and the administration of vatinoxan was able to increase PaO2 and SpO2 and minimize the detrimental effect of hypoxemia by blocking the effects of the α2 agonist on the peripheral α2 receptors [128].
2.5 Diazepam and Midazolam (Benzodiazepine Derivatives)
Benzodiazepine derivatives like diazepam and midazolam are classified as minor tranquilizers. These drugs are used for their anxiolytic, anticonvulsant, and central muscle‐relaxing effects. Benzodiazepines produce little or no analgesic effect, but they can reduce the dose requirement of the concurrently administered general anesthetics [22]. Benzodiazepines produce minimal cardiovascular depression. For this reason these drugs are favorable for use in animals with increased anesthetic risk. Benzodiazepines can be used as alternatives to α2 agonists to produce tranquilization when adverse effects associated with α2 agonists (e.g. hypoxemia, pulmonary edema, or increased airway pressure) become undesirable. Diazepam and midazolam are the two most commonly used benzodiazepines in clinical veterinary practice. Diazepam is insoluble in water; its injectable solution contains 40% propylene glycol as solvent. IV propylene glycol administered rapidly sometimes results in hypotension and vascular irritation. Dilution, mixture of the injectable solution of diazepam with water, or a water‐soluble drug solution may cause cloudiness of the mixture which does not affect the potency of the drug. Midazolam is two to three times more potent than diazepam. Its injectable solution is water soluble. Thus, IM administration of midazolam will not cause tissue irritation [129]. In contrast to the general perception that benzodiazepines like diazepam and midazolam do not produce an analgesic effect, Kyle et al. [130] and Lizarraga and Chambers [131] reported that midazolam appeared to provide mediation of antinociception at the level of the spinal cord in sheep. Midazolam was rapidly absorbed with an elimination t½ of midazolam of 0.79 and 0.94 hours following IV and IM administration, respectively. A transient decrease in respiratory rate has been observed during midazolam‐induced tranquilization [132]. Diazepam and midazolam can be used as a preanesthetic for their anxiolytic and muscle‐relaxing effect, or they can be used with ketamine to improve muscle relaxation during anesthesia [133]. Other benzodiazepines, including flurazepam (2 mg/kg IV) [134], lorazepam (0.1 mg/kg IV) [135], and brotizolam (1–10 mg/kg PO) [136], have been used in pigs.
2.5.1 Cattle, Small Ruminants, and Camelids
Diazepam can be administered alone to produce dose‐dependent CNS depression from mild sedation to recumbency for 15–30 minutes. The tranquilizing effects of diazepam in healthy animals tend to be variable and somewhat unreliable [10]. Doses from 0.55 to 1.1 mg/kg IM have been recommended for use in ruminants and swine [137]. Diazepam at 0.2 mg/kg IV has been used to produce mild tranquilization for performing a transdermal tracheal wash [10]. Diazepam (0.1 mg/kg IV) has been administered with xylazine (0.2 mg/kg IV) to a bull to produce immobilization for wire placement during mandibular fracture repair. No additional local anesthetic was needed during the wiring process. The duration of deep sedation was 30 minutes and the bull stood within an hour after administration of the drugs [138]. Diazepam (0.1 mg/kg IV) and butorphanol (0.1 mg/kg IV) induce recumbency for a short period of time in camelids [139].
Midazolam (0.2 mg/kg IV) was able to reduce the response of sheep to painful mechanical stimulation [130]. In goats, IM midazolam (0.6 mg/kg) induced 20 minutes of sedation. Hypnosis with recumbency occurred and lasted for 10–20 minutes when midazolam was administered intravenously at 0.6 and 1.2 mg/kg. Increasing the dose to 1.2 mg/kg enhanced the degree of reflex suppression, and the animals appeared to be in a light plane of anesthesia as indicated by the lack of response to mechanical stimulation applied using the tail base clamp [140]. In goats with urethral obstruction, when the effect of increasing the urine output of xylazine is contraindicated, diazepam or midazolam can be given alone or with other anesthetics to induce anesthesia. Flumazenil, a benzodiazepine antagonist, can be administered at 0.02 mg/kg IV or a 1 : 13 ratio (1 part of flumazenil to 13 parts of diazepam) to antagonize the CNS effects of diazepam and midazolam [10].
2.5.2 Swine
Diazepam has been given to miniature pigs at doses from 5.5 to 8.5 mg/kg IM with maximal sedation occurring within 30 minutes following administration [22]. Prolonged recovery has occurred when large doses of diazepam are given intramuscularly to older sows and boars. A continuous rate infusion (CRI) of diazepam (CRI: 1 mg/kg/hour IV, following 0.5–10 mg/kg IM and 0.44–2 mg/kg IV) has been used in pigs to maintain long‐term hypnosis and sedation for up to 6 hours in a research setting [141, 142]. Satisfactory sedation with 0.1–0.5 mg/kg of midazolam IM has been reported [18], whereas a calming effect and sedation occur within 3–4 minutes following intranasal administration of 0.2–0.4 mg/kg of the drug [143]. In piglets and adult swine, midazolam administered either intramuscularly or intranasally at 0.1–0.2 mg/kg produced effective tranquilization [143, 144]. Midazolam (1 mg/kg IM) has been combined with azaperone (4 mg/kg IM) to produce preanesthetic tranquilization prior to induction with propofol [145]. Midazolam in general has minimal cardiopulmonary effects. However, it has been shown to cause a 20% decrease in heart rate and 50% decrease in respiratory rate in pigs receiving 0.1 mg/kg IM of midazolam [144].
2.6 Chloral Hydrate
Chloral hydrate was one of the first general anesthetics used in large animal practice. Chloral hydrate itself does not have a CNS‐depressing effect; it depends on its metabolite, trichloroethanol, to produce sedative and anesthetic effects. This latency of action as well as the narrow margin of safety of the drug makes it an undesirable anesthetic for use in clinical practice. Nonetheless, chloral hydrate is a very reliable sedative. In horses, chloral hydrate is often administered as an alternative when other tranquilizers or sedatives fail to produce the desired calming effect. Chloral hydrate does not have an analgesic effect, thus an additional analgesic is required if the animal is in pain or the procedure being performed is painful. Chloral hydrate is very irritating to the tissue. Therefore, IV injection of the drug is better via an IV catheter to prevent accidental perivascular injection and the consequential severe tissue damage. Chloral hydrate has been used to sedate unapproachable but confined cattle via oral administration. Water should be withheld for 24–36 hours prior to offering the animal diluted chloral hydrate drinking solution to ensure complete consumption of the drug. The dose recommended for oral administration is 100–150 g in 8–12 l of water per animal for sedation and 5–7 g per 100 kg (220 lb) for light to moderate narcosis [146].
In pigs, oral chloral hydrate (13 g/50 kg [110 lb]) produced sedation within 20–30 minutes following administration via a stomach tube [147]. Though intraperitoneal administration (4–6 ml of 5% solution/kg) has been reported in the pig, the technique is not recommended as peritonitis is a common complication [148]. However, Jennings reported intraperitoneal chloral hydrate administration (0.3 mg/kg in 5% solution) produced sedation within 30 minutes with a duration of 60 minutes. No tissue irritation or signs of peritonitis were observed [146]. Chloral hydrate (1–4 ml of 5% solution) has been used in combination with azaperone (4 mg/kg IM) in 500 pigs to produce general anesthesia for 2 hours with complete recovery to standing within 4–5 hours [149].
References
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2 2 DeRouchey, J., Goodband, B., Tokach, M. et al. (2009). Digestive system of the pig‐anatomy and function. In: North American Veterinary Community Conference, Orlando, FL, USA, 375–376.
3 3 Gross, M. and Booth, N. (1995). Tranquilizers, α2‐adrenergic agonists, and related agents. In: Veterinary Pharmacology and Therapeutics, 7e (ed. H. Adams), 311–357. Ames: Iowa State University Press.
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