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Nonhuman Primate Anesthesia and Analgesia Guidelines I. PURPOSE This document has been designed by the ULAM veterinary staff as a guideline for tranquilization, anesthesia and analgesia of laboratory nonhuman primates. This is not intended to be an inclusive tutorial on all possible drug combinations that can be used in nonhuman primates. The following guidelines are also general recommendations and consequently have not factored in specific research-associated concerns. If you have questions about the use of anesthetics or analgesics for your particular situation or if you have questions or comments about this document, please contact the ULAM veterinary staff at [email protected] or (734) 936-1696. The ULAM Training Core at [email protected] or (734) 763-8039 can be contacted to provide training in these techniques at no charge. II. DEFINITIONS A. Special Concerns in Primate Anesthesia 1. Pre-anesthetic evaluation: a. All subjects should be in good health prior to the administration of general anesthesia. If an animal has any pre-existing medical conditions or diseases (anemia, high blood pressure, diabetes, kidney problems, etc.), please consult the ULAM veterinarians prior to the administration of any drugs. 2. Handling & Restraint: a. Keep in mind that nonhuman primates, regardless of origin, are still wild animals and will resist restraint. Direct contact with nonhuman primates without the use of chemical restraint is not recommended. Personal protective equipment should always be worn when handling nonhuman primates to help prevent the transmission of zoonotic diseases (such as herpes B) to the handler or the spread of tuberculosis (TB) to the nonhuman primate. The amount of restraint (generally chemical) and its duration should be kept to the minimum necessary to complete the procedure. All necessary equipment and reagents for the procedure should be ready prior to restraint. The use of pre-anesthetic sedatives/tranquilizers will help reduce anxiety and the subsequent doses of other agents. 3. Pre-anesthetic fasting: a. Nonhuman primates can vomit and aspirate stomach contents while under general anesthesia. To help prevent this, animals should be fasted for 12 hours prior to general anesthesia. Juveniles or small species such as marmosets, squirrel monkeys and tamarins should only be fasted 4-6 hours to help avoid hypoglycemia. Do not withhold water prior to anesthesia. In the event of an emergency, when pre-anesthetic fasting is not an option, the primate should be intubated and placed in lateral recumbency (with its body and head lying on its side). Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines III. PROCEDURES A. Vascular access: 1. Placement of an intravenous catheter allows for easy and rapid administration of fluids and drugs during the procedure. This may be a lifesaving factor if an emergency arises. For major surgery or long procedures (> 30 min.), an intravenous catheter should be placed. The cephalic or saphenous veins are most commonly employed for vascular access. For arterial sampling or direct blood pressure monitoring, the femoral artery is most commonly employed. Intramuscular injections are generally given in the thigh or back muscles (parallel to the spine). The smallest possible injection volume should be employed. B. Fluids: 1. Fluid support should be provided for major surgery or procedures lasting longer than 30 minutes. Intravenous fluids should be given at an initial rate of 5- 10ml/kg/hr for most procedures. Blood loss should be replaced with a three-fold volume of fluids (e.g.100ml blood lost is replaced with 300ml of IV fluids). Accurate administration of fluid volume is important especially for patients less than or equal to 5 kg. Use of a fluid pump and mini-drip (administration set that delivers 60 drops/ml) is recommended for these individuals. Choice of fluid should be made on case-by-case bases under veterinary consultation. C. Hypothermia: 1. Primates are prone to hypothermia during anesthesia. Animals that weigh less than 5kg, those undergoing long procedures and those given Telazol® are most at risk. Hypothermia can cause bradycardia, low cardiac output, and delay recovery from anesthesia. Serial evaluations of body temperature during anesthesia and recovery should be performed. Please refer to the Anesthesia and Sedation Monitoring Guidelines for recommendations on maintaining body temperature under anesthesia. D. Endotracheal intubation: 1. Airway control via endotracheal intubation is highly desirable during anesthesia and required in some situations where controlled ventilation is mandatory (e.g. thoracotomies). Administration of inhalation anesthetics is best accomplished via an endotracheal tube. Intubation of nonhuman primates requires some skill and practice and is best accomplished using a laryngoscope. Prior to attempting endotracheal intubation, training should be obtained through ULAM. IV. MONITORING AND RECOVERY A. Intraoperative and postoperative monitoring is of vital importance for proper patient management during anesthesia and recovery. The goals of intraoperative monitoring are to maintain adequate anesthetic depth while preserving the normal function of organ systems. Anesthetic depth may be ascertained by evaluating palpebral and corneal reflexes, jaw tone, and the absence of movement in response to painful stimuli. Reduction and/or loss of these reflexes and responses are associated with an adequate surgical depth of anesthesia. Increased respiratory rate in response to surgical stimuli is a sensitive Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines indication of inadequate depth of anesthesia. Increases in heart rate may be due to pain perception or from increased blood level of carbon dioxide, hypoxia, or hypotension. 1. Cardiovascular (CV) monitoring: a. Heart rate and rhythm, pulse quality, and capillary refill time should be evaluated at regular intervals to assess cardiovascular status. The use of an esophageal stethoscope, ECG, and blood pressure monitor can help facilitate CV monitoring. 2. Respiratory monitoring: a. Proper monitoring of the respiratory system involves quantitation of oxygenation and ventilation. For evaluating oxygenation, mucus membrane color is most commonly used, however it is a very insensitive technique. Patients may become dangerously hypoxic by the time a change in mucus membrane color (pink to blue) is noted. Increases in respiratory rate may also indicate low blood oxygen levels; however, this parameter is primarily regulated by blood levels of carbon dioxide. Normal vital signs for nonhuman primates can be found in Appendix 1. b. Pulse oximetry is a non-invasive method for continuous measurement of oxygen saturation and heart rate. However, serial arterial blood gas sampling is the gold standard for evaluating blood oxygenation. End-tidal CO2 monitors can also be used as a non-invasive measure of ventilation. V. AGENTS USED PREOPERATIVELY AND FOR CHEMICAL RESTRAINT A. The recommended dosages for all of the recommended agents are listed according to species in Tables I – IV. 1. Sedatives: a. Acepromazine • Acepromazine is a tranquilizer/sedative. Acepromazine is used as a preanesthetic and an anesthetic adjunct. It is often used in conjunction with ketamine. It can cause vasodilation and hypotension due to blockade of alpha-receptors on smooth muscle. Acepromazine should not be given with drugs that can lower the seizure threshold. b. Dexmedetomidine (Dexdomitor) • Dexmedetomidine is an alpha agonists that is used as a sedative, anesthetic and analgesics. It is similar in activity to medetomidine, but dexmedetomidine has twice the potency with the same pharmacological activity and equivalent analgesic and sedative effects. Alpha-receptor selectivity is nearly 1000 times that of xylazine. Due to its antagonism of alpha-receptors, these drugs can cause initial bradycardia, followed by hypertension. This is followed by hypotension. Lower respiratory rate and body temperature can also occur when using these drugs. If adverse reaction is observed, the effects can be reversed with atipamezole. c. Ketamine (Ketanest®, Ketaset®, Ketalar®) • Ketamine is the most common agent used for chemical restraint of nonhuman primates. It has a wide margin of safety and can be used alone or in combination with other drugs. Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines When used alone it produces immobility and some analgesia along with varying degrees of muscle contraction, tremors, and salivation. Ketamine is the agent of choice for restraint in order to safely perform clinical exams, short procedures, and diagnostic tests (TB test, phlebotomy etc.). Laryngeal, pharyngeal and corneal reflexes are preserved. Ketamine given alone is insufficient for endotracheal intubation, complete immobilization or for performing surgical procedures. When given at high doses or in susceptible individuals, seizures may occur. d. Ketamine-xylazine (Rompun®) • Ketamine-xylazine combinations provide complete immobilization, excellent muscle relaxation, analgesia sufficient for minor surgical procedures and a longer duration of action than ketamine alone. The use of these drugs together usually provides enough sedation and relaxation to enable endotracheal intubation; however, animals may still salivate profusely. Bradycardia and hypotension may occur, in particular at the high end of the xylazine dose. e. Ketamine-dexmedetomidine • Ketamine-dexmedetomidine combinations provide complete immobilization, excellent muscle relaxation, analgesia sufficient for minor surgical procedures and a longer duration of action than ketamine alone. The use of these drugs together usually provides enough sedation and relaxation to enable endotracheal intubation; however, animals may still salivate profusely. Dexmedetomidine is of the same class of drug as xylazine with a higher affinity for alpha 2 receptors, which lowers cardiovascular side effects. Bradycardia and hypotension may occur still, in particular at the high end of the dexmedetomidine dose. f. Tiletamine- zolazepam (Telazol®) • Telazol® is a combination of the dissociative anesthetic tiletamine and zolazepam, a benzodiazepine. Telazol has the advantage of providing rapid onset of action with smooth recovery. This drug is water-soluble and is given in smaller volumes than ketamine. Low doses may be used for chemical restraint. High doses can be used for minor surgical procedures and endotracheal intubation. Hypothermia may be a problem when this drug is used to induce general anesthesia. Seizures are rarely seen after Telazol administration as compared to ketamine. g. Anticholinergics (Atropine, Glycopyrrolate) • Anticholinergics block the parasympathetic nerves. Atropine or glycopyrrolate can be used as a pre-anesthetic to reduce salivation. Anticholinergics may also be used to prevent abnormal heart rhythms and slowing of the heart rate. The use of anticholinergics to prevent bradycardia in patients administered α-2 agonists such as xylazine and medetomidine is controversial. Bradycardia in these patients is in response to initial hypertension and decreased cardiac input, which is considered by many a normal physiologic response. h. Neuromuscular Blocking Agents (Pancuronium, Vecuronium) • Neuromuscular blocking agents are used in conjunction with general anesthetics to achieve greater control of muscle activity. Both drugs produce skeletal muscle relaxation and are Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines very useful when control of ventilation or muscle movement is needed (e.g. ophthalmic surgery). These agents do not have any anesthetic or analgesic properties and should only be used along with an anesthetic drug. Extreme care must be taken to ensure that the patient is at a proper level of anesthesia when using these agents. Since the ability of the animal to move is eliminated, parameters such as heart rate and blood pressure must be used to monitor anesthetic depth. These agents paralyze the diaphragm and cause respiratory arrest; therefore, the animal must be intubated and mechanically ventilated. Pancuronium lasts longer than vecuronium and produces mild increases in blood pressure and heart rate. VI. PREFERRED GENERAL ANESTHETIC AGENTS A. Inhalation Anesthesia: 1. Inhalation agents enable the anesthetist to precisely control the depth of anesthesia. They are the drugs of choice for procedures lasting longer than 30 minutes or for major surgical procedures. They can be delivered by mask or endotracheal tube, the latter being the safest and preferred method. Inhalation agents also produce reliable anesthesia in all primates. Placement of an endotracheal tube (intubation) requires the use of an injectable drug combination that produces greater degrees of jaw relaxation than can be achieved with ketamine alone. Ketamine-xylazine, Ketaminemedetomidine or Telazol® may be used for this purpose and can be given intramuscular (IM). Propofol may be used as well, but requires the placement of an intravenous catheter for delivery. When using inhalation anesthesia in primates, use of a bacterial/viral filter will help avoid potential contamination of the anesthesia machine. 2. Isoflurane (Forane®) a. Isoflurane is the most commonly used inhalation agent for all species and is considered by many to be the inhalation anesthetic of choice for nonhuman primates. Isoflurane's onset of action and recovery times are much shorter than for other inhalation agents. Other advantages of this agent are that it does not sensitize the heart to catecholamine induced arrhythmia’s and produces less myocardial depression. 3. Sevoflurane (Ultane®) a. Sevoflurane is an inhalational anesthetic similar to isoflurane.Sevoflurane has a very low blood/gas partition coefficient (0.6) allowing very rapid anesthesia induction and recovery. Because of the rapid recovery associated with sevoflurane use caution (and appropriate sedation) during the recovery phase. Sevoflurane can react with carbon dioxide absorbents to produce "compound A", a nephrotoxin, unless an oxygen flow rate of at least 1 liter per minute is used. B. Injectable Anesthetics: 1. Propofol (Diprovan®, Rapinovet®, Propoflo®) a. Propofol is a substituted phenolic drug (2,6,-diisopropylphenol) dissolved in a lipid vehicle giving it a white opaque appearance. Propofol must be given by IV injection. It has a very rapid onset of action and recoveries are very rapid and smooth. It provides good muscle relaxation for minor Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines procedures (suturing small wounds, catheter placement, MRI, CT scan, etc). It is also well suited for induction and endotracheal intubation for gas anesthesia. When used alone, it must be given by constant rate infusion or by repeated boluses if procedures longer than a few minutes are to be performed. For major or painful procedures, it should only be used in combination with an opioid. Apnea (cessation of breathing) is a common problem after IV bolus administration. This can be minimized by using a slow rate of administration, however, it is generally recommended that patients should be intubated along with its use. This drug can also produce profound hypotension. The vehicle that the drug is emulsified in readily supports microbial growth, and the entire contents of a vial must be used the same day it is opened. 2. Pentobarbital a. Pentobarbital is an injectable general anesthetic agent that for the most part has been replaced by the inhalation agents. It provides excellent muscle relaxation and analgesia sufficient for major surgical procedures. Pentobarbital does have some significant drawbacks. Severe respiratory depression occurs at high doses and depth of anesthesia is very difficult to control. Recovery from pentobarbital anesthesia can be very long. This drug is useful for neurosurgical procedures, imaging studies such as MRI, or non-survival procedures. VII. LOCAL ANESTHETICS (Lidocaine, Bupivacaine) A. Local Anesthetic Techniques 1. Local anesthesia fits the category of pre-emptive analgesia perfectly because it is usually administered prior to surgery. The duration of blockade is determined by both the agent used and to a lesser degree by the site of administration. Lidocaine has a fairly rapid onset (10-15 minutes) and short duration of action (1 to 11⁄2 hours) whereas bupivacaine has a slow onset (20-30 minutes) but longer duration of action (4 to 6 hours). The agents are often combined to provide rapid onset and long duration of effect. Not only is intra- and post-op analgesia provided by local anesthesia, but the anesthetic period is frequently stable because the lack of sensation prevents variable CNS stimulation. Aspiration of the syringe to assure the needle is not in a vessel is very important, as Lidocaine and Bupivacaine have adverse cardiovascular effects if administered systemically. Intravenous injection can result in non- resuscitatable cardiac arrest and death, so always aspirate prior to injection. VIII. ANALGESICS A. Signs of Pain: Signs of pain in nonhuman primates may include, but are not limited to, the following: • • • • • • Persistent vocalizations Restlessness Lethargy Inappetence Ungroomed hair coat Crouched posture Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines • • • • • Glassy eyes Social isolation Abnormal aggression Elevated respiratory rate Reluctance to move 1. Any procedure known to produce pain in humans or other species should be assumed to cause pain in nonhuman primates. In these instances analgesic drugs are indicated to decrease discomfort and to reduce pain associated morbidity and mortality. 2. The two most common classes of analgesic drugs used for nonhuman primates are the non-steroidal anti-inflammatory drugs (NSAIDs) and the opioids. NSAIDs are appropriate for treating mild pain or can be used in combination with opioids. For moderately to very painful procedures (thoracic, abdominal or orthopedic procedures), opioids are the analgesics of choice. B. NSAIDS: 1. Ketorolac is a potent NSAID that is available in oral and injectable form. In certain cases, its analgesic properties may be equal to or exceed those of the opiates. It has been used with good results in macaques and baboons. 2. Carprofen (Rimadyl®) a. Carprofen has overcome some of the limitations of traditional NSAIDS, and become a useful adjunct in the treatment of acute and chronic pain. Carprofen differs from other NSAIDS in that it is a weak inhibitor of cyclooxygenase activity and exerts only a weak influence on the formation of prostaglandin E2. The minimal effect on prostaglandin synthesis suggests that a spinal or central mechanism of action is responsible for carprofen's strong analgesic effects. Although it appears that carprofen may be an important adjunct for the treatment of acute post-surgical pain, by itself it is unlikely to provide adequate analgesia for moderately to severely painful animals and should not be viewed as a sole analgesic. Carprofen is available in oral and injectable form. 3. Ketoprofen (Orudis®, Oruvail®) a. Ketoprofen is a potent inhibitor of prostaglandin synthesis that is available in both injectable and oral form. Ketoprofen may be administered IV, IM, or SQ postoperatively to nonhuman primates as an alternative to carprofen. Ketoprofen should only be administered to animals with normal renal function since it may decrease renal perfusion in the presence of hypotension. 4. Long-term use of NSAIDS: Long-term use of NSAIDS has been associated with gastric ulcers and kidney disease. Consult with a ULAM veterinarian concerning repeated administration of these agents. 5. Opioids: a. Buprenorphine (Buprenex®) • Buprenorphine is an effective analgesic for mild to moderate pain. It has the advantage of a long duration of action with almost no sedation and minimal effects on heart rate and Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines respiration. One disadvantage is that it is dispensed in single use vials and for the most part can not be effectively reversed by naloxone. b. Morphine • Morphine is an inexpensive and effective opioid for use in both Old World and New World primates. It can be administered SQ, IM, by IV drip, and as an epidural. It will, however, produce dose dependent sedation and decreases in heart rate and respiratory rate. These effects may be more pronounced in New World monkeys. c. Oxymorphone • Oxymorphone is an alternative to morphine and has a longer duration of action. It has been reported to cause less respiratory depression than morphine. Some authors consider it to be the opioid of choice for nonhuman primates. Oxymorphone will produce dose dependent sedation and decreases in heart rate. It is also considerably more expensive than the other opioids. d. Tramadol (Ultram®, Ultram ER®) • Tramadol is a synthetic opoid which also inhibits serotonin and norepinephrine. Tramadol is useful for mild to moderate pain and also can be used for cough. Tramadol is available only in oral form in the United States. e. Opioid use in marmosets • Anecdotal evidence suggests that opioid use may cause severe respiratory depression in common marmosets (Callithrix jaccus). Avoid administration of opioids prior to or during anesthesia or sedation. Post-operative administration of opioids following recovery of spontaneous ventilation and voluntary movement is acceptable. IX. REVERSAL AGENTS A. Naloxone (Narcan®) 1. Naloxone is an opioid antagonist that is used to reverse the effects of morphine, oxymorphone, or fentanyl. It rapidly and effectively reverses opioid sedation, respiratory depression, and bradycardia. Naloxone can be given IV or IM. It should be noted that naloxone will also eliminate the analgesic effects of opioids and its duration of action may be shorter than the opioid it is being used to reverse. Careful monitoring and redosing may be needed if the animal begins to relapse as a result of this difference in duration of action. B. Yohimbine 1. Yohimbine is used to reverse the action of xylazine under similar circumstances as indicated for naloxone. In general, only one dose of yohimbine (0.1 mg/kg) is need to treat xylazine related problems. C. Atipamezole(Antisedan®): 1. Atipamezole is 200 to 300 times more selective for both α 2 and α 1 sites than yohimbine. It is superior to other clinically available compounds. Atipamezole can be used to reverse Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines dexmedetomidine and xylazine. Severe hypotension and tachycardia can occur following rapid IV injection. This can be prevented by giving the agent IM or very slowly IV. Atipamezole is produced at a strength that is more potent than dexmedetomidine, however the manufacturer has made it so that you give the same milliliter dosage to reverse the effects of the agonist. Example: If medetomidine is given IM 0.4mls, atipamezole 0.4mls IM reverses medetomidine. D. Flumazenil 1. Flumazenil is a benzodiazepine receptor antagonist that can be used to reverse diazepam and zolazepam. In general, only one dose of flumazenil is necessary to reverse benzodiazepine related problems. APPENDIX 1 Normal Vital Signs in Nonhuman Primates Species Rectal Temp (°F) Respiratory Rate † Heart Rate ‡ Callithrix jaccus Common marmoset 97 – 102.5 20 - 50 240 - 350 Macaca fasicularis Java/Cynomolgus 97 – 100.4 32 - 44 107 - 215 Macaca fuscata Japanese/Snow 175 - 253 Macaca mulatta Rhesus 98 - 102 10 - 25 150 - 220 Pan troglodytes 98 - 100 35 - 60 80 - 150 Pappio spp. Baboon 98 - 102 29 80 - 200 Saimiri sciureus Squirrel monkey 98 - 101 20 - 50 200 - 300 † 10 – 20% reduction in rates for anesthetized patients is acceptable ‡ low end of range is acceptable for anesthetized patients Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines Table I: Drugs & Doses for Macaca spp. Drug Anticholinergics Atropine Dose (mg/kg) & Route Approximate Duration 0.02 – 0.04 IM, IV, SC 20 – 30 min Glycopyrrolate 0.004 – 0.08 IM 45 – 60 min Injectable Agents Acepromazine 0.1 – 0.5 IV, IM 20 – 30 min 5 – 20 IM 10 – 20 min 4 IM 0.04 IM 20 – 30 min Ketamine Ketamine + Acepromazine Ketamine + dexmedetomidine 5 – 20 0.005 – 0.0075 IM 30 – 120 min Ketamine 7 IM + Xylazine 0.6 IM 30 – 120 min 2 – 6 IM 45 – 60 min Propofol* (induction) 2 – 5 IV bolus slowly 5 – 10 min Propofol* (CRI) Loading dose: 2 – 5 IV bolus slowly Infusion: 0.3 – 0.4 mg/kg/min Pentobarbital a 5 – 15 IV Telazol ® (Tiletamine/Zolazopam) Neuromuscular blockers b Pancuronium Vecuronium 0.08 – 0.1 IV 0.04 – 0.06 IV Inhalation Anesthestics a Isoflurane Sevoflurane 3 – 4% induction 1 – 3% maintenance 3 – 5% induction 1.5 – 3.5% maintenance Approved: 10/18/2012, Version: 2 30 – 60 min Nonhuman Primate Anesthesia and Analgesia Guidelines Local Anesthetics Lidocaine ≤0.4 – 0.8 local infusion 1 to 1 ½ hours ≤4 local infusion 4 – 6 hours Ketorolac 15 – 30 IM 15 – 30mg/animal initially; then 10 – 15mg/animal q8h Carprofen 2 PO, SQ, IM 12 hours Ketoprofen 2 IM, IV, SQ 24 hours 1 – 2 IM, SQ 2 – 4 hours 0.15 IM 4 – 6 hours 0.01 – 0.03 IM 6 – 8 hours 2 – 4 PO 12 hours Bupivacaine NSAIDs Opioids Morphine Oxymorphone Buprenorphine c Tramadol Reversal Agents Atipamizole (Antisedan) Dexmedetomidine reversal Flumazenil Diazapam/zolazopam reversal 0.15 – 0.3 mg/kg IM (same volume as used for dexmedetomidine) 0.02 mg/kg IV, IM Opioid Antagonist Nalaxone 0.1 – 0.2 IV, IM; PRN Opioid reversal a Intubation indicated when using this agent 1 -2 hours b Intubation and assisted ventilation mandatory when using this agent c Preemptive analgesia, particularly opiates like buprenorphine, can reduce the dose of anesthetics required for surgical anesthesia and increase the respiratory depression associated with anesthetics. When pre-emptive analgesia is used, consider reducing the dose of anesthetic (whether inhalant or injectable) to the low end of the recommended range. Anesthetic depth must be carefully monitored and drug doses may need to be titrated to maintain appropriate levels. With new projects, sexes, strains or anesthetic analgesic combinations, assess a subset of animals before expanding to use in a larger cohort. PRN = as needed Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines Table II: Drugs & Doses for Papio spp. Drug Anticholinergics Atropine Dose (mg/kg) & Route Approximate Duration 0.02 – 0.04 IM 20 – 30 min Glycopyrrolate 0.005 – 0.01 IM 45 – 60 min Injectable Agents Ketamine 10 – 15 IM 15 – 30 min Ketamine + Diazepam 7 – 10 IM 0.2 – 0.35 IM Telazol ® 4 – 10 IM Propofol a 2.0 – 4.0 IV bolus slowly for induction Continuous infusion 45 – 60 min 0.4 – 0.6 mg/kg/min Neuromuscular blockers b Pancuronium 0.08 – 0.1 IV Vecuronium 0.04 – 0.06 IV Inhalation Anesthestics a Isoflurane 1 MAC = 1.28% Analgesics Ketorolac Opioids Morphine 15 – 30 IM 1 – 2 IM, SQ 2 -4 hours Oxymorphone 0.15 IM 4 – 6 hours Buprenorphine c 0.01 IM 6 – 8 hours Opioid Antagonist Nalaxone 0.1 – 0.2 IV, IM; PRN a Intubation indicated when using this agent 1 – 2 hours b Intubation and assisted ventilation mandatory when using this agent c Preemptive analgesia, particularly opiates like buprenorphine, can reduce the dose of anesthetics required for surgical anesthesia and increase the respiratory depression associated with anesthetics. Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines When pre-emptive analgesia is used, consider reducing the dose of anesthetic (whether inhalant or injectable) to the low end of the recommended range. Anesthetic depth must be carefully monitored and drug doses may need to be titrated to maintain appropriate levels. With new projects, sexes, strains or anesthetic analgesic combinations, assess a subset of animals before expanding to use in a larger cohort. PRN = as needed Table III: Drugs & Doses for Saimiri sciureus Drug Injectable Agents Ketamine Dose (mg/kg) & Route Approximate Duration 10 – 30 IM 15 – 30 min Ketamine + Xylazine 10 – 20 IM 0.5 – 1.0 IM Telazol ® 5 – 10 IM Inhalation Anesthestics Isoflurane* 1 – 3% Opioids Morphine 1 – 2 IM, SQ 2–4 Oxymorphone 0.075 IM 4–6 Buprenorphine c 0.015 IM 6–8 Opioid Antagonist Nalaxone 0.1 – 0.2 IV, IM a Intubation indicated when using this agent 1 – 2 hours b Intubation and assisted ventilation mandatory when using this agent c Preemptive analgesia, particularly opiates like buprenorphine, can reduce the dose of anesthetics required for surgical anesthesia and increase the respiratory depression associated with anesthetics. When pre-emptive analgesia is used, consider reducing the dose of anesthetic (whether inhalant or injectable) to the low end of the recommended range. Anesthetic depth must be carefully monitored and drug doses may need to be titrated to maintain appropriate levels. With new projects, sexes, strains or anesthetic analgesic combinations, assess a subset of animals before expanding to use in a larger cohort. PRN = as needed Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines Table IV: Drugs & Doses for Callithrix jacchus Drug Injectable Agents Atropine Dose (mg/kg) & Route Approximate Duration 0.04 IM, SQ Ketamine 15 – 20 IM Ketamine + Xylazine 15 – 20 IM 1.0 – 1.5 IM Telazol ® 5 IM 15 – 30 min 15 min Inhalation Anesthestics Isoflurane a 1 – 3% Opioids b,c Oxymorphone 0.075 IM 4 – 6 hours Butorphanol 0.02 SQ 6 hours 0.005 – 0.1 IM 6 – 8 hours Buprenorphine Opioid Antagonist a Nalaxone 0.1 – 0.2 IV, PRN Intubation indicated when using this agent 1 – 2 hours b Use caution in marmosets. May cause severe respiratory depression. See Section VII.B.5.e. c Preemptive analgesia, particularly opiates like buprenorphine, can reduce the dose of anesthetics required for surgical anesthesia and increase the respiratory depression associated with anesthetics. When pre-emptive analgesia is used, consider reducing the dose of anesthetic (whether inhalant or injectable) to the low end of the recommended range. Anesthetic depth must be carefully monitored and drug doses may need to be titrated to maintain appropriate levels. With new projects, sexes, strains or anesthetic analgesic combinations, assess a subset of animals before expanding to use in a larger cohort. PRN = as needed. X. EMERGENCY RESUSCITATION A. In the event of cardiopulmonary arrest, contact the ULAM Veterinary staff at 936-1037 or 764-0277. These instructions are provided as a guideline for emergency treatment prior to the arrival of ULAM Veterinary staff. Follow the “ABCs” (airway, breathing, cardiovascular support, drugs) for basic CPR. B. The most important procedure is to ventilate the patient. Establishing control of the airway and breathing should be the first priority, do nothing else first!!! Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines 1. If the patient is not already intubated place an endotracheal tube. If an endotracheal tube is not available use a face mask to ventilate. 2. Ventilate with 100% O 2 at a rate of 1 breath every 5 seconds. If using inhalant agents make sure the vaporizer is turned off. 3. After establishing control of ventilation, start regular strong chest compressions (at least 1 per second). It is not necessary to coordinate compressions with ventilation. Rapid infusion of IV fluids should be started to support perfusion. 4. If no heartbeat can be heard or no pulses felt, then epinephrine should be given IV (see chart below). Reversal drugs should be given if opioids or xylazine have been used. Dopram® may be given to stimulate respiration if spontaneous breathing is not noted (see chart below). C. Have emergency drugs and instruments in the surgery suite ready for use. Dose in Milliliters Body Weight Kg Drug Concentration (Route) 2.5 5.0 7.5 10 12.5 14.0 Epinephrine 1:1000 (IV, IM, IT) 0.25 0.5 0.75 1.0 1.25 1.4 Atropine 0.54 mg/ml (IV, IM) 0.15 0.25 0.4 0.5 0.6 0.7 Naloxone 0.4 mg/ml (IV, IM) 0.6 1.25 2.0 2.5 3.0 3.5 Yohimbine 2 mg/ml (IV) 0.13 0.25 0.38 0.5 0.60 0.70 Dopram ® 20 mg/ml (IV) .25 0.5 .75 1.0 1.25 1.4 XI. REFERENCES • APV Primate Formulary http://www.primatevets.org/Formulary.xls • Flecknell, P. (1996) Laboratory Animal Anesthesia, Second Edition, Academic Press, Ltd., London. • Flecknell PA and Waterman-Pearson A. Pain Management in Animals. W.B. Saunders, Philadelphia, PA. 2002. • Fox JG, Anderson LC, Loew FM, Quimby FW eds. Laboratory Animal Medicine 2nd Ed. Academic Press, London England, 2002. • Gaynor J, Muir W, Handbook of Veterinary Pain Management, Mosby, St. Louis Missouri, 2002. • Hawk, C. et al. (2005) Formulary for Laboratory Animals, Third Edition, Blackwell Publishing, Ames, Iowa. • Hrapkiewicz K, Medina L, Holmes D, Clinical Laboratory Animal Medicine 2nd ed. Iowa Sate University Press, Ames, Iowa, 1998. • Plumb, DC. (2002). Veterinary Drug Handbook Iowa State University Press, Ames, Iowa. Approved: 10/18/2012, Version: 2 Nonhuman Primate Anesthesia and Analgesia Guidelines • Popilskis, S. Kohn, D. (1997). Anesthesia and Analgesia in Dogs and Nonhuman Primates. In Anesthesia and Analgesia in Laboratory Animals (D.F. Kohn, S.K. Wixson, W.J. White, and G.J. Benson, eds.), pp. 233-253. Academic Press, San Diego, California. • Primate Medicine Department, California National Primate Research Center, University of California, Davis. • Swindle MM, Vogler GA, Fulton LK, Marini RP, Popilskis S. (2002). Preanesthesia, Anesthesia, Analgesia, and Euthanasia. In Laboratory Animal Medicine 2nd Edition (JG Approved: 10/18/2012, Version: 2