The principles of anesthesia utilized in other species can be applied to nonhuman primates. The purpose of this section is to briefly outline the principles of anesthesia, peri-anesthetic management, and information on the use of anesthetics and analgesics commonly used in nonhuman primates.

Readers are strongly encouraged to consult with a veterinarian who has experience in primate anesthesia and to utilize veterinary or human anesthesiology tests to augment their understanding of the information provided in this condensed format.

Important Link: IACUC Approved Analgesics, Anesthetics & Sedatives

Anesthesia is described as the loss of sensation to the entire or any part of the body. It is induced by drugs that depress the activity of nervous tissue locally, regionally or within the central nervous system.

Analgesia is defined as the insensibility to pain without loss of consciousness.

Sedation is a calm state usually accompanied with drowsiness.

Tranquilization refers to a state characterized by calmness without drowsiness or unconsciousness, where analgesia is not usually provided.

Anesthetics may be used simply for chemical restraint in nonhuman primates to minimize risk to personnel and distress or potential injury to the animals. Many anesthetic regimens are able to provide pain relief in addition to the unconsciousness, which is important for surgeries and other potentially painful procedures. Analgesics are commonly used pre-emptively prior to surgery to reduce post-operative pain and are usually continued after animals recover from anesthesia to extend pain relief. Sedatives and tranquilizers are often used to reduce the amount of general anesthetic needed, as well as to counteract some of their negative physiologic effects. It is the responsibility of those planning to use nonhuman primates to consult with a veterinarian to select the appropriate anesthetics and analgesics to ensure that pain is alleviated. To withhold the use of anesthetics and analgesics must be scientifically justified and approved by the facility’s Institutional Animal Care and Use Committee.

Training in the use of anesthetics is very important for persons unfamiliar with their use. People who administer anesthetics should be familiar with the stages of anesthesia because these are used to determine whenever an animal requires more of less anesthesia for a given procedure. Moreover, familiarity with the signs of anesthesia allows staff to provide a more consistent application of anesthesia. Veterinary support is often appropriate for anesthesia where surgery or prolonged recumbency is anticipated and, under special circumstances, may require the use of advanced skills and techniques beyond the scope of this chapter.

Stage I: termed the stage of voluntary movement, it lasts from the initial administration of the anesthetic until the loss of consciousness. Some analgesia may be present. This stage is the most variable.

Stage II: termed the stage of delirium or involuntary movement, it lasts from the onset of unconsciousness until the onset of regular breathing. Depression of the central nervous system causes the patient to lose voluntary control and reflexes become more primitive and exaggerated. In the nonhuman primate, excessive salivation may occur, and because the gag reflex is pronounced, vomiting may occur during this stage. It is important this stage be short.

Stage III: termed the stage of surgical anesthesia. Patients are unconscious with progressive depression of reflexes. Muscles become replaced, and swallowing and gag reflexes and response to painful stimuli are lost.

Stage IV: termed the stage of respiratory arrest. The central nervous system is very depressed. The heart will only keep beating for a short time after this stage begins unless immediate resuscitative steps are taken.

Respiration - Breath holding can occur in Stages I and II, and breathing is irregular in Stage II although it becomes more regular as Stage III is entered. As the depth of anesthesia increases in Stage III, the muscles used to expand the chest and diaphragm weaken. This causes respiration to become shallow and, consequently, the respiratory rate increases. In late Stage III, the abdominal muscles are responsible for respiration. Respiration stops at Stage IV.

Circulation - Heart rate, blood pressure and capillary refill time (CRT) are the parameters used to assess the circulatory system during anesthesia. CRT is the amount of time it takes a capillary bed in the gums, conjunctiva, or tongue to refill after blanching when digital pressure is applied. Normal CRT is less than 1 second. It is often monitored in the absence of more sophisticated methods such as arterial pressure. Arterial pressure is the most reliable indicator of the adequacy of circulation. During Stages I and II, the pulse is strong and accelerated, and arrhythmias may occur in Stage II. In Stage III, the pulse rate is regular although accelerated slightly, and pain stimulation can cause the pulse rate to increase or become irregular. As anesthesia deepens, blood pressure declines and the pulse weakens.

Ocular Signs - These signs include eyeball positions and movement; pupillary size and light reflex; lacrimation; and palpebral, corneal, and conjunctival reflexes. While ocular signs can be helpful indicators of depth of anesthesia, they tend to be a variable. Injectable anesthetics such as ketamine and tiletamine influence these signs. Because these two anesthetics produce muscle contraction, nonhuman primates anesthetized with these drugs have eyelids that do not blink even when the cornea or the conjunctiva is touched, and their pupils are dilated and unresponsive to light. In nonhuman primates, eyeball position, pupillary size and light reflex, and palpebral reflexes are often monitored, especially when patients are anesthetized with gaseous anesthetic agents. In Stage III, the globe of the eye is usually rotated down, pupils are constricted and unresponsive to light, and the palpebral reflex is absent or sluggish. Late Stage III can be characterized by dilated pupils that are unresponsive to light. As anesthesia is reduced, the palpebral and pupillary light reflexes return, and Stage II the globes turn upward.

Pharyngeal and upper airway reflexes - Coughing (or gagging) and laryngospasm are usually lost in early Stage III, allowing endotracheal intubation by experienced personnel. Attempts to perform endotracheal intubation before this reflex is lost can result in vomiting. The use of neuromuscular blocking drugs to assist with intubation is not routinely necessary. Special care must be taken when attempting to intubate animals that have not been fasted in order to avoid the potential aspiration of vomitus.

Other signs - Muscle tone progressively declines after Stage II, and its return during recovery from anesthesia is a signal of reduced depth of anesthesia. Loss of jaw tone, muscle tone in the limbs and anal sphincter, and a change in the character of respirations from a thoracic to abdominal pattern are signs that indicate deepening anesthesia. Response to painful stimuli such as the digital reflex (pinching the web between fingers or toes) usually returns in early Stage III anesthesia, but can be influenced by the type of anesthetic being used.

Lack of response to painful stimuli provides a means to determine the extent of analgesia present in a nonhuman primate. Signs of pain are variable among individuals and species. Conscious nonhuman primates frequently mask signs of pain. Observers familiar with the animals may detect subtle behavioral changes that may be the result of pain; however, the frequency of analgesic administration is often determined by the perceived level of discomfort a human might be expected to feel.

During anesthesia, it is possible to utilize physiologic indicators as listed in the table to assess pain. Personnel administering anesthetics can make adjustments utilizing these indicators in conjunction with their assessment of the signs of anesthesia to provide animals with optimum anesthesia while animals are unconscious.

The selection and use of anesthetic agents is best done in consultation with veterinary professionals who can utilize their professional expertise to develop the most appropriate anesthetic protocol for a given situation. A careful pre-anesthesia assessment of the animal to determine drugs and dosages needed, while considering drug effects that may impact either the animal or the research objective, will help prevent complications and confounding results.

Ideally, the anesthetic protocol should be designed so that the procedure can be accomplished efficiently, thus ensuring patient comfort as a result of consistent application. It may be necessary to perform a pre-study anesthetic trial to provide personnel with adequate training to consistently administer the anesthesia and to ensure that the anesthetic protocol is adequate for the intended use.

Patient evaluation - The health status of the animal prior to anesthesia can affect the outcome of an anesthetic procedure. History and physical examination are the best ways to assess for the presence of disease. Laboratory tests are only necessary based on the patient’s history and physical examination results. Aged or debilitated animals and those with experimentally induced disease can require special care for successful anesthetic outcomes, and anesthesia should be done under the supervision of an experienced veterinarian. Anemia, hypoproteinemia, and decreased hemoglobin oxygen saturation concentration are examples of preexisting physiological conditions that may require additional treatment and support prior to and during an anesthetic procedure.

Patient preparation - To avoid complications resulting from vomiting during anesthesia, food in usually withheld from animals to allow the stomach to empty. Small marmosets are typically fasted 6 to 8 hours, while the larger species are fasted 12 hours. Hypoglycemia may result if small or your animals are fasted for prolonged periods. It is generally not necessary to withhold water and it is contraindicated in patients with kidney disease. For surgeries that involve the lower intestinal tract, preoperative bowel cleansing may need to be done beginning up to 48 hours prior to anesthesia through the use of electrolyte enemas (GoLYTELYŽ, Braintree Laboratories, Braintree, MA) or cathartics used for human patients. Where the risk of infection is high, prophylactic antibiotics may also be administered prior to surgery. Preoperative analgesics should be administered in cases where post-procedural pain is anticipated. Consultation with a veterinarian prior to the administration of drugs for these purposes is strongly advised because their use may be contraindicated in individual animals or research studies.

Airway - An unobstructed airway must be maintained. Cheek pouches of Old World species should be checked immediately after sedation to remove any food or other objects that might be aspirated, because fasting these animals will not ensure that cheek pouches are empty. In the event salivation or vomiting occurs during anesthesia, suction equipment is useful to prevent aspiration. Endotracheal intubation can help prevent breathing impairment during anesthesia; however, endotracheal tubes can become obstructed and personnel monitoring intubated animals must be alert to recognize this complication.

Position - Normal breathing and circulation should be maintained during anesthesia by placing the animal on its side or back, restraining the limbs with padded ties, and positioning the head to allow saliva to run out of the moth rather than pool in cheek pouches or accumulate in the back of the mouth where it might be aspirated.

Prevention of hypothermia/hypovolemia - An anesthetized animal loses the ability to maintain body temperature and can quickly develop hypothermia if supportive measures are not used to maintain body heat. Warmed IV fluids and circulating warm water blankets are commonly used, and circulating warm air units are very useful for animals undergoing prolonged anesthesia. Protecting animals from metal surfaces that conduct heat away from the body should be routinely done. The use of heat lamps may produce thermal burns in anesthetized animals, so they must only be used with extreme caution and only when animals are closely monitored.

Eye protection - Ophthalmic lubricant should be used routinely tin anesthetized animals to protect the corneas from dessication. The eyes of patients anesthetized with ketamine or tiletamine/zolazepam remain open, thereby increasing the potential for dessication or irritation.

Urine collection - Catheterization of the bladder, especially for animals undergoing abdominal surgeries or prolonged procedures, is routinely performed to prevent urination during surgery. This helps to prevent contamination of the surgical site, provide better visualization of the abdomen, and prevent heat loss through moisture evaporation.

Patient monitoring - The goal of good anesthesia should be to provide a level of anesthesia sufficient to perform the procedure. Reflexes are involuntary, purposeful and orderly responses to stimulus. They are lost as brain function is depressed by general anesthesia. Reflexes commonly assessed to monitor depth of anesthesia are found in Table 1.

Monitoring these reflexes requires access to the head and/or limb of the animal. The extent of monitoring necessary should be determined when the procedure requiring anesthesia is planned. Table 2 lists commonly used monitoring parameters and methods. Due to the small size of marmoset and squirrel monkeys, devices developed for rodents may be better for these species. Many anesthetic procedures that involve surgery require that much of the animal be covered from view by surgical drapes. This can prevent the use of direct visualization methods to monitor the depth of anesthesia such as respiratory rate, reflexes, eye position, and muscle tone.

Physiological monitoring methods can assist with patient monitoring in these circumstances, but require specialized monitoring equipment as detailed in Table 2. At a minimum, for short surgeries or procedures involving only anesthesia, heart rate, respiratory rate, CRT, and jawtone are adequate to assess anesthesia in nonhuman primates. Prolonged anesthesia or complicated procedures may require more sophisticated monitoring to ensure that patients remain physiologically stable. Equipment designed for use in small animal veterinary practice or for infant humans can often be used on nonhuman primates; however, some electrical monitoring devices may have limits on their ability to detect parameters that fall outside the normal limits of humans.

Recordkeeping - Procedures that require the use of anesthesia generally involve drugs with usage controlled by the Drug Enforcement Administration. To obtain such drugs, appropriate licensure is required by state and federal authorities, and drugs must be maintained in double-locked, secured cabinets with records of usage scrupulously maintained. Individual anesthesia records should document the procedure being performed, specific drug used, dosage, time of administration, monitoring parameters (usually 10-15 minute intervals for uneventful procedures), and other pertinent observations with respect to the animal procedure as they occur. Carefully maintained anesthetic records can alert staff to trends that may require action to avert a negative anesthetic outcome. Retrospectively, these records document adequate care and use of the animals, and provide investigative personnel with information pertinent to the research.

Environmental considerations - Nonhuman primates recovering from anesthesia should be kept warm. Metal cages will conduct body heat away from the animal, possibly leading to hypothermia. Placing recovering animals in cages in rooms with increased ambient temperatures, the judicious use of supplemental heat devices such as heat lamps, chemical heating pads, and laying animals on disposable underpads to protect them from contact with bare metal are all methods that can be used to maintain normothermia. The administration of warmed IV fluids can also be used during recovery from anesthesia. Recovery areas should be quiet and preferably separate from species such as dogs and swine because nonhuman primates may become frightened if they awaken in the presence of perceived predator species.

Position - Animals should be maintained in a position that allows normal breathing and minimizes swelling and soilage of surgical sites.

Monitoring - Vital signs (i.e., heart rate, respiratory rate, rectal temperature) should be checked until animals start to return to consciousness. Once animals exhibit voluntary movement and can swallow, visual checks may be all that is safe and prudent for the caregiver to perform. Animals can occlude their airways while still in Stage I anesthesia; therefore, they should be monitored closely until they can maintain an upright posture.

Treatments - These are generally determined by the reason for the anesthesia rather than the anesthesia itself. However, hypoglycemia is a common problem in animals that have been fasted for anesthesia. Treat with dextrose (25% dextrose at 2.5 ml/kg) in the post-anesthetic period. This will hasten recovery of New World species. If nonhuman primates show prolonged return to consciousness following discontinuation of anesthesia, a veterinarian should be consulted to assess the animal and institute appropriate post-anesthetic treatment.

Injectable anesthetics are often used to initiate anesthesia in nonhuman primates because they can be given to animals while they are manually restrained or in their home cages through the use of squeeze-back restraint devices. Sedatives and tranquilizers supplement anesthetics and are usually used to augment an anesthetic by countering some of its negative effects.

Although anticholinergic drugs, sedatives, and tranquilizers are considered separate pharmacologic agents from anesthetics, they are included in the following list because they are used in conjunction with anesthetics. Table 4.7 provides dosages, routes of administration, and duration of effect for the pre-anesthetics and anesthetics commonly used in nonhuman primates.

Atropine is used to prevent slowing of heart rate and minimize the production of saliva and bronchial secretions. It produces effects for approximately 1 hour in most species.

Glycopyrrolate has actions similar to atropine but its effects can last at least twice as long as those of atropine.

Tranquilizers include drugs such as diazepam and midazolam, which are controlled substances. These agents provide muscle relaxation without analgesia and the y may decrease heart and respiratory rates. Flumazenil reverses the effects of these drugs.

Sedatives include drugs such as xylazine and medetomidine. These agents provide sedation, muscle relaxation, and analgesia. They lower heart rate and blood pressure and produce peripheral vasoconstriction. The use of these sedatives is contraindicated in aged or sick individuals. Reversal agents, such as yohimbine, atipamazole and tolazoline, competitively bind to the same receptors.

Ketamine is a controlled substance that is most commonly used for chemical restraint via intramuscular (IM) injection. It is a dissociative anesthetic and has minimal negative cardiovascular effects. With ketamine, the eyes of the patient remain open and muscle rigidity is marked when it is used alone. Ketamine does not provide sufficient analgesia of the patient for most surgical procedures unless it is used in combination with other pre-anesthetic drugs such as xylazine. Animals often maintain the swallow/gag reflex when anesthetized with ketamine. Recovery may take several hours after ketamine anesthesia.

Tiletamine/zolazepam is a combination of a dissociative anesthetic and tranquilizer. It is a controlled substance. Tiletamine/zolazepam has a longer duration of effect than ketamine in larger nonhuman primates, and it is most often used instead of ketamine for chemical restraint and short procedures on small monkeys (marmosets, tamarins, squirrel monkeys, and capuchin monkeys) and chimps.

Barbiturates include drugs such as thiopental and pentobarbital, which are controlled substances. Thiopental is short-acting, must be given intravenously (IV), and is often used to facilitate endotracheal intubation prior to the use of an inhalant gas anesthetic. Pentobarbital is long-acting, produces dose-dependent cardiovascular depression, and the effects can be unpredictable. Prolonged, violent recoveries discourage its routine use for survival anesthetic protocols.

Propofol is a sedative hypnotic drug that is ultra-short-acting and provides minimal analgesic effects; Fentanyl may be used with it to provide intra operative analgesia. It must be given IV, either as a bolus or continuous infusion. Apnea can occur after induction of anesthesia using propofol. When used for chemical restraint, patients anesthetized with propofol require close monitoring, because return to consciousness can occur within minutes after propofol is stopped.

Local anesthetics include lidocaine and bupivicaine. They provide local analgesic effects with few systemic effects when used to infiltrate tissue. Small quantities of lidocaine can also be used topically to help prevent laryngospasm during attempts at endotracheal intubation. Direct application to the vocal cords of several drops of an anesthetic, using a tuberculin syringe with a short catheter attached to it, is a safe administration method. Bupivicaine has a longer duration of effect than lidocaine and is often used as an intra-operative adjunct to general anesthesia for long acting pain control when nerves are cut.

Halothane requires a calibrated, precision vaporizer to administer safely. Reaching a desired depth of anesthesia in animals anesthetized with halothane takes longer as compared to isoflurane. Intra cranial pressure increases under halothane anesthesia due to increased cerebral blood flow. Halothane can sensitize the heart muscle to the effects of catecholamines, which can result in cardiac arrhythmias. Monitoring heart rhythm when halothane is administered is recommended.

Isoflurane requires a calibrated, precision vaporizer to administer safely. The animal’s depth of anesthesia is quickly adjusted because isoflurane is eliminated almost solely through respiration instead of metabolism. Isoflurane causes minimal cardiovascular depressant effects. Cerebral blood flow is increased in animals anesthetized with isoflurane; however, unlike halothane, preanesthetic hyperventilation will prevent this effect.

Nitrous oxide is used only to reduce the amount of other inhalant anesthetic gases in order to reduce their negative effects. It produces minimal respiratory depression and has a slight cardiovascular sparing effect when used in conjunction with more potent inhalant anesthetics. Nitrous oxide produces less anesthesia in nonhuman primates than in humans; consequently, it is never used alone. Nitrous oxide administration must be stopped prior to discontinuing oxygen administration to allow re-equilibration between nitrogen gas and nitrous oxide present in the blood and gas compartments of the body.

Table 4.8 provides information on dosage, route of administration, and duration of effect of the analgesics commonly used in nonhuman primates. Opiod analgesics such as morphine, buprenorphine, oxymorphone, and fentanyl are often used to supplement anesthetics that do not provide adequate analgesic effects needed to perform surgery. Oftentimes, to control pain post-operatively, it is necessary to administer an opioid such as buprenorphine as a pre-anesthetic agent so that pain is not perceived after it occurs. It is possible to reverse the effects of opioid drugs through the use of opioid antagonist drugs such as naloxone. All opioid drugs have a potential for abuse and are thus controlled substances.

Nonsteroidal anti-inflammatory drugs (NSAID) such as aspirin and ketorolac are used to minimize pain caused by inflammation. They do not block pain receptors as the opioid drugs do and, hence, they are not used to supplement anesthesia in the same manner as opioid drugs. In nonhuman primates, NSAIDs are less commonly used because many are oral medications and are not uniformly accepted by all animals. Adequate dosages of NSAIDS may not be ingested by oral administration following surgery.

Morphine is an opioid drug that can be used to provide analgesia during operative procedures. Its side effects include vomition, constipation, and respiratory depression. It has no significant effect on cardiac output and can be reversed by naloxone.

Oxymorphone is an opiod drug that is approximately 10 times more potent than morphine as an analgesic agent. It produces minimal respiratory depression and is usually used to augment injectable anesthetics. Barbiturate dosages can be reduced by two thirds when oxymorphone is used as a pre-anesthetic agent. Sensitivity to loud noises can be appreciable when this drug is used. Naloxone will reverse oxymorphone.

Fentanyl is an opioid drug that is approximately 250 times more potent than morphine as an analgesic agent. It has very short duration of effect, approximately 30 minutes, when administered IV or IM and it is most often given to nonhuman primates as IV boluses or continuous IV infusions. Like oxymorphone, sensitivity to loud noises is marked in unanesthetized animals. Respiratory depression, apnea, or panting can occur; thus, it is best used when animals are intubated and ventilatory support can be provided. Atropine or glycopyrrolate should be used to offset the bradycardia fentanyl produces. Naloxone will reverse fentanyl.

Buprenorphine is approximately 30 times more potent than morphine as an analgesic agent. It is widely used for post-operative analgesia in nonhuman primates because it has longer duration of effect than other opiod drugs (up to 12 hours). Because it has a slow onset of action, administration as a pre-anesthetic can ensure that pain is controlled in the early post-operative period. It can cause respiratory depression. Naloxone will reverse buprenorphine’s effects.

Aspirin is an NSAID used to control mild to moderate pain produced from inflammation. Oral and rectal suppository formulations are available. Drug absorption is affected by the size of the gastrointestinal tract and stomach emptying when oral formulations are used. Consequently, wide variations in plasma concentration can occur. Side effects include gastric and intestinal ulceration. Renal disease can occur if aspirin is used in patients with hypovolemia, congestive heart failure, or other cardiac impairment. Flavored children’s formulations may be better accepted by nonhuman primates and are available in lower concentrations that are safer to administer to small animals.

Ketorolac is an NSAID that is available as an injectable formulation. Its side effects are similar to those of aspirin. It can be used to control moderate to severe pain caused by inflammation.

Inhalant anesthetics are often used on nonhuman primates to perform operative procedures. These anesthetics are volatile liquids and can be administered with an anesthetic machine. For safety, these agents should only be administered using equipment that has been designed precisely for the specific agent, and by personnel with the knowledge to do so. Anesthetic machines and associated vaporizers require regular maintenance to ensure that these agents can be safely administered. It is necessary to have compressed oxygen available to deliver an inhalant anesthetic to the patient, and waste anesthetic gases must be collected or directly vented into nonrecirculating air exhaust systems. The equipment used for administration of these agents to humans and animals can be adapted for safe use on nonhuman primates. It is beyond the scope of this manual to describe in detail the use these systems; consultation with a veterinarian who has experience anesthetizing nonhuman primates using gaseous anesthetics is recommended for people desiring to purchase and use these systems in Old or New World species. A reference is provided for the reader needing more information.

Endotracheal intubation is routinely performed to ensure a patent airway in anesthetized animals, and to administer a gas anesthetic while preventing environmental contamination of the surrounding room with the agent. Intubation is also necessary to assist with ventilation in the event an animal should stop breathing. The technique used on nonhuman primates is similar to the techniques described elsewhere for small animals.

• Endotracheal tube; cuffed models are preferred except for very small nonhuman primates and infants; tube sizes range from 2 mm inner diameter to 8 mm for most species of nonhuman primate

• Laryngoscope with a blade long enough to reach into the pharynx of the animal; straight or curved blades may be used

• Cotton gauze or umbilical tape to secure the tube in position

• Sterile lubricant

• Cotton gauze sponges

• Syringe to fill the cuff

• Stylet to fit into the tube

• Ambu bag

• Topical anesthetic, tuberculin syringe, and catheter for its administration

• Face mask and inhalation anesthetic machine with oxygen

• Emergency drugs (see Table 4.9)

Procedure - Endotracheal intubation of nonhuman primates is similar to that of other mammalian species. The position the animal is placed in before attempting the procedure is often based on personal preference.