Great ape veterinary care often requires the use of general anesthesia to insure patient and caregiver safety. Anesthetic protocols utilized in great apes have both similarities and differences from those used in domesticated species, as well as those used in human medicine. In addition, some unique anatomical and frequently encountered disease states may pose an increased challenge to the veterinarian when working with these animals.
General anesthesia in great apes is usually needed to accomplish thorough physical examinations, invasive procedures, complicated diagnostics and treatments, surgeries and dental care. Anesthesia carries inherent risks and the clinician must balance the risk of anesthesia with the benefit of improved diagnostics and treatment options for these large and powerful animals. There are a number of commercially available anesthetics that may be used alone, or in combination, to induce and maintain general anesthesia in great apes. Having a complete understanding of the animals’ unique anatomy and physiology, paired with the proper anesthetics, can minimize the risks of anesthesia, especially when dealing with compromised individuals.
Induction of Anesthesia
Anesthetic inductions that minimize stress (e.g., hand-injection of induction agents rather than darting, when possible) are preferred, and all apes should be held off of food for 12–24 hr prior to anesthesia (realizing that this change of routine may make patients wary of veterinarians and staff). If hand-injections are not feasible, a remote drug delivery system can be used to deliver the anesthetic induction drugs intramuscularly. Other factors to discuss prior to anesthesia include animal and personnel considerations. Animal considerations include factors such as the safety of enclosures where anesthesia will be induced, method of induction, alternate approaches for induction, ability to separate animals. Personnel considerations include the safety of induction protocol and area, prediction of dart trajectory and clearance of personnel and what steps would need to occur if there were an accidental human drug exposure or injury. Also remember to assure that there are adequate amounts of induction drug and supplemental dosing available and review prior anesthetic records. Assuring clear exits and paths to work area appropriate means for transport following induction, adequate preparation for anesthetic emergencies and emergency response procedures in the event of an animal awakening/escape during transport are all also vital to complete planning for anesthetic events in great apes.
A major concern during the anesthesia of great apes is the incidence of hypoxemia. Maintenance of airways, especially in animals without endotrachael intubation and during the recovery phase of anesthesia, can be difficult- particularly in mature male gorillas and orangutans due to their large size, heavy neck musculature, and the sagittal crest. Hypoventilation may occur due to excessive ventroflexion of the head and subsequent airway occlusion, or secondary to large, gas filled intestines and abdominal pressure on the lungs. Positioning the apes on their sides or propping their upper bodies up at a slight angle if in dorsal recumbency with head and neck extended can help alleviate these issues. There is a tendency for these animals to collapse their chins towards their chests when recovering and this can result in a blocked airway. To avoid this, extubation should occur as far into the recovery period as possible and the animals should be placed in lateral recumbency with their down arm extended cranially and head extended.
There are a number of possible causes of hypoxemia in an anesthetized animal. In larger apes, atelectasis (focal areas of alveolar collapse) is a concern and may result from the immobilization itself, or from pressure from the large gastrointestinal tract on the lungs. It seems that pressure from the gastrointestinal tract is most notable when animals are in dorsal recumbency, and switching to a lateral position may help to alleviate some compression of the lungs. Obesity can also result in a decrease in functional reserve capacity or airway obstruction, and obese animals must have an airway secured as soon as possible following anesthetic induction. Hypoventilation as a result of anesthetic drugs may result in hypoxemia, and the provision of supplemental oxygen, whether via endotracheal tube or nasal cannulae, is recommended, even if inhalant anesthetics are not used. Dissociative anesthetics generally maintain respiratory rate, although tidal volumes may be decreased, and the respiratory pattern may be altered (apneustic breathing has been described following ketamine). Potent opioids are the drugs that are most commonly associated with respiratory depression, and this effect may be magnified in the presence of other anesthetic agents. The inhalant anesthetics (isoflurane, sevoflurane) may also contribute to hypoventilation, however if these agents are delivered in 100% oxygen, hypoxemia is unlikely. Monitoring using a pulse oximeter is an important way that blood oxygenation can be monitored, and it is recommended that a pulse oximeter is available for all immobilizations for this reason.
In addition to aspects of anesthesia that may result in hypoxemia, the anesthetist must anticipate anatomical features that may predispose to hypoxemia in the great apes. Compared to other veterinary species, the trachea of the great apes is shorter, and long endotracheal tubes can easily pass the carina and result in one-lung ventilation. With only one lung intubated, both hypoxemia and hypoventilation may result, as atelectasis proceeds in the unventilated lung. Following intubation, the anesthetist should auscult both hemithoraces to verify that breath sounds are heard on each side (see below for more details).
The relatively long arms of the great apes require attention during anesthesia to make sure that they are not placed in a manner that will create strain or pressure points. In larger apes, the hands may be loosely tied together to prevent one arm from falling off of the procedure table, or they may be rested on the thighs. The forearm or upper arm may also be used for non-invasive blood pressure measurement.
Hypothermia, hyperthermia, pressure necrosis and potential nerve damage to peripheral limbs, and thermal burns from heating sources are all a risk in anesthetized great apes and should be avoided. Recovery on padded or heavily bedded surfaces is preferable. Care should be taken to lubricate the eyes well with sterile lubricating ointments before recovery on bedding to try to avoid corneal abrasions.
Intubation can occur once the ape is sedate enough to have slack jaw tone. Face masks and supplemental gas anesthetic delivery to attain this level of relaxation is sometimes required and it is important to monitor the animal closely for signs of regurgitation and aspiration during this phase of induction. When using injectable drugs alone, without intubation, supplemental oxygen supplied via a facemask or intra-nasally via an oxygen line will improve oxygenation.
Intubation can generally be performed with the ape in either in lateral or dorsal recumbency with the head extended to straighten the airway, and assistance in opening of the mouth and retraction of the tongue can make intubation easier.
A long, curved laryngoscope and an airway exchange catheter can make intubation easier, especially in cases where the animal is regurgitating or when the animal has excessive laryngeal tissue, as is sometimes the case in large male orangutans and gorillas. Laryngeal spasms can occur in apes so the use of topical local anesthetic sprays may aid intubation.
In general, cuffed endotracheal tubes with an inner diameter ranging from 6 mm to 11 mm are appropriate for apes, depending on individual sizes. As mentioned previously, great apes have shorter tracheas than would be expected and it is easy to intubate a main- stem bronchus if not careful. Auscultation of all lung fields using positive pressure ventilation and/or thoracic radiographs should be used to confirm tube placement. If pulse oximetry readings are low during gas anesthesia in an intubated animal, withdrawal of the endotracheal tube by a few centimeters may be enough to return the blood oxygen saturation to normal. Cuffed endotrachael tubes should be used and reinforced endotrachael tubes with extended lengths work well in the larger animals. Either a straight long (14–18 cm) Wisconsin laryngoscope blade or a large (#5 or larger) mackintosh laryngoscope blade may be used to aid in intubation, the latter possibly more helpful if intubation will occur with the ape in dorsal recumbency. If anesthesia is not adequate for intubation (manifested by swallowing, arm movement, or retraction of the tongue), additional injectable anesthesia (generally ketamine) can be given, or inhalant anesthetics may be provided by mask until the patient has relaxed.
The great apes are also prone to laryngospasm which can complicate endotracheal intubation and delay oxygenation and ventilation. Laryngospasm may occur following extubation and all patients should be monitored closely during recovery, with adequate anesthetic drugs available to re-induce anesthesia if necessary. When performing direct laryngoscopy, it is important to avoid direct contact of the laryngoscope blade with the epiglottis or aretenoids. Placing the tip of the blade in the valecula, at the base of the tongue, will allow the anesthetist to push down on the tongue, which will pull the epiglottis forward for a good view of the aretenoid cartilages. Lidocaine (maximum of 2 mg/kg) may be sprayed onto the aretynoids and may decrease laryngospasm during intubation. If bronchospasm occurs, the anesthetist may appreciate a distinct difficulty in ventilating for the patient, and hypoxemia and hypoventilation may occur.
Terbutaline (0.05 mg/kg IV or IM) may be used to treat bronchoconstriction, but may cause transient tachycardia. Laryngospasm can also result from aspiration of gastric contents as a result of emesis during induction.
The anesthetist should have many sizes of endotracheal tube available (usually at least endotracheal tubes that are one size smaller, and one larger, than the anticipated size). An extremely helpful tool is a small stylette or airway exchange catheter that may be placed between the aretynoids during difficult intubations and serve as a guide for endotracheal intubation by threading the end of the stylette through the Murphy eye of the endotracheal tube. Airway exchange catheters in particular (e.g., as manufactured by Cook Medical, Bloomington, IN) may be helpful in large male apes that may have large amounts of redundant oropharyngeal mucosa. Large male orangutans in particular may have elongated soft palates, and with a mobile larynx and excessive perilaryngeal mucosal tissue, can present a difficult intubation. Non-cardiogenic pulmonary edema has been reported in a male orangutan, believed to have been secondary to airway obstruction during anesthetic induction.1 The airway exchange catheters also can be attached to an anesthetic circuit and can be used to provide oxygen while intubation is proceeding. Prior to intubation, and following extubation, extension of the chin and neck may be necessary to allow maintenance of a patent airway. The chin should be extended until respirations are quiet and regular, and animals should be recovered in lateral recumbency to allow saliva to drain.
Mature orangutans have large air sacs, which connect directly to the trachea. Due to the propensity of orangutans to have extensive air sac infections, securing the airway with a cuffed endotrachael tube is essential in these animals when trying to prevent aspiration of infected materials. If an air sac infection is suspected or confirmed, the airway should be secured as soon as possible following anesthetic induction (even in the cage where the animal was immobilized) to prevent aspiration of air sac contents into the lungs. If the laryngeal air sac contains “fluid” secretions, these animals are at increased risk for aspiration of the fluid via the ostia which connect the air sacs to the trachea and the anesthesiologist should be prepared to suction, drain the airsac, and/or maintain upright positioning until intubation. Depending on the circumstances of the infection, the orangutan may be kept in a seated position until intubation can be achieved, with the hope that backflow of air sac secretions will be minimized. Other secretions such as saliva may pool in the oropharynx, especially with anesthesia using dissociative agents. Long sponge forceps with gauze or a suction device with Yankauer tip should be available to clear the airway if necessary.
In general, it is convenient to obtain intravenous (IV) access during long procedures. An IV catheter will allow administration of intravenous fluids, as well as provide an easy route for administration of additional anesthetics or other medications. The saphenous veins are usually visible on the posterior aspect of the calf, and the cephalic veins are usually easy to identify and support intravenous catheterization. For monitoring of direct blood pressure, or for arterial blood gas analysis, the metatarsal artery is easily accessed on the dorsal aspect of the hind limbs. The femoral artery is also easily located in the inguinal area, but hemostasis of this artery following venipuncture may be more challenging than the metatarsal artery, which may be bandaged following catheter or needle removal.
Sedation and Anesthesia
Pharmacologic agents used for the sedation and anesthesia of the great apes can roughly be divided into the general classes: pre-anesthetic anxiolytics, induction agents and anesthetics. In several instances, especially during short procedures, many of these agents may also serve duel functions.
Preanesthetic Medications Anxiolytics
Anxiolytic agents are not widely used as preanesthetic agents in primates. Benzodiazepines are GABAA agonists and provide some degree of sedation. This sedation is not enough to allow safe handling of larger primates. Therefore, the benzodiazepines are used primarily in combination with the cyclohexamines to smooth the induction of anesthesia with these drugs. Telazol, a combination of the benzodiazepine zolazepam and the cyclohexamine tiletamine, is a frequently used induction agent. Miller et al. reported that oral administration of detomidine (0.5 mg/kg) and ketamine (10mg/kg) reduced the stress of sedation and reduced the reaction of six lowland gorillas to darting with no screaming or charging.2
Opioids are used extensively in primate anesthesia to control pain. It typically is used intra- and post-operatively, but has been studied for use as a pre-operative sedative. Kearns et al reported the use of oral carfentanil alone and in combination with droperidol for induction of anesthesia. 3 Complete anesthetic inductions were achieved in 20 minutes, however, all apes showed respiratory depression and cyanosis. In human pediatric populations, using oral opiods causes a high incidence of nausea and vomiting and this may also be a risk in the great apes when these agents are used. This has been seen in one institution using oral fentanyl, and the increased risk of aspiration is a factor to be considered.
Alpha2 Agonists produce sedation and analgesia by presynaptically inhibiting the release of noradrenergic and serotonergic pathways of the brain and spinal cord. The most potent and selective of the Alpha2 Agonists is medetomidine. In the humans the D- enantiomer, dexmedetomidine, provides excellent sedation. Dexmedetomidine may be used in conjunction with local anesthetics for human craniotomies where patients need to be able to respond to commands. Its use in the great apes has had varied levels of success and is predominately used as an adjunct to ketamine for induction of anesthesia.
Induction Agents: Ketamine
Ketamine is often used as both a chemical restraint agent or as an induction agent. It has a wide safety margin and has been given in doses ranging from 0.5 to 20 mg/kg. In the great apes the dose range is usually in the 5 to 15mg/kg range. Ketamine can be administered IV, IM, PO or rectally. Ketamine is an NMDA receptor agonist in the thalamoneocortical and limbic systems. It produces a dissociated anesthetic state. Ketamine can increase heart rate, cardiac output and mean arterial pressure. In addition, it can cause elevated ICP and thus should be avoided in cases with elevated ICP. A disadvantage of Ketamine is that it produces profound salivation. This can be attenuated by the anticholinergic drug gylcopyrrolate.
A common drug combination for induction of anesthesia is the sedative Telazol and Ketamine. The combination reduces the amount of Ketamine needed for induction (telazol 2–4 mg/kg and ketamine 1–3 mg/kg). This combination produces a reliable smooth induction, stable cardiopulmonary function and good muscle relaxation.
The combination of ketamine and medetomidine is more controversial. Horne, et al. compared the effects of 30–40 mcg/kg medetomidine and either ketamine (2 mg/kg) or telazol (1.25 mg/kg) in chimpanzees. 4 The authors found that both combinations produced sedation within 2–5 minutes and light anesthesia within 3–15 minutes. The medetomidine/ketamine combination produced a more rapid emergence and return of normal behavior than the medetomidine/telazol combination. Medetomidine caused a transient hypertension that usually resolved in about 15 minutes. In contrast to the report by Horne, et al., other reports have shown an unreliable depth of anesthesia and spontaneous arousal with the use of medetomidine.
As noted previously Telazol is a 1:1 combination to the cyclohexamine, tiletamine and the benzodiazepine, zolazapam and has been used in many great apes.5 It can be used alone or in combination with ketamine and / or medetomidine. The usual dose ranges in apes varies from 1.5–6 mg/kg IM. Telazol typically produces a smooth and rapid induction and stable respiratory and cardiac conditions under anesthesia. Prolonged anesthetic recoveries have been reported.
Propofol is an alkylphenol dissolved in a lipid solution. Propofol is a sedative hypnotic that produces sedation as a GABA agonist in the CNS. Propofol is ultra short-acting due to its metabolism by the P450 enzymes throughout the body and is metabolized nearly ten times more rapidly than thiopental. Propofol is a potent vasodilator and can directly decrease cardiac contractility, which can result in hypotension. In addition, it is a potent respiratory depressant and can produce apnea. Propofol can be used for both induction of anesthesia and for maintenance of anesthesia. Interestingly, the author’s experience has been that the dose of propofol needed to maintain anesthesia in the great apes is 5-10 times less that in humans.
Maintenance of Anesthesia
Anesthesia can be maintained either through inhalational agents or through intravenous medications. Considerations such as duration of anesthetic event, what needs to occur during anesthetic event (painful procedures, high risk, etc.), transport of animals, may all influence the choices when deciding how to maintain anesthesia. In cases where the ape needs to be transported, total intravenous anesthesia (TIVA) may be the method of choice.
All the common inhalational anesthetics have been used in primates. Isoflurane has traditionally been the preferred agent. Halothane is no longer produced in the U.S. for human use. Sevoflurane has almost completely replaced halothane and isoflurane for use in humans. The potency of inhalational anesthetics is measured in minimal alveolar concentration (MAC), which is the minimal concentration required to prevent movement to noxious stimulus in 50% of subjects. Sevoflurane is less potent than isoflurane. Its MAC in great apes is around 2.0% compared to 1.2% for isoflurane. The solubility of sevoflurane is less than that of isoflurane. Therefore, the onset and recovery from sevoflurane should theoretically be faster with sevoflurane. Sevoflurane and isoflurane have minimal effects on cardiac function, but can cause dose dependent reduction in systemic vascular resistance (SVR).
As noted earlier, propofol can be used for maintenance of anesthesia in primates. In humans, the usual dose for maintenance of anesthesia is 150–250 mcg/kg/min, whereas in the authors experience anesthesia can be maintained in the great apes with doses as low as 25 mcg/kg/min. It has been shown that propofol alone has no significant analgesic properties and therefore should be used in conjunction other drugs to reduce the physiologic response to pain.
As stated earlier opioids are often used with either inhalational or intravenous anesthetics to reduce pain associated with surgical stimulation. Opioids have minimal effects on cardiac contractility even at very high concentrations. Use of opioids lowers the MAC requirement for inhalational anesthetics.
Morphine is one of the most commonly used analgesics. It produces analgesia and sedation. Studies have revealed a myriad of opiate receptors in the central nervous system. Specific receptors are implicated in the various effects and side effects of morphine.
Fentanyl is approximately 100 times more potent than morphine. It is much more lipid soluble and crosses the blood brain barrier. It can be given in low doses (1–2 mcg/kg) for analgesia as an adjunct to general anesthesia or at high doses (50–150 mcg/kg) as a sole anesthetic. Even at large doses fentanyl has minimal effects on cardiac output.
Novel Drug Use in the Great Apes
The author’s experiences at the Fort Worth Zoo with anesthetizing the great apes have shown the apes to be extremely sensitive to anesthetic agents. They seem to be particularly prone to hypotension both with inhalational and intravenous drugs. As a response to this it has become this author’s practice to routinely start an infusion Dopamine. Dopamine stimulates dopaminergic, alpha and beta adrenergic receptors. Doses of 2–10 mcg/kg/min have an inotropic effect, increasing cardiac contractility. This can significant improve blood pressures during surgery.
In addition to using inotropic agents, the author also routinely uses the non-depolarizing muscle relaxant cis-atracurium. Cis-atracurium competitively inhibits acetylcholine at the motor end-plate in muscle. It is the relaxant of choice for subjects with hepatic or renal dysfunction because it is eliminated by hydrolysis and Hoffman degradation. Using cis-atracurium allows the apes to be maintained at a lower depth of anesthesia without them moving. This is particularly helpful in apes who are hypovolemic as it reduces the cardiac effects produced by high concentrations of anesthetics.
Finally, at the Fort Worth Zoo the author has recently employed the use of the ultra-short acting opioid remifentanil. Remifentanil has a rapid onset and a half-life of 3-6 minutes. Because of the ultra-short half-life remifentanil is administered as a continuous infusion. It has the same potency as fentanyl and is easily titrated for effect.
There is a significant amount of active research into the incidence and causes of cardiac disease in the great apes. What is known is that affected animals develop systolic cardiac dysfunction that can progress to congestive heart failure, and may cause clinical signs such as exercise intolerance, lethargy, and tachypnea. In apes with suspected cardiac disease that require anesthesia, medetomidine decreases cardiac output by increasing cardiac afterload through intense peripheral vasoconstriction. Even though dissociative agents can cause tachycardia and mild decreases in cardiac output, they are probably the safest drugs to use as a basis for an anesthetic protocol for apes with cardiac disease, from the perspective of both the handlers and the ape. If a cardiac exam will be performed during the anesthetic, an anesthetic protocol should be used that will allow comparison to previous exams. In general, telazol (3–4 mg/kg IM) or ketamine (6-10 mg/kg) should allow safe initial immobilization, and apes can be subsequently maintained on an inhalant anesthetic protocol for the remainder of the exam, although this may not always be necessary (and will also affect the echocardiographic exam). Inhalant anesthetics can cause hypotension due to vasodilation, but intravenous fluids should be used sparingly if at all in apes with cardiac disease to prevent volume overload.
Much as in other animals, anesthesia for dental prophylaxis and surgery can be maintained using inhalant anesthesia, but may be supplemented by dental blocks which will result in a smoother, more reliable anesthesia and provide some analgesia following the procedure. In general, lidocaine (a total of 2–4 mg/kg for all blocks) is preferred to bupivacaine both to limit possible toxicity, and because it is relative short acting, preventing self-trauma from prolonged loss of sensation.
Ophthalmologic surgery may require the use of neuromuscular blocking agents to maintain a central eye position to allow intraocular surgery. The use of all neuromuscular blocking agents must be monitored using a nerve stimulator, and this therapy may be reversed at the end of the procedure if the effects of the drug are still present. The author prefers intermittent boluses of cis-atracurium to maintain eye position due to a short duration of action and rapid breakdown by Hoffman degradation. Frequently, smaller doses can be used than those that cause full neuromuscular blockade, and the ability of the patient to ventilate adequately must be evaluated prior to recovery from anesthesia.
Techniques and drugs used to sedate and anesthetize the great apes are many. This allows the anesthetist to tailor an anesthetic to fit the needs of the patient being anesthetized. With the advent of newer, safer drugs, even elderly apes can now be safely anesthetized.
1. Kenny, D.E., F. Knightly, B. Haas, L. Hergott, I. Kutinsky, and J.L. Eller. 2003 Negative-pressure pulmonary edema complicated by acute respiratory distress syndrome in an orangutan (Pongo pygmaeus abelii) . J Zoo Wildl Med. 2003 Dec; 34(4):394–9.
2. Miller M., M. Weber, B. Mangold, and D. Neiffer. 2000. Use of oral detomidine and ketamine for anesthetic induction in nonhuman primates. Proc. Am. Assoc. Zoo Vet., Int. Assoc. Aqua. Ani. Med. Annu. Conf. 179–180.
3. Kearns K.S., E.C. Ramsay, and B. Swenson. 1996. Oral anesthetic induction of chimpanzees (Pan troglodytes) with droperidol and carfentanil citrate. Proc. Am. Assoc. Zoo Vet. Annu. Conf. 401–403.
4. Horne W.A., B.A. Wolfe, T.M. Norton, and M.R. Loomis. 1998. Comparison of the cardiopulmonary effects of medetomidine ketamine and medetomidine-telazol induction on maintenance isoflurane anesthesia in the chimpanzee (Pan troglodytes). Proc. Am. Assoc. Zoo Vet., Amer. Assoc. Wildl. Vets. Annu. Conf. 22–25.
5. Sleeman J.M. Great apes. In West, G., D. Heard, and N. Caulkett, editors: Zoo Animal and Wildlife Immobilization and Anesthesia, Oxford, 2009, Blackwell Publishing.