Chapter 56 Side Effects of Etorphine and Carfentanil in Nondomestic Hoofstock
Immobilization of nondomestic hoofstock species presents unique challenges and risks to the zoo and wildlife veterinarian. The successful outcome depends on careful planning of the anesthetic event and consideration of factors that may adversely affect the success of anesthesia, especially the conditions surrounding immobilization (e.g., captive vs. free-ranging animals, environmental temperature, size and type of enclosure), as well as knowledge of the species to be immobilized and their often unique response to specific immobilizing agents.
To minimize morbidity and mortality and safely and effectively immobilize ungulates, induction of anesthesia should be rapid and without excitement. During immobilization, adequate muscle relaxation, good analgesia, and minimal cardiopulmonary depressant effects should be present. Recovery should be rapid, smooth, and complete after administration of the reversal agent(s). There is no ideal protocol, and each immobilization must account for many variables, including the number and experience of the personnel, the available equipment to monitor the immobilized animal effectively, and most importantly the experience and skill of the veterinarian performing the immobilization. Some species, such as giraffes, present unique challenges because of their size and anatomic features (e.g., long neck).2
A variety of different anesthetic agents have been used with variable success for the immobilization of captive and free-ranging nondomestic hoofstock species. In most cases, potent opioid agents such as carfentanil citrate, etorphine hydrochloride (M99), and more recently thiafentanil (A-3080) are used either alone or more often in combination with synergistic agents such as α2-adrenergic agonists (e.g., xylazine, medetomidine) and dissociative agents (e.g., ketamine hydrochloride) to facilitate rapid induction of anesthesia. The addition of synergistic agents allows for a lower dose of the opioid agent and a reduction of side effects, such as possible excitement during induction of anesthesia, poor muscle relaxation, and hypertension during immobilization. In most cases, administration of specific antagonists facilitates rapid, smooth, and complete recovery.
Before selecting an anesthetic protocol, it is mandatory to be familiar with the anesthetic side effects of the agent(s) being selected and be aware of species-specific reactions to the drugs being used. There are pronounced species differences in response to opioid agents and their antagonists. A combination that works effectively in one species may not work in another and may result in poor quality induction, severe cardiopulmonary depression, incomplete or stormy recovery, including renarcotization.
In most ungulate species, administration of potent opioid agents (etorphine, carfentanil, thiafentanil) in combination with synergistic agents (e.g., xylazine, medetomidine, ketamine) will produce rapid immobilization, adequate muscle relaxation, analgesia, and in most cases, rapid recovery after administration of specific antagonist. Opioid agents have a wide margin of safety and are fast acting, but they also cause central nervous system (CNS) depression, poor muscle relaxation if used alone, and pronounced cardiopulmonary depression.11,19 Species differences exist in the sensitivity to opioid agents, and administration of these agents alone is often associated with excitement, myopathies, regurgitation, and tachypnea/tachycardia or, depending on the species, bradycardia/bradypnea. Arterial hypotension or more often hypertension is seen after opioid administration, and species differences are apparent. All opioids are excreted by the kidneys after hepatic metabolism.
Worldwide, etorphine hydrochloride (M99) is the most common opioid agent used for immobilization of hoofstock. Etorphine may be used either alone or in combination with neuroleptic synergistic agents. Induction times with etorphine are usually longer compared with other opioid agents, such as carfentanil. The most common side effect associated with etorphine immobilization is pronounced respiratory depression, but common opioid effects (e.g., excitement, poor muscle relaxation, bradycardia or tachycardia, renarcotization) may be seen after administration of the opioid antagonist.
Carfentanil is a potent synthetic opioid with a morphinelike mode of action. It is more potent than etorphine and has a longer duration of action than etorphine and thiafentanil. Carfentanil is approved as an immobilizing agent for cervidae and provides good analgesia during immobilization. As with all opioids, carfentanil is fast acting and has been used in numerous hoofstock species for rapid induction of anesthesia.4,5,10,20,21 When used alone, carfentanil is rapidly absorbed and often associated with hyperexcitability during induction, poor muscle relaxation, tachycardia, hypertension, tachypnea, regurgitation, and prolonged recovery periods if an inadequate low dose of the antagonist is administered.18,20,21
Thiafentanil oxalate (A-3080) is a synthetic, short-acting fentanyl derivative with less potency than carfentanil and has been used successfully for the immobilization of various hoofstock species.7,8,14,24 Compared with carfentanil and etorphine, thiafentanil offers the advantages of shorter duration of action and fewer cardiopulmonary depressant effects. In most cases, cardiopulmonary parameters are maintained at physiologic levels.7,8 The effects of thiafentanil can be antagonized rapidly and completely with the opioid antagonist naltrexone hydrochloride, with no reports of renarcotization.9
Before immobilization, numerous factors (e.g., captive vs. free-ranging animal, isolated or within a herd) must be taken into account in selecting an anesthetic protocol that includes safe and effective dosages of the opioid and the synergistic agent(s). The health status of the animal, species-specific sensitivities to a particular drug combination, and available equipment for transport and monitoring should also be determined. The key for prevention of complications associated with immobilization is preparedness and careful planning of the procedure, including determination of the location where the animal will recover.
During recumbency, immobilized hoofstock, especially large species, are susceptible to the development of complications, which may include cardiopulmonary compromise, development of shunts, ventilation/perfusion mismatches, hypoventilation, and hypoxemia. In immobilized hoofstock, increased peripheral resistance and systemic hypertension are often seen.
The anesthetic effects of opioid agents, especially if used alone, are variable, dose dependent, and sometimes species specific. A key factor for the safe immobilization of captive and free-ranging hoofstock species is a rapid, smooth, and predictable induction of anesthesia. Again, good muscle relaxation and adequate analgesia should occur during immobilization, and cardiopulmonary parameters should be kept within physiologic ranges. Both carfentanil and etorphine fulfill most of these requirements, but if used alone, either may also cause hyperexcitement during induction, poor muscle relaxation, severe respiratory depression, especially at high dosages, and hypertension. Effects and quality of induction are dose dependent.23 To decrease the opioid dosage, improve muscle relaxation, and maintain cardiopulmonary parameters, synergistic agents such as xylazine, medetomidine, and ketamine are often added to the anesthetic protocol.6 The quality of anesthesia, including muscle relaxation and recovery time, is species dependent and in some species better with etorphine combinations than carfentanil combinations.13
Physical trauma after drug administration may be encountered at any time during induction and recovery. The key to prevention of trauma is selection of an effective dose and drug combination that produces rapid immobilization and minimizes excitement. For rapid reversal of anesthesia, effective antagonists and dosages should be selected. Also, environmental conditions should be evaluated and any potentially hazardous objects within an enclosure removed.
All opioid agents cause respiratory depression, including a decrease in respiratory rate and tidal volume.17,20 Relative arterial oxygen saturation (Spo2), as indicated by pulse oximetry, is typically less than 90%. Arterial blood gas (ABG) analysis often confirms marked to severe respiratory depression, as indicated by low arterial oxygen tension (Pao2; <60 mm Hg) and arterial blood oxygen saturation (Sao2) of less than 90%, confirming severe hypoxemia.20 Arterial carbon dioxide tension (Paco2) values are often greater than 50 mm Hg, indicating pronounced hypercapnia. Decreased pH values indicate respiratory acidosis. The risk of mortality and development of capture myopathy is particularly increased in hyperthermic and hypoxemic ungulates because the oxygen demand by the tissue, especially muscle, cannot be met.
The effects of carfentanil, etorphine, and thiafentanil on cardiovascular parameters include decreases in heart rate, arterial hypertension or hypotension indicated by increase or decrease in systolic, diastolic, and mean arterial pressures, as well as potentially premature ventricular contractions, premature atrial contractions, and junctional escape rhythm. Dama gazelles (Gazella dama) immobilized with carfentanil alone were hypertensive after drug administration (systolic arterial pressure [SAP] >150 mm Hg), but increases were within ranges reported in other domestic and nondomestic ungulates.21 The ABG parameters in these gazelles were well maintained and did not indicate episodes of hypoxemia. Hypoxemia and hypercapnia were not observed, but these effects may be species and dose dependent.
Bongo antelopes (Tragelaphus eurycerus isaaci) immobilized with a carfentanil-xylazine combination showed decreases in heart rate throughout the immobilization period, whereas severe systemic hypertension (SAP >200 mm Hg) was noted after 45 minutes of immobilization and thereafter. In these antelopes, significant increases in plasma norepinephrine and decreases in plasma 3,4-dihydroxyphenylacetic acid concentrations have been associated with the development of hypertension.20 Heart rates and systemic arterial pressures are often higher with carfentanil than with etorphine.13
Studies in domestic goats comparing the cardiopulmonary effects of carfentanil and etorphine demonstrated that both agents will cause increased systemic and left ventricular end-diastolic pressures as well as increased total peripheral resistance. A dose-dependent increase in left ventricular stroke volume, mean pulmonary artery pressure, Pao2, Paco2, and body temperature was seen. Both etorphine and carfentanil induced hypertension, bradycardia, and bradypnea in goats, and effects were seen more rapidly with carfentanil than with etorphine.12
In hoofstock species, administration of opioid agents will increase vagal tone and release of histamine, prolactin, and somatotropin. In addition, decreased motility of the gastrointestinal (GI) tract, increased bladder tone, and decreased tone of the uterus is typically present. Opioids raise the pain threshold, reduce the perception of pain, are effective in inducing analgesia, and are the drugs of choice for the treatment of acute and severe pain. However, the duration of action varies among species and is usually relatively short.