HuiChu Lin Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL, USA Injectable anesthetics can be used to produce short‐term anesthesia for minor diagnostic and surgical procedures, or they can be used for induction of general anesthesia followed by maintenance of inhalation anesthesia for longer procedures. Short‐term injectable anesthesia is often preferred for field procedures. Compared to inhalation anesthesia, injectable anesthesia offers the advantages of ease of administration, rapid transition from awake to unconsciousness, and minimal apparatus required for its use. However, it is often difficult to maintain a consistent level of anesthesia with an injectable anesthetic, particularly when it is administered by intermittent repeated dosing. When an injectable anesthetic is used repeatedly to prolong anesthesia, accumulation of the anesthetics may cause prolonged recovery. The goal of balanced anesthesia is to provide narcosis (unconsciousness), analgesia, and muscle relaxation, which ideally can be produced by administration of a single drug. But in reality, the large dose of an injectable anesthetic which is often required to achieve balanced anesthesia and maintain anesthesia for lengthy procedures is often associated with severe adverse effects. The combinations of different classes of anesthetics are frequently used to achieve desirable anesthetic effects with as few side effects as possible. The choice of the anesthetics used for field anesthesia should be based on the intrinsic pharmacological effects of each anesthetic, types of surgery or diagnostic procedures performed, and the duration of the procedure. This chapter describes the pharmacology of commonly used injectable anesthetics and their uses for field anesthesia in farm animal species. Ketamine is a dissociative anesthetic. Presently, ketamine is the most commonly used injectable anesthetic in large animal practice. It has a rapid onset of action following intravenous (IV) administration with the maximal effect occurring within 1 minute as a result of its small molecular weight, high lipid solubility, and a dissociation constant (pK a 7.5) value near physiologic pH allowing rapid diffusion of anesthetic across the blood–brain barrier into the central nervous system (CNS). Ketamine produces dose‐dependent unconsciousness and analgesia. Termination of the anesthetic effect after a single dose of ketamine depends on rapid redistribution of the drug from the CNS to peripheral muscle and fat tissues [1]. The primary CNS site of action appears to be mediated through the thalamoneocortical projection system. Ketamine selectively depresses neuronal function of the neocorticothalamic axis and the central nucleus of the thalamus, and at the same time it stimulates parts of the limbic system, including the hippocampus [2, 3]. Therefore, ketamine anesthesia is characterized by unconsciousness while maintaining eye reflexes (palpebral and corneal reflexes) and pharyngeal–laryngeal reflexes (e.g. swallowing reflex). Evidence indicates that antagonism of ketamine on the N‐methyl‐D‐aspartate (NMDA) receptors is responsible for most of the anesthetic, analgesic, psychotomimetic, and neuroprotective effects of the drug [4]. On the cellular level, ketamine‐induced anesthesia is believed to be mediated through (i) noncompetitive antagonism on the NMDA glutamate receptors, (ii) action on the voltage‐dependent sodium and potassium channels and calcium channels, (iii) depression of the acetylcholine receptors, (iv) enhancement and prolongation of the γ‐amino‐butyric acid (GABA) receptors that link to chloride channels (GABAA) [5], and (v) depression of nociceptive cells in the medial medullary reticular formation and activity of the laminae I and V of the dorsal horn [6, 7]. Ketamine does not depress cardiovascular function; instead, it causes direct stimulation of the CNS leading to increased sympathetic outflow, resulting in increased heart rate and arterial blood pressures during anesthesia [8]. Several contributing factors for the ketamine‐induced increased sympathetic outflow have been identified including (i) sympathomimetic effects mediated within the CNS [9], (ii) inhibition of the neuronal uptake of catecholamines by sympathetic nerve endings [10], (iii) direct vasodilation of the vascular smooth muscle [11], and (iv) an inotropic effect on the myocardium [12]. Plasma concentrations of epinephrine and norepinephrine increase within 2 minutes after IV administration of ketamine and return to control concentrations 15 minutes later; this increase reflects increased sympathetic outflow due to sympathomimetic effect induced by ketamine [13]. As a result, heart rate and arterial blood pressure increase transiently following IV administration of the drug. However, the cardiovascular‐stimulating effects of ketamine can be blunted or prevented by prior administration of a benzodiazepine [14, 15], droperidol [16], acepromazine, or α2 agonist or by concomitant administration of inhalation anesthetics, including nitrous oxide [17, 18]. In the CNS, ketamine induces significant increases in cerebral blood flow (CBF), intracranial pressure (ICP), and cerebrospinal fluid (CSF) pressure as a result of cerebral vasodilation and elevated systemic arterial blood pressure [19–25]. Direct smooth muscle relaxation of bovine middle cerebral arteries via inhibition of calcium uptake has been reported, supporting the finding that ketamine causes cerebral vasodilation [26]. However, the mechanism of ketamine‐induced elevated ICP remains controversial. In awake goats, ketamine increases CBF and ICP when the partial pressure of arterial carbon dioxide (PaCO2) is allowed to rise, but CBF and ICP remain unchanged when PaCO2 is maintained at a preketamine concentration [27, 28]. In piglets with increased ICP, a further increase in ICP paralleling a rise in PaCO2 was observed during ketamine anesthesia. When ventilation was controlled, no increase in ICP was observed in piglets with normal or elevated ICP [28]. Increased skeletal, thoracic, and abdominal muscle tone can impede venous return from the head to cause an increase in intracranial blood volume and pressure [28, 29]. Ketamine does not depress ventilatory responses to hypoxia at clinically recommended doses [30]. Hypoxic pulmonary vasoconstriction is preserved during ketamine anesthesia but potentiated during propofol anesthesia in dogs [31]. Nonetheless, arterial oxygenation and functional residual capacity are usually well‐maintained during ketamine anesthesia [32–35]. Ketamine is a potent bronchodilator capable of preventing and reversing wheezing in human patients with asthma requiring anesthesia and intubation [36, 37]. At clinically useful doses, this bronchoprotective effect is mediated primarily via depression of neurally (vagally) induced vasoconstriction [38]. In sheep, ketamine induces a transient decrease in the partial pressure of arterial oxygen (PaO2) in the presence of decreased or increased respiratory rate [39–41]. The transient apnea induced by ketamine appears to be dose dependent. At higher doses, respiration is characterized by an apneustic, shallow, and irregular pattern [42–44]. Severe ventilatory depression or arrest due to overdosage has been reported in human patients, cats, and ponies [44–46]. Ketamine often causes increased salivation and secretion of mucus in the respiratory tract, which can be reduced by administration of an anticholinergic drug. Laryngeal and pharyngeal reflexes usually are well maintained during ketamine anesthesia. Swallowing reflexes may be present but somewhat obtunded and most animals can be intubated when anesthetized with ketamine [47]. Ruminants normally salivate profusely during ketamine anesthesia. Total amounts of salivary secretion in conscious adult cattle and sheep have been reported to be 50 and 6–16 l per 24 hours, respectively [48, 49]. If the trachea is left unprotected during anesthesia, aspiration of a large amount of saliva can occur and may cause pneumonia. Ketamine alone does not provide muscle relaxation. Muscle jerking and sometimes rigidity are present following the induction of anesthesia. Acepromazine, diazepam, xylazine, and medetomidine can be used in combination with ketamine to enhance the degree of analgesia and muscle relaxation during anesthesia. Ketamine has been shown to produce intense analgesia even at subanesthetic doses [50]. Proposed mechanisms responsible for the analgesic actions of ketamine include blockade of spinoreticular tracts [51, 52], depression of nuclei of the medial medullary reticular formation [6], suppression of lamina in the dorsal horn of the spinal cord [7, 53, 54], interaction with CNS and spinal cord opiate receptors [55–58], and antagonism of NMDA receptors [4]. Studies also indicate that ketamine induces visceral analgesia as evidenced by inhibition of nociceptive responses to graded tests in rats [59–61]. Furthermore, NMDA receptors appear to be more involved in hyperalgesic responses after peripheral tissue injury and inflammation rather than nonnoxious somatic inputs [60, 62]. Ketamine administered at 0.25–0.5 mg/kg intramuscularly every 6–8 hours has been used in combination with opioids or nonsteroidal anti‐inflammatory drugs (NSAIDs) to provide pain relief in goats suffering severe pain due to burn injury, polyarthritis, or osteomyelitis [63]. An IV bolus injection of ketamine (2 mg/kg) followed by continuous infusion of 0.2% (2 mg/ml) ketamine in physiologic saline at a rate of 10 ml/min induces dissociative anesthesia for both minor and major surgeries (toe amputation, laparotomy, etc.) in cows weighing 450 kg (990 lb) [64]. Intramuscular (IM) administration of ketamine alone or in various combinations with other drugs in calves has been used to induce chemical restraint or anesthesia, but this technique is impractical for adult cattle due to the large volume of drug required for the size of the animal. Presently, IV ketamine (2.2 mg/kg) is commonly administered concomitantly with or after IV administration of xylazine (0.1–0.2 mg/kg) for short‐term anesthesia in both large and small ruminants. Tracheal intubation is easily achieved in cattle anesthetized with this combination. Anesthesia may be safely prolonged by intermittent IV injection of 1–2 mg/kg of ketamine given slowly to effect. Alternatively, a continuous infusion of 2 mg/ml of ketamine in 0.9% NaCl solution, 5% dextrose solution, or 5% guaifenesin in 5% dextrose solution is administered at a rate of 10 ml/min for animals with a body weight of 450 kg (990 lb) to prolong anesthesia [65]. In sheep, ketamine alone (22 mg/kg IV) may cause side effects such as tachycardia, muscle rigidity, and mild salivation during anesthesia and marked ataxia during recovery [66]. However, at a low IV bolus dose of 2 mg/kg followed by 4 ml/min of continuous infusion of 0.2% ketamine in 5% glucose solution (2 mg/ml) for up to 2 hours, ketamine produced safe anesthesia in pregnant ewes [67]. In goats, IM ketamine (10 mg/kg, 84 minutes) [68] produced longer duration of anesthesia than in goats that were administered with IV ketamine (6 mg/kg, 15–30 minutes) [69]. Levinson et al. [70] reported that ketamine caused an increase in uterine blood flow but did not produce detrimental effects on fetal cardiovascular or acid–base status. When administered intramuscularly or intravenously to pregnant goats, ketamine rapidly traversed the placental membrane, resulting in an increase in fetal heart rate and blood pressure. Fetal arterial pH value (pHa) and PaO2 decreased while PaCO2 increased during anesthesia. The detrimental effects of ketamine on the fetus appeared to be greater with IV administration than with IM administration [71]. When administered to induce general anesthesia, ketamine reportedly increased basal uterine tone as well as the intensity of the contractions in both pregnant and nonpregnant women. Nonetheless, the study showed that human fetal mortality is less with ketamine than with thiopental [72]. Similar to cattle and small ruminants, ketamine (1 mg/ml) is often combined with 5% guaifenesin and given to effect (1.5–2.2 ml/kg IV) to induce and maintain general anesthesia for 15–20 minutes in camelids. When using xylazine and ketamine combination to induce satisfactory anesthesia and to facilitate tracheal intubation, camelids appear to require a higher dose of ketamine (3–5 mg/kg) [73] as opposed to the lower dose of 2.2 mg/kg normally used for cattle and small ruminants [74]. Ketamine administered intramuscularly alone (11 mg/kg) to pigs provides anesthesia that may more appropriately be considered chemical restraint [42]. Although immobilization occurred within 3–5 minutes, muscle relaxation was considered poor with only a brief period of analgesia. IV administration of an additional 2–4 mg/kg of ketamine prolonged immobilization [42]. Violent reactions in pigs to initial IM injection of ketamine with subsequent muscle tremor, extensor rigidity, panting respiration, and erythema have been reported [75]. Other side effects including tachycardia, hypertension, and poor muscle relaxation, as seen in other species, are also observed in pigs. Concurrent administration of diazepam (1 mg/kg IM) or xylazine (2 mg/kg IM) with ketamine provided deep sedation and good muscle relaxation and minimized adverse reactions, but unforutunately pigs still responded to surgical stimulus, for example incision of the abdominal wall [75, 76]. Telazol, a proprietary combination of tiletamine (dissociative derivative) and zolazepam (benzodiazepine derivative), produces anesthesia similar to the commonly used anesthetic combination of diazepam and ketamine. Tiletamine and zolazepam are combined in a 1 : 1 ratio by weight of base and marketed as Telazol. The combination of the drugs is supplied in a sterile vial as a lyophilized powder containing 250 mg of tiletamine and 250 mg of zolazepam. It is recommended that the drug be reconstituted immediately before use with 5 ml of sterile water, resulting in a combination of 50 mg of tiletamine and 50 mg of zolazepam per milliliter of the solution. Telazol has a wide margin of safety and has been used to produce safe anesthesia in a wide variety of animal species, including wildlife. The pH of the injectable solution of Telazol is between 2 and 3.5; though acidic, it does not cause tissue irritation and the animal’s reactions to IM injection of the drug are minimal. Induction of anesthesia is rapid and smooth, as is recovery in most species. Compared with ketamine, Telazol anesthesia produces better muscle relaxation, more profound analgesia, and longer‐lasting effects. The swallowing and eructation/vomiting reflexes are retained. Muscle relaxation and general lack of response to external stimuli add to Telazol’s usefulness. Telazol induces analgesia from interruption of sensory input into the brain, which usually persists after the anesthetic effect has subsided. The animal’s eyes remain open, even during surgical anesthesia. Protective reflexes, such as coughing, swallowing, and corneal and pedal reflexes, are maintained. Increased salivation is a common occurrence in most animals administered with Telazol. An anticholinergic drug (e.g. atropine and glycopyrrolate) can be administered with Telazol to reduce salivation [77]. In llamas, Telazol causes no significant changes in heart rate [78]. In calves, Telazol (4 mg/kg IV) induces a transient decrease followed by an increase in heart rate. The mechanism of the transient decrease in heart rate is believed to be caused by tiletamine’s negative inotropic and chronotropic effects [79]. The direct depressant effect of tiletamine was clearly demonstrated in denervated myocardium [80]. A decreased amplitude of myocardial contraction was observed when tiletamine (0.5–5 mg) was administered into the coronary circulation of an isolated rabbit heart preparation [81]. The subsequent increase in heart rate is attributed to direct CNS stimulation leading to increased sympathetic tone and perhaps decreased vagal tone [82]. Changes in arterial blood pressure and systemic vascular resistance induced by Telazol are characterized by a decrease followed by an increase after IV injection to calves. Tiletamine may play a major role in the unique biphasic hemodynamic changes occurring after Telazol administration [79]. In calves, the biphasic response in arterial blood pressure induced by Telazol (4 mg/kg IV) is reversed when Telazol is combined with xylazine (0.1 mg/kg IV). The hemodynamic effects of Telazol are offset by the initial vasoconstrictive effect and delayed sympatholytic and parasympathomimetic effects of IV xylazine [83]. In sheep, butorphanol (0.5 mg/kg IV) administered preanesthetically does not influence the decrease in mean systemic and pulmonary arterial pressures induced by Telazol (12 mg/kg IV). Heart rate does not change significantly when butorphanol is administered with or prior to Telazol, although increased systemic vascular resistance is observed [84]. In calves, left ventricular stroke work index and rate pressure product follow a similar biphasic response as seen with blood pressure and systemic vascular resistance after Telazol injection [79]. Cardiac output remains unchanged in calves and llamas [78, 79]. Decreased cardiac output is observed in sheep given butorphanol/Telazol [84]. In calves receiving xylazine and Telazol, cardiac output decreased transiently and was associated with an increase in afterload and a decrease in heart rate [83]. Respiratory rate usually increases in most species following Telazol injection. In calves, low doses (LDs) of Telazol (4–8 mg/kg IV or IM) increase respiratory rate for 30–60 minutes. Apnea may occur when larger doses (10 mg/kg IM) of Telazol are administered, but spontaneous breathing usually soon resumes without respiratory support. In sheep, although respiratory rate remains unchanged, apneustic breathing and decreased inspired minute ventilation and tidal volume are observed after Telazol administration (12 or 24 mg/kg IV) [74]. In llamas, mild respiratory depression accompanied by hypoxemia is also evident [78]. Hypothermia may occur after Telazol injection as a result of profound muscle relaxation. Body temperature should be monitored, as supplemental heat may be required during Telazol anesthesia, particularly in small patients. In ruminants, Telazol produces smooth induction of anesthesia rapidly with gradual and prolonged recovery [85]. The pharmacologic effect of Telazol is predominated by tiletamine since zolazepam has very minimal cardiovascular effect, but it is capable of enhancing the anesthetic effect and muscle relaxation of tiletamine. As a result, Telazol causes cardiovascular stimulation rather than depression [85, 86]. In calves, Telazol alone (4 mg/kg IV) induced 45–60 minutes of satisfactory anesthesia with minimal cardiovascular depression [79]. Telazol comes as 500 mg powder, and it is usually reconstituted with 5 ml of sterile water into 100 mg/ml solution. The drug is very water soluble, thus it can be reconstituted with a smaller volume of sterile water into an injectable solution with higher concentration. For example, adding 2.5 ml of sterile water into 500 mg of Telazol powder results in an injectable solution with final concentration of 200 mg/ml. Because of this, Telazol has been recommended for use to capture free‐ranging cattle when a smaller volume is necessary to fill the darts of a tranquilizing gun [65]. Xylazine or detomidine can be used to substitute sterile water to reconstitute Telazol powder to ensure effective chemical restraint of free‐ranging cattle. A combination of Telazol, ketamine, and xylazine (TKX‐Ru) has been used successfully to capture wild ruminants. Telazol (8–20 mg/kg IV) has been used successfully to anesthetize sheep undergoing surgical procedures. Induction is rapid and exceptionally smooth, and duration of surgical anesthesia ranges from 40 minutes to 3.7 hours. Excessive salivation can be controlled by administration of 0.066 mg/kg of atropine sulfate [87]. IV doses of 12 or 24 mg/kg of Telazol cause a significant decrease in minute ventilation and respiratory airflow that is characterized by an apneustic breathing pattern [88]. IM administration of 12 mg/kg of Telazol appears to be the optimal dose, with surgical anesthesia lasting approximately 30 minutes. The analgesic effect was found to be most profound around the head, the neck, and the trunk, whereas poor analgesia was found in the distal portion of the limb and perineal area [89]. Hypoventilation and hypothermia have been observed in sheep anesthetized with Telazol alone or with xylazine. Assisted or controlled ventilation with O2 supplementation may be required in the presence of severe hypoventilation and hypoxemia [90]. In llamas, Telazol (4.4 mg/kg IM) provides good chemical restraint and immobilization for 2 hours, but the degree of muscle relaxation and the quality of analgesia are not sufficient for major surgery [78]. In free‐ranging adult guanacos, Telazol (4–6 mg/kg) produced immobilization for an average duration of 7 minutes (1.5–53 minutes) [91]. When xylazine (0.4 mg/kg IM) was combined with Telazol (2 mg/kg IM), longer duration of recumbency (112 ± 9 minutes) and analgesia (51.3 ± 7 minutes) occurred. Hypoxemia with PaO2 lower than 60 mmHg was observed in these llamas while in lateral recumbency and breathing room air. Nevertheless, arterial oxygen saturation from a pulse oximeter (SpO2) values remained relatively high (83–95%) in this study [92]. When morphine (0.5 mg/kg IM) was added to xylazine (0.15 mg/kg IM) and Telazol (2 mg/kg IM) combination, the duration of analgesia was longer (48 ± 5 minutes) than that of xylazine (28 ± 5 minutes) or morphine (5 ± 5 minutes) alone with Telazol. Similar to the previous study, hypoxemia (PaO2 < 60 mmHg) developed 5 minutes after administration of the same drug combinations and soon after the animals were placed in lateral recumbency position regardless of the anesthetic combinations used [93]. Telazol alone in pigs (doses range from 4.4 to 22 mg/kg) induces rapid immobilization but does not produce adequate muscle relaxation and analgesia sufficient for surgery. A hyperresponsive reflex characterized by exaggerated limb withdrawal is common and often persists throughout the course of immobilization. Similar responses have been described in swine receiving ketamine alone [42]. Ganter and Ruppert [94] reported that 10 mg/kg of Telazol given intramuscularly induced rapid immobilization with an average duration of 33.7 ± 15 minutes. Although muscle relaxation was described as good, analgesia was poor. During recovery, the pigs were excited and salivated excessively. It appears that zolazepam in pigs does not induce the same degree of muscle relaxation or suppress hyperresponsiveness as effectively as it does in other species [95–98]. Propofol (PropoFlo™) is a unique short‐acting anesthetic. Structurally, propofol does not relate to any of the injectable anesthetics currently available in veterinary practice. Propofol is only slightly water soluble and comes as a white, oil‐in‐water emulsion containing 10 mg of propofol, 100 mg of soybean oil, 22.5 mg of glycerol, and 12 mg of egg lecithin per milliliter in sterile glass ampules. Because this emulsion contains no preservative, after the ampule is opened the contents should be used or discarded within 8 hours. Rapid recovery from propofol is believed to be the result of a combination of rapid redistribution of the drug to peripheral muscle and fat tissues as well as rapid hepatic and extrahepatic metabolism [99, 100]. Complete recovery without residual sedation and ataxia makes propofol a popular choice for outpatient procedures. A single dose of propofol (2 mg/kg IV) produces approximately 10 minutes of anesthesia with complete recovery occurring in 20–30 minutes [101, 102]. Propofol is best used for induction before inhalation anesthesia; it also can be used as a continuous infusion to maintain short‐term anesthesia [103–105]. Supplemental analgesic drug should be administered to provide pain relief following surgery since propofol at subanesthetic dose does not provide analgesia [106]. A comparative study was performed to evaluate propofol (3 mg/kg IV), thiopental (8 mg/kg IV), or ketamine (10 mg/kg IV) as induction agents in goats. The result of this study indicated that propofol was superior to thiopental or ketamine as an induction agent because of the rapid and uneventful recovery it produced [107]. A new formulation of propofol, PropoFlo 28, recently has become available. The injectable solution is also a white, water‐in‐oil emulsion. Instead of 1 mg/ml of benzyl alcohol, 20 mg/ml is added to the original propofol to extend its shelf life up to 28 days. Due to its extremely short duration of action and high cost, the clinical use of propofol and PropoFlo 28 is somewhat limited in farm animal species, especially in adult cattle. A single dose of propofol (2–6 mg/kg) induces approximately 10 minutes of anesthesia with complete recovery in 20–30 minutes in sheep [102, 103, 108, 109]. Propofol is best used for induction before inhalation anesthesia; it also can be used as a continuous infusion to maintain short‐term anesthesia [103–106]. Propofol alone does not provide analgesia. Concurrent administration of an analgesic such as opioids or NSAIDs is beneficial to provide pain relief during painful procedures. At Auburn University College of Veterinary Medicine, morphine (0.2–0.4 mg/kg IV), midazolam (0.2–0.4 mg/kg IV), and propofol (2.5–3 mg/kg IV) combination has been used frequently to induce anesthesia followed by isoflurane maintenance for surgery in goats. In camelids, 2 mg/kg of propofol does not induce muscle relaxation adequately for tracheal intubation. However, a light plane of anesthesia can be achieved with additional infusion of 24 mg/kg/hour. Llamas were able to maintain a sternal recumbency position 10–15 minutes after the discontinuation of the propofol infusion [110]. For cesarean section, pregnant camelids can be sedated with xylazine (0.1–0.2 mg/kg IM) and butorphanol (0.06–0.12 mg/kg IM), and general anesthesia induced with propofol (3.5 mg/kg IV) with diazepam (0.5 mg/kg IV) or guaifenesin. Though anesthesia can be maintained with propofol infusion for cesarean section, fetal ventilatory function may be better maintained when isoflurane in O2 is used [111]. In pigs, total IV anesthesia has been maintained with 2 mg/kg of propofol as a loading dose and a continuous infusion of 9, 11, or 13 mg/kg/hour. Decreased heart rate, cardiac index, and dose‐dependent ventilatory depression were observed with an infusion of 13 mg/kg/hour. Depending on the total dose of propofol administered, pigs recovered and assumed sternal recumbency within 30 minutes after being administered lower doses (9 and 11 mg/kg/hour), while 60 minutes was required for pigs that received a high dose (HD) (13 mg/kg/hour)[112]. Endotracheal intubation and positive pressure ventilation may be required immediately following induction as transient apnea occurred frequently with propofol. The cardiovascular effects of propofol administered at 7.5, 15, and 30 mg/kg/hour in newborn piglets were studied. Only mean arterial blood pressure decreased 25% from baseline values; heart rate and left ventricular pressure remained unchanged for all doses [113]. Alfaxalone is a synthetic neuroactive steroid anesthetic. The drug is insoluble in water, but it is solubilized in cyclodextrin and marketed as Alfaxan®. Original Alfaxan is presented as an aqueous solution of 10 mg/ml without preservative and it is recommended that the unused portion be discarded after 1 day. In 2018, a preservative was added to Alfaxan and this was marketed as Alfaxan Multidose with a shelf life of 28 days. Alfaxalone produces general anesthesia and muscle relaxation by enhancing the actions on the γ‐amino‐butyric acid type A (GABAA ) receptors [114]. The drug can be administered either by IV or IM injection. Alfaxalone is a short‐acting, nonirritant, and noncumulative anesthetic with a wide safety margin. Thus, it is suitable for induction of anesthesia or for maintenance of anesthesia by continuous infusion. No contraindications were indicated when using alfaxalone with preanesthetic sedative, analgesic, or anticholinergic agents, but its administration with other injectable anesthetics is not recommended. Alfaxalone is approved by the Food and Drug Administration (FDA) for use in dogs and cats in the USA, therefore its use in farm animal species is considered as extralabel use. Alfaxalone (2 mg/kg IV) has been used in sheep to induce short duration of anesthesia [115]. The duration of anesthesia and the time to standing were 6.4 ± 3.6 and 22.0 ± 10.6 minutes, respectively. There were no significant changes in arterial blood pressures and respiratory rate, and apnea was not observed. Heart rate increased significantly immediately following alfaxalone administration, which lasted for 20 minutes before returning to baseline values [115]. A decrease in PaO2 and an increase in PaCO2 were accompanied by a significant decrease in SpO2 and pHa for 15–20 minutes following induction. The authors of the study suggested that the effects of alfaxalone on ventilation and blood gas values were minimal but positioning of the sheep during anesthesia may have greater contribution to the changes in PaO2 and PaCO2 [115]. In goats, the quality of induction with alfaxalone was compared to that of ketamine [116]. Goats were sedated with midazolam (0.1 mg/kg IV) and anesthesia was induced with midazolam (0.1 mg/kg IV) and alfaxalone or ketamine at 2 mg/kg IV over 30 seconds. Goats that received alfaxalone did not require an additional dose for endotracheal intubation, whereas five of nine goats that received ketamine required an additional 1 mg/kg of ketamine to facilitate intubation. Anesthesia was maintained with isoflurane in O2 along with continuous infusion of 0.5–1 mg/kg/hour of ketamine during orthopedic surgery [116]. Heart rate and systolic and mean arterial blood pressures decreased significantly from preinduction values with the alfaxalone group. Apnea occurred in five of nine and three of nine goats for the alfaxalone and ketamine group, respectively. All goats were placed on mechanical ventilation throughout anesthesia [116]. Subjective observation by the investigators suggested that goats receiving alfaxalone were less responsive to the placement of the mouth gag and laryngoscope during the intubation process. Seven of the nine goats in this group showed transient focal (blinking or facial twitching) or generalized (limb paddling or muscle tremors) muscle movement. These muscle movements were of short duration and did not seem to be related to anesthetic depth [116]. In nonpremedicated alpacas, the mean dose of IV alfaxalone, propofol, and ketamine‐diazepam to allow for endotracheal intubation was 2.1 ± 0.1 mg/kg, 3.3 ± 0.4 mg/kg IV, and 4.4 ± 0.6 mg/kg of ketamine and 0.2 ± 0.0 mg/kg of diazepam, respectively [117]. The quality of induction was reported to be good to excellent. Mild excitement or muscle rigidity was observed in one alpaca receiving propofol. No muscle rigidity, twitching, or tremors were observed in those receiving alfaxalone. The mean duration of anesthesia was 12.0 ± 1.9, 10.9 ± 2.5, and 10.0 ± 1.5 minutes for alfaxalone, propofol, and ketamine–diazepam, respectively. However, alpacas receiving alfaxalone required longer time to stand (34 ± 7 minutes) than those receiving propofol (19 ± 8.6 minutes) or ketamine–diazepam (25 ± 3.7 minutes) [117]. Heart rate was significantly higher with alfaxalone than with ketamine–diazepam. All alpacas, regardless of the treatment, developed hypoxemia with PaO2 values below 60 mmHg and required O2 supplementation and mechanical ventilation. The quality of recovery was worse for those receiving alfaxalone in that alpacas exhibited clinical signs of tremors, paddling, rolling, thrashing, and seizure‐like activity during recovery. Nevertheless, all alpacas recovered successfully [117]. Alfaxalone has been administered IV to azaperone‐premedicated pigs at 0.7–0.9 mg/kg for induction of anesthesia. Muscle twitching was observed [118]. When alfaxalone was administered IM (5 mg/kg) with diazepam (0.5 mg/kg), the combination produced faster onset of recumbency (140–260 seconds), deeper sedation, and better muscle relaxation with minimal side effects. Tracheal intubation can be performed with either alfaxalone alone or alfaxalone with diazepam [119]. Respiratory rate decreased significantly for 5 minutes following induction, but apnea was not observed [119]. When compared to ketamine (10 mg/kg IM) and dexmedetomidine (0.01 mg/kg IM), alfaxalone (5 mg/kg IM) and dexmedetomidine (0.01 mg/kg IM) produced deeper sedation and better quality of induction of anesthesia [120]. Muscle twitching and limb movement were observed in some pigs receiving alfaxalone and dexmedetomidine, whereas slight excitement with grunting occurred in those receiving ketamine and dexmedetomidine [120]. Alfaxalone in combination with sedatives and analgesics can be used to produce safe anesthesia in pigs. However, the volume of the drug required for larger pigs (1% solution in cyclodextrin, >10 ml for pigs up to 22 kg [48.4 lb] body weight) may be a limiting factor for widespread use of alfaxalone in pigs. Guaifenesin is a central muscle relaxant frequently used in large animal practice. The drug acts by interrupting impulse transmission in the internuncial neurons of the spinal cord, brain stem, and subcortical areas of the brain. Unlike neuromuscular blocking drugs, guaifenesin produces muscle relaxation, not muscle paralysis. In cattle, IV guaifenesin administered at 50 mg/kg induced ataxia and muscle relaxation. Recumbency occurred at a dose of 100 mg/kg [121]. Only minimal changes on respiratory muscle activity and respiratory and cardiovascular functions were observed when guaifenesin was administered at the therapeutic dose [122]. However, a significant decrease in arterial blood pressure and acute respiratory acidosis occurred following the administration of guaifenesin (165 mg/kg) to buffalo calves [123]. Guaifenesin doses three to four times higher than the dose required to induce recumbency can result in respiratory paralysis [124]. Guaifenesin is not an anesthetic, and it does not produce anesthesia or analgesia. Therefore, guaifenesin should always be used in combination with anesthetic(s), for example ketamine, thiopental, or propofol, for good muscle relaxation during anesthesia [65]. Nevertheless, guaifenesin alone at 15–25 mg/kg IV induces mild standing sedation in large ruminants and camelids, but the amount of drug administered should be carefully titrated to avoid excessive muscle relaxation and recumbency [125]. Guaifenesin comes as a powder and can be reconstituted with 5% dextrose to make up 5% (50 mg/ml) or 10% (100 mg/ml) injectable solution by a compounding pharmacist. Thrombophlebitis has occurred following the administration of 5% guaifenesin solution [126]. However, hemolysis, hemoglobinuria, and venous thrombosis are more likely to occur with solution of 10% or greater [127]. Guaifenesin, xylazine, and ketamine combination, referred to as Triple Drip, is a popular injectable anesthetic combination for short‐term anesthesia in large and small ruminants, camelids, and pigs. Because of the breed and species variation in sensitivity to xylazine and individual difference for the anesthetic dose requirement, adjustment of the concentration of each drug in Triple Drip and the rate of infusion of the mixture is very important to ensure safe anesthesia. Acepromazine, diazepam, xylazine, and medetomidine can be used in combination with ketamine to enhance analgesia and muscle relaxation during anesthesia. IV administration of xylazine (0.1–0.2 mg/kg) prior to or concomitantly with ketamine (2–3 mg/kg) is the most commonly used combination to induce short‐term anesthesia in cattle of all ages. Lowering the dose of xylazine in cattle weighing more than 600 kg (1320 lb) may be appropriate [128]. While IM xylazine (0.1–0.2 mg/kg) and ketamine (10–15 mg/kg) can be used in young calves, this is impractical for adult cattle because of the large amount of ketamine required [101]. Tracheal intubation is easily achieved in cattle anesthetized with this combination (Figure 4.1). Duration of anesthesia with IV xylazine and ketamine is approximately 20–30 minutes in most cases. Anesthesia may be safely prolonged by IV administration of a third to half of the original dose of each drug or 1–2 mg/kg of ketamine given slowly to effect for additional 15 minutes [65]. In calves anesthetized with xylazine and ketamine, the decrease in heart rate induced by xylazine is offset by the increased sympathetic tone from subsequent administration of ketamine. When xylazine and ketamine are administered simultaneously, no significant changes in heart rate, cardiac output, and arterial blood pressure are observed [129, 130]. Thus, it appears that administration of xylazine prior to or simultaneously with ketamine offers the advantage of minimizing the decrease in heart rate and arterial blood pressure induced by xylazine alone [131]. Respiratory rate often increases after xylazine and ketamine administration, but it is usually accompanied by a decrease in PaO2 and an increase in PaCO2 [132, 133]. Arterial pH decreases slightly as a result of accumulation of PaCO2. Only minor changes in base excess and bicarbonate are observed during xylazine and ketamine anesthesia, indicating hypoventilation is minor without the need for metabolic compensation [132]. Alternatively, anesthesia can be maintained with a continuous infusion of ketamine (2 mg/ml) in 0.9% NaCl solution or 5% dextrose solution at a rate of 10 ml/min [65]. A bolus injection of ketamine (2 mg/kg IV) followed by continuous IV infusion of 0.2% (2 mg/ml) ketamine in 0.9% NaCl solution at a rate of 10 ml/min in cows produces anesthesia appropriate for minor and major surgeries (e.g. toe amputation, laparotomy, etc.) [64]. LDs of xylazine (0.05 mg/kg IV or 0.05–0.1 mg/kg IM) and ketamine (2 mg/kg IV or 4 mg/kg IM) combined have been used to produce anesthesia with less intensity of analgesia and shorter duration of recumbency [125]. As mentioned in Chapter 3, IV xylazine (0.1–0.2 mg/kg) and diazepam (0.1–0.2 mg/kg) induce approximately 30 minutes of immobilization with analgesia in adult cattle [134]. Depending on the desired level of analgesia, HD of xylazine with LD of diazepam is suitable for procedures requiring a greater degree of analgesia, whereas LD of xylazine with HD of diazepam is preferred for animals with high anesthetic risk. Figure 4.1 Endotracheal intubation using the digital palpation technique in a bull anesthetized with xylazine (0.1 mg/kg IV) and ketamine (2.2 mg/kg IV). Ketamine (1 mg/ml) can be mixed with 5% guaifenesin (50 mg/ml) solution to maintain short duration of anesthesia in ruminants [86]. A combination of guaifenesin (50 mg/ml), ketamine (1–2 mg/ml), and xylazine (0.1 mg/ml), often referred to as Bovine Triple Drip or GKX, can be used for procedures that require longer duration of anesthesia [135]. Anesthesia using Bovine Triple Drip can be induced with 0.55–1.1 ml/kg initially and maintained with 2.2 ml/kg/hour in adult cattle and 1.65 ml/kg/hour in calves. Onset of anesthesia is gradual but smooth, muscle relaxation is excellent, and tracheal intubation is easy. Supplementation with O2 (5–10 l/min) during prolonged procedures may help prevent hypoxemia. Mild hypoventilation is observed when this anesthetic mixture is used. Recovery to standing with Bovine Triple Trip usually occurs within 40–45 minutes after discontinuation of the infusion. Surgical procedures that have been performed in cattle anesthetized with Bovine Triple Trip include femoral fracture plating and pinning, penile surgery, umbilical hernia repair, cesarean section, and celiotomy [74]. The concentration of xylazine and/or ketamine should be reduced to 0.05 and 1 mg/ml, respectively, for procedures lasting longer than 2 hours to prevent accumulation of the drugs and prolonged recovery. Because cattle anesthetized with Bovine Triple Drip may regurgitate due to profound muscle relaxation, tracheal intubation is recommended immediately following induction [101]. A combination of higher doses of ketamine, xylazine, and butorphanol (Ketamine Stun) than those used for standing sedation and chemical restraint can be used to produce a short duration of recumbency and anesthesia. Onset of recumbency occurs within 1 minute following IV bolus injection of ketamine (0.3–0.5 mg/kg), xylazine (0.025–0.05 mg/kg), and butorphanol (0.05–0.1 mg/kg). Animals may appear to be “awake” but are not responsive to external stimulations. Many minor surgical procedures can be performed under this level of light anesthesia. Mild involuntary head or limb movements can occur which are not a response to surgical stimulation. Purposeful movement or vocalization indicates inadequate depth of anesthesia, and half of the initial doses of xylazine and ketamine should be administered to produce appropriate depth of anesthesia. Surgical anesthesia is produced with this combination; however, local anesthetic can be administered to the surgical field to enhance analgesia. A short period of anesthesia (15–20 minutes) is achieved with this combination. IM or subcutaneous (SC) administration of the same combination, ketamine (0.1 mg/kg), xylazine (0.05 mg/kg), and butorphanol (0.025 mg/kg), produces recumbency but with less analgesia as compared to that produced when administered by IV injection. Recumbency occurs within 3–10 minutes and lasts for 45 minutes following SC injection. Endotracheal intubation can be accomplished with this technique [125]. Initially, the combination of butorphanol (0.0375 mg/kg), ketamine (3.75 mg/kg), and xylazine (0.375 mg/kg) was described by Dr. Larue Johnson at Colorado State University. The combination was made by adding 1 ml of xylazine (100 mg) and 1 ml of butorphanol (10 mg) to 10 ml (1000 mg) of ketamine and administering the combination at a dose of 1 ml/20 kg (44 lb) IM. Recumbency occurs within 3–5 minutes with 20–30 minutes of anesthesia. Half of the original dose of each drug can be administered to extend the duration of anesthesia. This dose combination is recommended only for healthy animals as the combination contains a higher dose of xylazine [136] than that described by Abrahamsen [125]. Recovery to standing time is expected to be longer with this dose combination. In clinical practice, IV butorphanol (0.025–0.05 mg/kg), xylazine (0.1–0.15 mg/kg), and ketamine (0.5–1 mg/kg) has been used to produce 30 minutes of surgical anesthesia for complicated umbilical surgery. Xylazine and butorphanol are administered to produce profound sedation and followed by ketamine to induce anesthesia. Miesner [137] indicated that endotracheal intubation during these surgical procedures greatly improved the quality and duration of the anesthesia. If surgery requires an hour or longer, IV infusion of Bovine Triple Drip can be used to extend the duration of anesthesia. IV administration of medetomidine (0.02 mg/kg) and ketamine (2.2 mg/kg) induced lateral recumbency for 94 ± 25 minutes in Holstein calves [138]. Muscle relaxation was adequate for endotracheal intubation in all calves. During anesthesia, heart rate remained unchanged, but arterial blood pressure increased significantly. Respiratory rate increased significantly immediately following drug administration, but mean values for PaO2, PaCO2, and pHa remained within normal ranges. Atipamezole and tolazoline were each effective in reversing medetomidine and ketamine anesthesia with recovery to standing occurring in 4 ± 3 and 16 ± 9 minutes, respectively, after injection. Yohimbine is the least effective of the three α2 antagonists in shortening the duration of medetomidine and ketamine anesthesia; calves did not stand for 48 ± 20 minutes after the injection [138]. Medetomidine (0.02 mg/kg IV) combined with a lower dose of ketamine (0.5 mg/kg IV) was reported to produce anesthesia of 32 minutes for calves undergoing umbilical hernia surgery. The intensity of analgesia produced by the lower dose of ketamine in this combination was not sufficient to prevent signs of pain during surgery, and administration of a local anesthetic solution at the incision site was required. Similar to xylazine and ketamine combination, anesthesia can be prolonged with administration of half of the initial dose of each drug if needed [139]. In cattle, diazepam (0.1 mg/kg IV) administered prior to ketamine (4.5 mg/kg IV) produces 10–15 minutes of surgical anesthesia. Endotracheal intubation can be achieved with this combination, but swallowing reflex may still be present. Animals usually stand 30 minutes after this combination of drugs is administered [101, 128]. In calves, Telazol (4 mg/kg IV) induces 45–60 minutes of satisfactory anesthesia with minimal cardiovascular depression [79], and induces rapid immobilization when administered in doses of 4–12 mg/kg intramuscularly. When Telazol is administered at a dose of 10 mg/kg or greater, apnea occurs. Muscle relaxation is profound, but analgesia is minimal. The overall response is characteristic of general anesthesia. Xylazine can be administered at a dose of 0.1–0.2 mg/kg IM in combination with Telazol (4 mg/kg IV) to increase the duration of anesthesia for an additional 15 and 25 minutes for 0.1 and 0.2 mg/kg, respectively. However, higher doses of xylazine tend to increase the incidence of apnea [140]. By administering a combination of xylazine (0.1 mg/kg IV) with Telazol (4 mg/kg IV), a longer duration of profound muscle relaxation and analgesia was observed when compared to Telazol (4 mg/kg IV) administered alone [83, 140]. A combination of TKX‐Ru has been used successfully to capture wild ruminants. When 500 mg of Telazol is reconstituted with 2.5 ml of ketamine (100 mg/ml) and 1 ml of xylazine (100 mg/ml) with a final volume of 4 ml, the concentration of each drug is 125 mg/ml of Telazol, 62.5 mg/ml of ketamine, and 25 mg/ml of xylazine, respectively. The recommended IM dose of the mixture is 1.25–1.5 ml/125 kg (275 lb) for small cattle and 1 ml/125 kg (275 lb) for larger, adult cattle. Recumbency usually occurs within 5–10 minutes following IM administration of TKX‐Ru. Twenty minutes is required for the initial administration to reach peak anesthetic effect before repeat dosing is considered. Recovery to standing with this combination usually occurs within 40–60 minutes following TKX‐Ru administration. Ketamine and guaifenesin mixture or Bovine Triple Drip described previously can be administered following TKX‐Ru to maintain longer duration of anesthesia [141]. A combination of tiletamine–zolazepam (Telazol), ketamine and detomidine (TZKD) has been administered to induce anesthesia in calves and free‐ranging cattle [142, 143]. The TZKD mixture is created by adding 5 ml of 100 mg/ml of ketamine and 4 ml of 10 mg/ml of detomidine into 500 mg of Telazol, resulting in a final concentration of 55.5 mg/ml of ketamine, 55.5 mg/ml of Telazol, and 4.4 mg/ml of detomidine. Three doses of TZKD, 1 ml/100 kg (220 lb) (LD), 1.3 ml/100 kg (220 lb) (medium dose, MD), and 1.5 ml/100 kg (220 lb) (HD) were given to calves in separate occasions. The onset to recumbency was 6 ± 2, 5 ± 2, and 4 ± 1 minutes for LD, MD, and HD, respectively. The duration of anesthesia was 30 ± 8, 32 ± 6, and 52 ± 7 minutes and the duration of total recumbency time was 83 ± 19, 113 ± 13, and 128 ± 13 minutes, for LD, MD, and HD, respectively [142]. The duration of analgesia, as evidenced by lack of response to pin prick stimulus, was 5 minutes for LD and 35 minutes for MD and HD. Similarly, a significant reduction in response to electrical stimulus was also observed at 35 and 55 minutes for MD and HD, respectively [142]. Mild bradycardia was observed with all doses. The most notable side effects of this combination were respiratory depression and hypoxemia which was accompanied by significant decreases in PaO2 and O2 saturations [142]. It is believed that the adverse effect of detomidine, an α2 agonist, is responsible for the respiratory depression and hypoxemia observed with this combination. TZKD has been used to immobilize and anesthetize 53 free‐ranging cattle for minor surgical procedures (e.g. subconjunctival infiltration, orchiectomy, goring repair, abdominal herniorrhaphy) or medical treatment (e.g. stroma treatment, joint infiltration) [143]. Most of these procedures are considered to cause minimal to moderate pain and local or regional anesthetic techniques can be applied to enhance the analgesic effect. The mean IM dose of the combination used was 1.07 ml/100 kg (220 lb). Most procedures required less than 1 hour to complete with the exception of two abdominal herniorrhaphy and one goring injury, which required one repeated dosing at 42 ± 3 minutes after the initial administration. One of the herniorrhaphy surgery was prolonged and required three repeated dosings with a final dose of 2.9 ml/100 kg (200 lb). Good analgesia occurred in 51 animals but was fair in two animals. The onset of anesthesia occurred at 6.1 ± 2.8 minutes following drug administration. The duration of anesthesia ranged from 5 to 119 minutes [143]. Atipamezole (0.02–0.06 mg/kg IM), an α2 antagonist, was administered at 6–41 minutes to those requiring only one single dose of TZKD. In those receiving repeated dosing, atipamezole was administered at 75–124 minutes after the initial dose [143]. Animals receiving a single dose of TZKD stood at 12.1 ± 8.4 minutes, whereas those who received repeated doses stood at 23.0 ± 14.4 minutes after the administration of atipamezole [143]. None of these animals were fasted, but no incident of regurgitation or bloating occurred even though 18 animals were placed in lateral recumbency and two were in dorsal recumbency [143]
4
Injectable Anesthetics and Field Anesthesia
4.1 Injectable Anesthetics
4.1.1 Ketamine
4.1.1.1 Cattle
4.1.1.2 Small Ruminants and Camelids
4.1.1.3 Swine
4.1.2 Telazol
4.1.2.1 Cattle
4.1.2.2 Small Ruminants and Camelids
4.1.2.3 Swine
4.1.3 Propofol
4.1.3.1 Small Ruminants and Camelids
4.1.3.2 Swine
4.1.4 Alfaxalone
4.1.4.1 Small Ruminants and Camelids
4.1.4.2 Pigs
4.1.5 Guaifenesin
4.2 Field Anesthesia
4.2.1 Cattle
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