procedures during the execution of the protocol. Investigators may arrange training for their technicians by contacting the Division of Laboratory Animal Resources (DLAR) (323-5885) or the Office of the University Veterinarian (257-2549).
Definitions:
Neuroleptic - produce central nervous depression, depression of excitability of the autonomic nervous system, a dulling of consciousness and a reduction of spontaneous motor activity.
Analgesia - relief from pain
Preemptive analgesia - managing pain before it begins
Tranquilization - a state of behavioral change in which the patient is relaxed, unconcerned by its surroundings, and often, indifferent to minor pain.
Sedation - a mild degree of central depression in which the patient is awake but calm; larger doses of sedative may lead to narcosis.
Narcosis - a drug-induced state of sedation in which the patient is oblivious to pain.
Local anesthesia - loss of sensation in a limited body area.
Regional anesthesia - insensibility in a larger, though limited, body area.
Basal anesthesia - a light level of general anesthesia usually produced by preanesthetic agents. It serves as a basis for deeper anesthesia on administration of other agents.
General anesthesia - complete unconsciousness
Surgical anesthesia - unconsciousness, accompanied by muscular relaxation to such a degree that surgery can be performed painlessly and without struggle on the part of the patient.
Neuroleptanalgesia - a state of central nervous system depression and analgesia usually produced by a combination of a neuroleptic and a narcotic analgesic.
Factors Affecting Choice of Anesthetic and Analgesic Regimens
Dosage charts for anesthetic and analgesic agents state only the average amount of drug that would be expected to produce a desired level of anesthesia or analgesia under standard conditions. Consequently, animals must be monitored carefully and the dosages tailored to meet each clinical and research situation. The DLAR veterinarian(s) are available for consultation on the selection of the best agent and dosage to meet specific research needs.
Many factors can affect the activity of anesthetics. The species, strain, sex, age, physiologic status, relative body size, disposition/demeanor, presence of concurrent pain or distress, or medication are known to cause a variation in the amount of drug needed to produce a desired effect in an individual animal.
Numerous studies have shown that preemptive analgesia, managing pain before it begins, holds significant benefits for the animal. If the selected analgesic does not interfere with the research parameters, the quality of the data produced by use of the animal can be improved when the stress secondary to pain is removed. Analgesia is more effective when given before a painful procedure is introduced, and preemptive analgesia should be used whenever possible.
The duration of anesthesia produced by the anesthetic should coincide with the expected duration of the operative procedure. The duration of analgesia produced by the analgesic should coincide with the expected duration and intensity of post-operative pain generated by the procedure. The time required for post-surgical recovery from anesthesia, as well as the frequency of administration of analgesics should coincide with the level of post-surgical care that is available. Knowledge, experience and skill with available agents and equipment can affect the outcome of the use of anesthetics and analgesics.
Safety precautions would include the protection of humans from vapors of volatile anesthetics. This is best accomplished by the use of an approved gas scavenging system, or by using the volatile anesthetic agent inside an approved fume hood.
Many of the drugs described in this section have the potential for human abuse. Therefore, they must be maintained in a manner that is in compliance with all federal laws and requirements for the handling and storage of controlled substances. Drugs that are subject to control under the Drug Enforcement Agency (DEA) must be stored in a locked cabinet.
Controlled Substance
Public Law 91-513, Section 202:
"There are five schedules of controlled substances, to be known as schedules I, II, III, IV, and V." Oversight for compliance with the law resides with the Drug Enforcement Agency (DEA).
Schedule I - "The substances in this schedule are those that have no accepted medical use in the United States and have a high abuse potential."
Schedule II - "The substances in this schedule have a high abuse potential with severe physic or physical dependence liability. Schedule II controlled substances consist of certain narcotic, stimulant and depressant drugs."
Schedule III -"The substances in this schedule have an abuse potential less than those in Schedules I and II, and include compounds containing limited quantities of certain narcotic drugs and non-narcotic drugs..."
Schedule IV- "The substances in this schedule have an abuse potential less than those listed in Schedule III..."
Schedule V - "The substances in this schedule have an abuse potential less than those listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotic and stimulant drugs..."
Record Keeping Requirements:
A written record is required when any DEA controlled substances are used. The record should reflect the purchase/acquisition date of each drug, the volume received, the date and volume of each use of the drug, and the volume of drug remaining in the inventory. Each entry in the record should be signed by the person authorized to dispense the drug.
Individual animal clinical records should be annotated to reflect the use of the agents described above, showing the date and dose. All records should be stored in such a way that they are readily available for review by members of the IACUC, by authorized inspectors from the Office of Laboratory Animal Welfare (OLAW), the DEA, and/or the U.S. Department of Agriculture.
Pretreatment of the Surgical Patient:
Drugs such as anticholinergics, tranquilizers, or sedatives are given as anesthetic pretreatment for a variety of reasons. The primary goal of pretreatment with the majority of these agents is to minimize anxiety or excitement of the patient. Some drugs may be used to ease the transition to the first plane(s) of anesthesia, to decrease the amount of anesthetic agent, to prevent vomiting, or to control secretions.
Anticholinergic: (e.g., atropine sulfate, glycopyrrolate)
These agents block parasympathetic impulses to the cardiopulmonary system, glands and smooth muscle. Consequently, they prevent vasovagal reflexes, with concurrent slowing of the heart, and reduce salivary gland and bronchial secretions. The effectiveness of atropine varies among species.
Tranquilizers/Sedatives:
(Tranquilizers = phenothiazines [e.g., acepromazine] and butyrophenones [e.g., droperidol and azaperone]) (Sedatives = barbiturates, benzodiazepines [e.g., diazepam, zolazepam]).
The distinction between tranquilizers and sedatives is mainly semantic. One differentiating characteristic, however, is that tranquilizers at high dose levels tend to produce side effects without a loss of consciousness. Sedatives at high dose levels cause a profound CNS depression that resembles anesthesia. Tranquilizers calm the animal, facilitate handling for anesthetic induction, and reduce the amount of anesthetic required for induction and maintenance of general anesthesia, thereby decreasing the undesirable side-effects of the anesthetic agent. Tranquilizers also may enhance smooth anesthetic recoveries (usually in conjunction with analgesics). Tranquilized animals can be readily aroused by painful stimulation because tranquilizers do not produce analgesia.
Tranquilizers can, in some settings, provide skeletal muscle relaxation when the relaxation produced by the anesthetic agent is insufficient. This effect may be observed in rabbits and cats with the administration of a combination of acetylpromazine and ketamine hydrochloride. This activity is not as pronounced, however, as the skeletal muscle relaxation which results from the administration of neuromuscular blocking agents (e.g. succinylcholine).
Sedatives produce a mild degree of central nervous system (CNS) depression in which the animal is conscious but calm and not nervous. These agents will produce a psychological calming of an animal but do not exert hypnotic or analgesic effects. Animals can become aroused and can react to painful procedures.
Loud noise stimulation can reverse the calming effects of these drugs. When used as preanesthetics, ample time should be allowed for the drug to reach its maximum effect, before attempting to induce anesthesia. All tranquilizers and sedatives share many of the described characteristics, but each drug has its own diverse pharmacologic properties, along with contraindications.
Alpha2-Adrenergic Agonists: ( e.g., xylazine, detomidine, medetomidine)
This class of drugs mediates analgesia, anxiolysis, sedation, sympatholysis, and control of hypertension. These drugs are usually classified as sedative-analgesics and skeletal muscle relaxants. There is wide species variation in the reaction to these drugs. Xylazine sedation may be reversed using yohimbine, tolazoline, or idazoxan. Atipamezole is a highly selective and potent 2-antagonist that rapidly reverses sedation as well as other behavioral and physiologic effects of medetomidine.
Nonchemical pretreatment:
Nonchemical pretreatment procedures, such as withholding food prior to surgery, are advisable to prevent regurgitation of stomach contents and aspiration into the respiratory tract while the animal is anesthetized.
General Anesthetics:
Anesthetics produce, in a controllable manner, both loss of consciousness and an absence of motor response to noxious stimuli. This unconsciousness, analgesia, and muscle relaxation should be sufficient to allow the performance of painful procedures without the subject experiencing pain.
Animals should be in good health before the administration an anesthetic agent. The animal's physical condition should be evaluated to assure that there are no disease conditions that may compromise the well being of the animal during anesthesia.
The level of anesthesia should be limited to the induction of the minimal degree of CNS depression necessary for performing the procedure. When an injectable anesthetic agent is used, drug dose calculation should be based on body weight and age. Because of the wide variation within and among species, there is really no such thing as a predetermined anesthetic dose. General anesthesia must be given "to effect," as noted in physiologic responses and in response to noxious stimuli. It is important to realize that some drugs take time to take effect. Many anesthetic deaths can be attributed to giving the anesthetic insufficient time to work. This is especially true of parenterally administered drugs (e.g., barbiturates) - once they are injected, there is little the anesthetist can do to control the outcome.
To avoid hypothermia, body temperature should be monitored and maintained throughout the anesthetic process. Conservation of body heat is an integral part of anesthetic management. Especially in small animals, core body temperature can fall precipitously during general anesthesia. Hypothermia, when added to other factors, can produce an irreversible sequence of events leading to death. To avoid thermal burns, water heating pads rather than electrical pads, should be used.
During lengthy procedures, anesthetized animals may become dehydrated. To help maintain normal hemodynamics, warm, balanced electrolyte solutions should be administered, by continuous intravenous drip, throughout the surgical procedure. Rodents may be administered fluids via the subcutaneous route.
The anesthetist's responsibility for the animal’s welfare extends beyond the completion of the surgical procedure. Continuous monitoring by a trained person should be provided until the animal is able to maintain itself in sternal recumbency and is breathing normally. Some anesthetics and analgesics affect animals for days after administration. Therefore, it is important to check animals daily for signs of anorexia, fever, vomiting, or abnormal respiration or heart rate.
Stages of General Anesthesia
Stage I
Stage of Analgesia; loss of pain without loss of consciousness or sense of touch. This stage exists from the moment of induction to the loss of consciousness. Respiration is unchanged, and the pupils may not change or exhibit moderate reflex dilation. Analgesia is present.
Stage II
Excitement Stage: loss of consciousness to the onset of regular respiration. In this stage, the higher cerebral centers are depressed with loss or inhibition of the secondary centers. Excitement and struggling may occur. This is one of the danger periods of anesthesia during which vomiting and physical injury may take place. Therefore, the anesthetist should strive to cause the patient to pass through this stage as quickly as possible. In order to obtain a smooth and rapid induction, careful attention must be paid to proper and adequate premedication, proper restraint of the animal, and minimal sensory stimuli. Respiration is irregular; there may be periods of breath-holding. The pupils show reflex dilation. Muscular tone is increased, while analgesia is present.
Stage III
Surgical Anesthesia: from the onset of regular respiration to the cessation of spontaneous respiration due to central respiratory paralysis from the action of the anesthetic agent.
Plane 1 - Respiration is regular with an increase in tidal volume. There is nystagmus and the pupils are constricted. There is a loss of the vomiting, eyelid, and pharyngeal reflexes. Small muscle tone is lost. Although swallowing is retained in upper first plane, it is of value primarily in recovery from anesthesia.
Plane 2 - Respiration is regular but shallower. The eyeballs are fixed (central) and the pupil is in mid-dilation. There is a loss of the corneal, visceral, laryngeal, and cough reflexes. The large muscles are beginning to relax in this plane.
Plane 3 - This plane is entered when there is the beginning of progressive intercostal muscle lag, in which diaphragmatic movement precedes the action of the intercostals. It ends with the cessation of intercostal movement. The pupil is moderately dilated and all muscle tone (except diaphragmatic) is lost.
Plane 4 - Respiration shows complete intercostal paralysis and breathing is diaphragmatic. Inspiration is short and gasping, with retraction of the intercostal spaces. The pupils show paralytic dilatation.
Stage IV - begins with respiratory paralysis and progresses quickly to circulatory failure.
Pertinent notes on the signs of anesthesia
The eyelash reflex is related to the eyelid reflex. If the eyelash is stroked or the eyelid is opened, the patient will actively attempt to close its eye in the second stage. In the third stage, the eyelid will close passively, or will remain open, and stroking the eyelash will elicit no response.
Since swallowing will occur before vomiting when the patient is becoming "light," the continuous presence of the anesthetist’s hand on the patient’s chin may aid in detecting signs of swallowing, and permit an increase in the depth of anesthesia before vomiting occurs.
Pupillary size may be influenced by pre-anesthetic drugs, and may not be a reliable sign of anesthetic depth. However, a widely dilated pupil, with little or no iris visible, should always cause concern, since it may be the result of excessively deep anesthesia or hypoxia.
Evaluation of anesthetic effects:
Test pedal (toe pinch) and palpebral reflexes, and the tone of jaw and anal sphincter muscles. Reflexes are absent and muscle tone is relaxed during surgical anesthesia.
Monitor depth and rate of respiration - increase in depth and decrease in rate signifies surgical anesthesia.
Monitor heart rate - slowing indicates surgical anesthesia. An increase in rate during the performance of a surgical procedure often indicates that the depth of anesthesia is not adequate and the animal is feeling pain. A decrease of rate during surgery may signify an overdose of anesthetic.
Monitor body temperature - temperature falls during anesthesia; warming causes faster metabolism of anesthetic agent. Maintain body temperature at normal levels, usually 37ºC, if possible