Precautions

It is essential that any personnel working with nonhuman primates (NHP) be well versed in primate behavior, husbandry and enrichment requirements, zoonoses and non-infectious hazards. It is important to consider, before your practice takes on NHP medicine, the philosophical, legal, and ethical implications for you, your staff, and your clients. Some strong convictions exist in the public and our veterinary community. It is important that you decide, before you engage your staff in this process, whether or not you will consider work with some taxa such as macaque species and great apes. With primates, it is highly recommend that you develop guidelines with primate owners agreeing to appropriate testing for their species before you initiate that working relationship. You need to feel comfortable that this working relationship has full disclosure from a safety standpoint for both you and your staff. Ethical issues such as primate canine extractions need to be considered before your frontline staff receives the call. Utilize policies developed by the American Veterinary Medical Association (www.avma.org) and American Association of Zoo Veterinarians (www.aazv.org) as guides for your practice. Finally, keep abreast of the legal limitations regarding the species you are being asked to evaluate. Dr. Adolf Maas provides an excellent overview in Veterinary Clinics Exotic Animal Practice of the legal implications of exotic pet practice. A rigorous program of veterinary care, as well as a well established occupational health and personnel protective equipment training program needs to be in place before any NHP is handled.

Non-Human Primate Restraint

Whenever possible, chemical restraint should be used to minimize the risk of injury and zoonotic disease to the handlers, veterinarian and NHP. The type of restraint used will vary greatly depending on the species, size, health and temperament of the NHP, the owner / caretaker, and the clinical setting. Any time a NHP is handled, personal protective equipment (PPE) such as appropriate protective clothing (i.e. TYVEK^® suit, coveralls, scrubs with long sleeves), a HEPA mask (protective against TB), latex gloves, bite gloves, and eye/face shields should be worn. Control of the arms, legs, head/ teeth and the prehensile tail (new world species) must be controlled. Restraint of animals should be both effective and as gentle as possible, with emphasis on protecting animals and handlers from injury.

A squeeze cage, where back or front wall is moveable, will restrain the primate against the bars for easy injection, and is preferable. Not many veterinary clinics have these cages available, although if a large percentage of clients own NHP as pets, they are well worth the investment. Please see resources section below for a list of some suppliers. Primates can be easily trained to transfer into crates and cages for this goal.

NHP (<12 kg) - At least one handler, plus the veterinarian, is needed for a safe manual restraint. It is recommended that the owner of the primate should not be one of the handlers. When reaching into a transport box, cage or net, it is critical to get control of the head prior to placing the animal in the proper primate restraint position. Then, the animal can be manipulated with a firm grasp to the animal from behind, just proximal to the elbows. The arms should be gently rotated so that the elbows are almost touching behind the animals back. Excessive force may result in fractures or luxations, especially in severely debilitated and undernourished animals. Once the arms have been properly restrained with one hand (while supporting the body), the ankles can then be grasped with the other hand and the legs extended until the NHP is in a stretched position.

NHP (12 - 15 kg) - At least two handlers are needed and anesthesia is highly recommended. It is very important to never underestimate the strength of these animals. Heavy leather gloves with arm extensions may be worn, although restraint may be difficult with these on and they may provide a false sense of security. Many NHP have penetrated such gloves with their teeth. The use of nets, pole syringes, grab poles and rabies poles may be sufficient to give the veterinarian time to quickly inject the NHP with a sedative or induction agents. Non-human primates are very intelligent and have been known to grab syringes with hands, feet, and tail to redirect them towards the handler or veterinarian. They have a tremendous memory and what works once, may not work again.

NHP (>15 Kg) - Unless severely debilitated, these animals should always be chemically restrained in order to prevent human injury. Training and behavioral conditioning can be used to accomplish several tasks such as EENT exam, auscultation, blood collection, and injections without anesthesia, but a thorough examination and more invasive diagnostics require chemical restraint. This can be used to your advantage if you have a client or handler you can trust to administer a sedative or immobilizing agent via hand injection. Typically, however, in a hospital or holding facility situation, remote immobilization equipment will be required for chemical immobilizations on these large primates. Many anecdotal stories have been shared of lesser and great apes catching a dart prior to injection. Know your patient and prepare for multiple scenarios.

Chemical Restraint and Anesthesia

Considerations - The species variability as well as the clinical presentation of the NHP will play a significant role in the strategy for chemical restraint including drug choices and dosages needed.

 The mental state of the animal needs to also be factored into the drug and dose choices as an excited or agitated NHP will often times require higher dose/ dosages that the trained NHP receiving a hand injection under "comfortable" conditions. Alternatively, a debilitated animal may require much less.

 The incredible size range variation in this group of animals also needs to be considered when dosing any drug. Ideally, age and weight of the individual prior to anesthesia plan development is needed for this consideration. In general, smaller and younger primates require larger doses per kilogram body weight than do larger and older animals.

 Fasting may be problematic in small primates due to hypoglycemia. Typically, callitricid species can be fasted 2-3 hours prior to anesthesia. Small to medium size primates are typically fasted 6-8 hours and all larger primates can be easily fasted for 12 hours.

 Size considerations for endotracheal (ET) tubes ranging from 300 gm marmosets to 40kg baboons or bigger also need to be accommodated. Intubation is similar to domestic species with careful consideration of laryngospasm by using topical anesthetics. Most primate species have relatively short trachea permitting accidental intubation on a unilateral bronchus and ventilating only one side. This can be check by measuring ahead of time, using short ET tubes, and ausculting all lung fields during ventilation for air movement in all fields.

 In small NHP such as marmosets, tamarinds, and smaller prosimians, hypothermia while under anesthesia can be life-threatening and should be prevented by the use of supplemental heating devices.

Premedications - The use of premedications may make anesthetic induction smoother, both from a handling point of view as well as decreasing the amount of drug needed to induce anesthesia. Commonly used pre-anesthetics include acepromazine at 0.2-1.0 mg/kg PO, SC, IM ( Boehringer Ingelheim, Vetmedica Inc. St. Joseph, MO 64506 USA), diazepam at 0.1-1.0 mg/kg PO, IM, I V ( Hospira Inc, Lake Forest, IL 60045 USA) and midazolam hydrochloride at 0.05-0.5 mg/kg PO, IM, IV (Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J. USA). In a healthy animal, the owner may give these premedications at home approximately 30-60 minutes before presentation. It must be stressed to the owner that they cannot be given in a large volume of food or liquid because of increasing the chances of regurgitation and vomiting during anesthetic induction. Atropine sulfate at 0.02 - 0.04 mg/kg IM (Vedco, Inc., 5503 Corporate Dr., St. Joseph, MO 64507 USA) or glycopyrrolate at 0.005-0.01 mg/kg IM (Fort Dodge Animal Health, Fort Dodge, Iowa 50501 USA) can be given for prevention of bradycardia and hypersalivation.

Tranquilizers and anesthetics - In small NHPs, anesthetic chamber induction may be performed. These species can be trained to transfer into an induction chamber for gas administration. It is important to remember that "stress", hyperthermia and emesis may occur. The chamber must be secured and escape- proof. Intramuscular dosing is the most practical route to use on non-human primates. This limits the choices of drugs to those that can be given in small volumes and that are not muscle toxic. Unless the NHP has been trained to accept hand-injections, some type of mechanical restraint or remote injection device must be used. Mechanical restraint may include: trained handlers, nets, squeeze cages, etc. or a pole syringe. Remote drug delivery systems can also be used effectively. These include the use of blow darts and remote injection pistols and rifle systems. Remember that dosages may vary widely depending on animals' size, age and temperament. (See Table 1 for drug listing). Below are general descriptions on the most common drug classes used.

 Ketamine hydrochloride (Fort Dodge Animal Health, Fort Dodge, Iowa 50501 USA) has traditionally been the drug of choice. It is generally safe, inexpensive, and allows for adequate restraint for minor procedures or to enable safe handling until animal can be placed on inhalant anesthesia. The dose range varies from 5-40 mg/kg IM depending on size and temperament with the larger animals (apes) getting closer to 5 mg/kg and smaller NHP (marmosets and tamarinds) getting 20 mg/kg. If the volume to be administered is large, the dose can be split up into multiple sites or a fraction of the initial dose may be enough to facilitate physical restraint and subsequent dosing. Ketamine is also available in more concentrated solutions, traditionally 200mg/ml, than the standard 100 mg/ml, from compounding pharmacies. One disadvantage of Ketamine is the lack of a reversal agent. It also has been known to cause seizures in lemurs.

 Tiletamine + zolazepam (Telazol: Fort Dodge Animal Health, Fort Dodge, Iowa 50501 USA) is licensed for use in non-human primates. Standard dosing of Telazol is 2-6 mg/kg IM. Recovery time from Telazol tends to be somewhat prolonged when compared to Ketamine and animals may be ataxic so injuries may occur during this time. There is no reversal agent for Tiletamine, but Flumazenil, (American Pharmaceutical Partners Inc. Schaumburg, IL 60173 USA) a benzodiazepine receptor antagonist (0.025-0.2 mg IV or IM every 30-60 sec until desired effect - max. dose 1 mg {human dose}) can be used to reverse the zolazepam. The short half-life of Flumazenil (approx. 1 hr) makes repeated dosing sometimes necessary.

 Opiates- primarily used as perioperative analgesics, they do produce profound respiratory depression in several species and should be used with cautious dosing in combination with other agents (i.e. benzodiazepines, alpha 2 agonists, and dissociatives). Investigations into oral administration of ultra-potent narcotics such as carfentanil have been reported in the literature with some success. Risk of accidental exposure to these dangerous narcotics is a risk that outweighs the potential benefits of this induction option. Accidental exposure kit with reversals/ antagonists and CPR certification are a necessity if this class is used.

 Alpha 2 agonists- Xylazine, Detomidine, Medetomidine and dexmedetomidine (Domosedan, Domitor and Dexdormitor, Pfizer Animal Health. Exton, PA 19341 USA) combinations have recently gained popularity in the literature for anesthesia in NHPs. Dosages are included in table 1 for xylazine, detomidine and medetomidine with dexmedetomidine being investigated and reported in the literature at half the dose/ dosage requirement. Medetomidine alone has been proven effective as a sedative-analgesic in a number of species, but has not worked well as a complete immobilizing agent in NHP. In addition to the profound sedation and analgesia seen with alpha 2-agonists such as medetomidine, significant effects on the cardiovascular system are also seen and need to be considered before this drug is chosen. Vasoconstriction with compensatory bradycardia may be seen. Reversal of alpha 2 agonists can be accomplished with drugs such as yohimbine (0.1mg/kg IM preferred, IV has anecdotally been reported to have excitatory effects in some species) or atipamezole (Antisedan: Pfizer Animal Health. Exton, PA 19341 USA) at approximately four to five times the dose of detomidine, medetomidine or dexmedetomidine (0.15- 0.3 mg IV, IM, SC) or a partial dose IV and the rest IM is an advantage of these combinations. 3 Alpha 2 + Ketamine combination for induction followed by isoflurane anesthesia has been proven to be safe and effective combination in NHPs. The oral dosing has been reported in the primary literature with variable effects and is believed to be associated with mucosal absorption rather than gastrointestinal absorption. This combination often requires supplemental drugs either via dart or hand injection such as Ketamine or zolazepam/ tiletamine. Alpha 1 + zolazepam/ tiletamine combination has been evaluated as an immobilizing agent in a variety of apes and Southeast Asian primates. This combination produced smooth inductions and complete immobilizations with minimal cardiovascular side effects.2 Medetomidine + midazolam +/- butorphanol combination has been anecdotally reported for a variety on NHPs; although, sensitivity to opiates should be considered carefully with respiratory depression as the primary concern.

Once an animal has been anesthetized, endotracheal intubation and IV catheter placement should be considered, especially for larger NHPs including great apes. It is important to remember blood borne pathogen safety guidelines whenever NHP blood / body secretions are encountered. In larger NHP- head and neck extension is needed to keep the endotracheal tube from kinking and occluding the airway and care must be taken not to move the tube past the bronchial bifurcation during head and body movements.

Analgesics: Analgesics should be routinely used whenever pain is present or anticipated. Oral dosing once the animal goes home can be used; however, it can sometimes be very difficult to medicate NHPs orally. The discriminating primate may detect even the most carefully disguised drug. There are compounding pharmacies available that will make up medications in a variety of flavors and formulations. If a procedure is scheduled enough in advance, these compounded formulations are usually the easiest way to medicate the NHP. Cutaneous pain control methods such as Fentanyl patches are generally not successful because they need to be applied prior to the procedure and non-compliance often occurs due to NHP peeling them off. Some oral analgesics include acetaminophen (5-10 mg/kg PO q 6 h); acetylsalicylic acid (5-10 mg/kg q4-6h PO); Carprofen (Rimadyl, Pfizer Animal Health. Exton, PA 19341 USA 2-4 mg/kg PO q 12-24h); ibuprofen (20 mg/kg q24h PO), and meloxicam (0.1-0.2mg/kg IM or PO q24 h). For injectable analgesics- see Table 1.

Recovery: After an anesthetic protocol has been completed and the recovery time is started- it is critical to be able to determine what and when NHPs need manual restraint during recovery for head position maintenance and when to release in an escape-proof and safe environment. This sometimes can be a challenging trial and learn decision matrix for small to medium NHPs. Easy signs for release are when they are fighting restraint again, have good head control and can potential rasp for balance within enclosure space. Large primates should not be restrained during recovery and should be placed in lateral recumbency with their collateral arm extended if at all possible and extubation should occur only after a complete swallow reflex is obtained. If the animal is a colony animal and must go back in with its group- care must be used in re-introduction, especially if animal has been out for an extended period of time or is still not fully recovered.

Resources

Primate caging and capture nets

 http://www.iacuc.arizona.edu/training/primate/rest.html

 http://www.labrepco.com/docs/Primate-Suspended-Primate-Cage.pdf

 http://lis.arc.nasa.gov/lis/Hardware_App/rahf_primate.html

 http://www.lenderking.com/primates/primates.htm

 http://www.brecinc.com/html/cage-02B.htm

 http://www.primateproducts.com/

Remote injection equipment

 http://www.daninjectusa.com/

 http://www.pneudart.com/

 http://www.telinject.com/

Table 1: Some Commonly Used Anesthetics and Analgesics in NHP1

Acknowledgement: The author would like to acknowledge Hayley Murphy, DVM for assistance with manuscript and table preparation.

References

1.  Carpenter JW. Exotic Animal Formulary. Greystone Publications. 2005; 272-274

2.  Fahlman A. Bosi EJ. Nyman GN. Immobilization of Southeast Asian Primates with Medetomidine, Zolazepam and Tiletamine, and Reversal with Atipamezole. Proc. American Assoc of Zoo Veterinarians 1999: 334.

3.  Fowler, M. Non-human Primates. 1995. Restraint and handling of wild and domestic animals, Iowa State University Press, Ames, IA. 236-246.

4.  Horne WA. Norton TM, Loomis MR. Cardiopulmonary Effects of Medetomidine-Ketamine-Isoflurane Anesthesia in the Gorilla (Gorilla gorilla) and Chimpanzee (Pan troglodytes). Proc. American Assoc of Zoo Veterinarians 1997: 140-142.

5.  Horne, WA. 2001. Primate anesthesia. Vet Clin N Amer-Exotic Animal; (2001); 4;1:239-266.

6.  Lennox, A, ed., et al. The Exotic Pet Practice, Veterinary Clinics of North America: Exotic Animal Practice, Volume 8 (3): 393-405, 475-496, 497- 530.

7.  Mitchell, M. 2007. Zoonotic diseases of exotic animals, Proceedings Central Veterinary Conference.

8.  Pye, G. 2008. Zoo medicine rounds, Veterinary Information Network (VIN).

9.  Ramer, J, Emerson, C, Paul-Murphy, J. 1998. Analgesia in non-human primates. Proc Am Assoc Zoo Vet; (1998);1998; 480.

10. West, G, Heard, D., Caulkett, N. Zoo Animal and Wildlife Immobilization and Anesthesia.