Abstract
Rabbit anesthesia is drastically different than anesthesia of domestic carnivores. Rabbits have a strikingly higher perianesthetic mortality as compared to dogs and cats. Based on a large study including 8209 rabbit anesthetic procedures, the risks of anesthetic and sedation-related death in rabbits was 1.39% (95% CI 1.14–1.64%) within 48 hours of the procedure, almost ten times greater than dogs. This indicated that approximately 1 rabbit out of 72 anesthetized or sedated died. The use of proper sedation protocols, multimodal analgesia including constant-rate infusions, induction without unnecessarily high anesthetic gas concentrations, and endoscopic-guided endotracheal intubation have drastically reduced the perianesthetic mortality in the authors’ institutions. In the current presentation we are going to discuss available protocols and best practices to minimize the risk of anesthetic-related mortalities in rabbits.
Introduction
Rabbit anesthesia is drastically different than anesthesia of domestic carnivores. Rabbits have a strikingly higher perianesthetic mortality as compared to dogs and cats.1,2 Based on a large study including 8209 rabbit anesthetic procedures, the risks of anesthetic and sedation-related death in rabbits was 1.39% (95% CI 1.14–1.64%) within 48 hours of the procedure, almost ten times greater than dogs.1 This indicated that approximately 1 rabbit out of 72 anesthetized or sedated died. When stratifying rabbits by healthy/diseased health status, healthy rabbits had a 0.73% risk of mortality, and diseased rabbits had a 7.4% risk of mortality.1 A more recent study found an even higher mortality rate within 72 hours of the procedure, equal to 4.8% (95% CI 0.025–0.086; 6 rabbits over 210 procedures).2 Unfortunately, while these studies are useful in order to identify this risk and to describe the risk to owners, there is limited clinical information that can be extrapolated reliably from the published reports to guide and improve future anesthetic events.
A further difficulty for selecting an ideal rabbit anesthesia relies in the fact that most published research studies include populations limited in numbers and procedures, making difficult to generalize their results to clinical patients. In the current presentation we are going to discuss available protocols and best practices to minimize the risk of anesthetic-related mortalities in rabbits. The veterinary practitioner should keep in mind that multimodal analgesia is fundamental in rabbits as well as in any other living beings.
Preparation of the Patient
Intravenous Catheter Placement
Placement of an intravenous catheter should be performed in every anesthetic event in order to administer fluids, analgesic drugs and, above all, emergency drugs if required. The marginal ear vein is the preferred site, but the cephalic and saphenous veins can be used as well. It is authors’ opinion that, in healthy animals, it is better to apply the intravenous catheter after premedication in order to avoid stress to the animal. If the patient is more critical and IM premedication is not appropriate, a racemic mixture of lidocaine and prilocaine (EMLA cream) can be applied 30 minutes before venipuncture in order to reduce pain and discomfort. If a catheter is already in place, it is important to check patency before anesthesia. It is key to perform intubation only once the rabbit has been properly premedicated and does not show any chewing or tongue movements. Preanesthetic medications are discussed later on in these proceedings.
Intubation
Fasting is avoided in rabbits, but it is fundamental to clean the rabbit’s mouth before intubation in order to remove food residues that could be otherwise pushed inside the trachea and inhaled. In order to achieve endotracheal intubation (ETI), a suitable depth of anesthesia should be induced by means of premedication (including combinations of benzodiazepine, dissociative agents, opioids and/or alpha-2 agonists) and, if needed, induction agents (e.g., propofol or alfaxalone). Lidocaine (spray or the injectable preparation instilled topically) can be used to desensitize the larynx.
Regardless of the method used for ETI, the rabbit should be placed in sternal recumbency with the neck and head extended dorsally and cranially but not completely vertical. A 2–4.4 mm ID uncuffed ETT should be available.
ETT in rabbits can be performed in different ways:
- Endoscopically guided ETI: A 2.7 mm endoscope at 30 or 0 degrees can be used. If feasible, it can be inserted into the endotracheal tube (ETT) and used as a guide to visualize the glottis and as a stylet to facilitate the ETT insertion. In ETT of smaller diameters a “side by side” technique is used, just to simply visualize the glottis. Endoscopic intubation is the only technique currently in use by the authors because (1) it allows visualization of the glottis and therefore inappropriate transport of food material into the trachea with the ETT; (2) once mastered, it is fast and allows adaptation to the different type of larynx of rabbits; and (3) it allows identification of alterations at the level of the glottis (e.g., laryngeal neoplasia).
- Blind: The ETT is inserted into the mouth and the breath sounds of the rabbit or the presence of condensation on the ETT itself are used to guide the insertion.
- Otoscope: For direct visualization of the larynx. The otoscope is inserted into the side of the patient’s mouth, then moved centrally and used to elevate the soft palate and visualize the glottis. An ETT can be inserted through the cone of the otoscope or with a “side by side” technique.
In the authors’ experience, endoscopically guided ETI allows insertion of a larger diameter ETT, thus decreasing airway resistance and work of breathing for the rabbits and allowing more accurate and reliable monitoring of end-tidal carbon dioxide (EtCO2). Since a few years ago, a supraglottic airway device (V-GEL, Docsinnovent) has been produced and marketed for use in rabbits. The device is made of a soft gel-like material and should provide a pressure seal around the airway and the esophagus. The authors had instances in which V-GELs resulted in poor rabbit oxygenation (low SpO2) and dislocated from the front of the glottis of the rabbit, resulting in ventilation in the gastrointestinal tract. Until a properly sized, clinical-based study compares the safety and effectiveness of supraglottic airway devices in rabbits with standard endotracheal intubation, the authors’ advice is to maintain the use of endotracheal intubation.
Induction of General Anesthesia (Isoflurane, Sevoflurane, Propofol and Alfaxalone)
Historically, induction with anesthetic gases has been considered safer in exotic small mammals than induction with injectable agents (such as propofol, etomidate or alfaxalone). However, there are several shortcomings associated with induction of anesthesia with anesthetic gases that need to be considered.
Isoflurane in rabbits causes apnea during induction and a severe cardiovascular depression at high concentrations.3,4,5 These are two main reasons why the use of anesthetic gases and especially the widely used isoflurane should be tailored in rabbits. Considering anesthetic mortality in healthy patients, it is possible that isoflurane accounts for some of the deaths observed. When isoflurane was administered in rabbits for anesthetic induction, long periods of apnea (>1 min) occurred together with bradycardia, hypercapnia and hypoxaemia.5 In another study, most animals struggled violently during induction with both isoflurane and sevoflurane.3 The authors of these studies warned against the use of isoflurane, sevoflurane, and desflurane for anesthetic induction of rabbits.3,5
During anesthesia, reaching high isoflurane concentrations in rabbits results in a dose-dependent cardiopulmonary depression attributable to vasodilation and negative inotropy.4 At an isoflurane concentration of 4.15% with mechanical ventilation, cardiovascular depression is severe.4 The authors mention that use of unnecessarily high isoflurane concentrations in this species should be avoided.4
The widespread use of endoscopic intubation has allowed a more consistent use of injectable agents for induction. The window of time required to intubate the rabbit may be shorter as compared to anesthetic gases (i.e., the rabbit may need to be intubated more quickly), but there are several cardiovascular benefits associated with the use of different injectable agents as induction.
Amongst injectable agents, propofol is commonly used, above all in rabbits, but recently alfaxalone has been licensed in this species as well. The main advantage of alfaxalone, compared with propofol, is that it can be used also IM (even if it is not licensed in rabbits for this route yet). When used IV, a dose-dependent respiratory depression and apnea are commonly reported.6,7 The Summary of Product Characteristics (SPC) of Alfaxan suggests that rabbits are pre-oxygenated before induction of general anesthesia and that oxygen is provided throughout the entire anesthetic procedure. Dosage is reported as 4 mg/kg in premedicated rabbits and 5 mg/kg in non-premedicated animals even if lower doses (1–2 mg/kg) are generally efficacious. Despite the fact that propofol is still the authors’ agent of choice for induction of anesthesia in rabbits, it must be remembered that apnea is common; therefore, the clinician should be confident with endotracheal intubation. Respiratory depression is dose related and can be decreased with slow administration of the drug. Nevertheless, we discourage inducing rabbits with propofol if endoscopic-guided intubation cannot be performed.
Constant Rate Infusions
Constant rate infusions (CRI) may be extremely advantageous in rabbits. A fentanyl CRI may reduce isoflurane MAC by approximately 60% in New Zealand white rabbits.8 Furthermore, in rabbits anesthetized with isoflurane, mean arterial blood pressure, systemic vascular resistance and cardiac output were significantly higher when different fentanyl concentrations were obtained through CRIs.9
Lidocaine CRI at 50 mcg/kg/min resulted in the reduction of isoflurane MAC by 10.5%, while a 100 mcg/kg/min CRI resulted in the reduction of MAC by 21.7%.10 Lidocaine also induced significant decreases in arterial blood pressure and heart rate, but the variables were still within the reference intervals for rabbits.10 When compared to buprenorphine for management of postoperative pain, a CRI of lidocaine provided better postoperative outcomes with respect to fecal output, food intake, and glucose concentrations, with similar pain scores.11 Thus, lidocaine appeared to be a suitable alternative to buprenorphine for alleviating postoperative pain with minimal risk of anorexia and gastrointestinal ileus.11
Vasopressors
Based on a recent study, phenylephrine might be more indicated than dopamine in order to increase MAP in anesthetized rabbits.12 Dopamine increased stroke index at the highest infusion rate of 30 mcg/kg/min; however, cardiac output and mean arterial blood pressure remained unchanged from baseline values. Within the dose range of 5 to 30 mcg/kg/min, dopamine was not an effective treatment for isoflurane-induced hypotension in rabbits. Phenylephrine instead, at a rate of 2 mcg/kg/min, increased mean arterial blood pressure to 62 mm Hg from the baseline value of 45 mm Hg. This was a result of an increase in systemic vascular resistance with a concomitant decrease in heart rate and no change in cardiac output. Phenylephrine was not effective at the dose of 0.125, 0.25, 0.5, 1.0 mcg/kg/min and only minimally effective at a dose of 2 mcg/kg/min. Blood lactate concentration increased with time when rabbits received either treatment.12
Anesthetic Drugs Commonly Used in Rabbits
Several anesthetic protocols have been used and published in rabbits. Classes of drugs commonly employed include sedatives (midazolam, alpha-2 agonists, acepromazine), opioids (butorphanol, buprenorphine, fentanyl, methadone) and ketamine. These drugs should be used in different combinations and at different doses depending on the procedure performed, the required degree of sedation and analgesia and on the animal’s temperament.
Alpha-2 agonists (medetomidine and dexmedetomidine) are commonly used in rabbits due to their sedative and analgesic properties and their anesthetic-sparing effect. However, important side effects must be remembered, above all at the cardiovascular level. Generally, there is an increase in systemic vascular resistance (SVR) and reflective reduction in heart rate followed by a centrally mediated bradycardia accompanied by normal or slightly increased/decreased SVR, depending on the species. In rabbits, SVR remains increased during dexmedetomidine infusions.13 Regarding the respiratory system, dexmedetomidine has been reported to affect the respiratory response to carbon dioxide in rabbits.14 The effects of alpha-2 agonists on gastrointestinal (GI) motility have been extensively studied both in human and veterinary medicine leading to controversial results. A recent study suggests a delayed transit motility in rabbits administered ketamine + medetomidine as compared to rabbits receiving ketamine + midazolam; however, the time to production of feces was identical in the two groups.15 Other side effects of alpha-2 agonists include hyperglycaemia and enhanced diuresis. The authors generally use dexmedetomidine at doses of 25–35 mcg/kg IM + ketamine ± benzodiazepine ± opioids, either as a standalone anesthetic protocol for short and noninvasive procedures (e.g., dentals, castrations), or as a premedication before induction with propofol as needed, with intubation and maintenance on isoflurane or sevoflurane.
Benzodiazepines, particularly midazolam, can be used in rabbits. Midazolam can be given intramuscularly, and side effects are very limited. In the authors’ experience, midazolam can be added to alpha-2 agonists, in very nervous healthy animals or can be given as the only sedative in critically ill patients. 0.5–1 mg/kg IM is the dose commonly used by the authors.
Ketamine can be used either for premedication or for induction of general anesthesia. Immobilization and analgesia are the main advantages offered by ketamine, whereas poor muscle relaxation is the main disadvantage; the latter can be overcome by adding benzodiazepines or alpha-2 agonists. Several studies evaluated the use of ketamine in association with other drugs in rabbits.16 An effective premedication consists of ketamine (4–5 mg/kg up to 10 mg/kg) with alpha-2 agonists and benzodiazepine all administered intramuscularly.
Opioids are the mainstay for perioperative analgesia in humans, dogs and cats; their use in rabbits has always been controversial due to their effects on GI motility. Opioid receptors are highly expressed at the GI level and endogenous endorphins activation of mu-opioid receptors has been reported to inhibit GI motility.17
In rabbits, morphine has been reported to inhibit the small intestine’s contractility in vitro,18 whereas buprenorphine is the opioid more commonly evaluated in clinical studies. Several studies have demonstrated a negative effect of buprenorphine on GI motility.11,19,20
The authors’ drugs of choice are methadone at doses of 0.2–0.3 mg/kg SC or IM or hydromorphone at doses of 0.3–0.5 mg/kg SC or IM. In a recent study on healthy rabbits20 methadone administration was associated with no negative effects on appetite and GI motility, compared to buprenorphine and hydromorphone.20 Butorphanol 0.3–0.4 mg/kg is used to enhance the activity of an alpha-2 agonist or benzodiazepine when sedation is required for nonpainful procedures, such as radiography or computed tomography. Nonsteroidal anti-inflammatory drugs and locoregional anesthetic techniques should always be considered in order to provide multimodal analgesia.
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