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Anesthesia and Analgesia in Rabbits and Rodents
TOPICS IN MEDICINE AND SURGERY ANESTHESIA AND ANALGESIA IN RABBITS AND RODENTS Sandra Wenger, Dr. med. vet., MSc, Dip. ECVAA
Abstract Rabbits and rodents are popular pets and are often presented to veterinarians for evaluation and medical treatment. Anesthesia in exotic pets is required for many diagnostic and surgical procedures and is associated with a higher perioperative risk in rabbits and rodents when compared with dogs and cats. Inhalation anesthetic agents are commonly used as the sole source of anesthesia in small rodents, whereas injectable agents in combination with inhalation anesthesia are often used for rabbits and larger rodents. Analgesia is an important component of exotic pet medicine. Although it may be difficult to recognize signs of pain in companion exotic mammals, adequate pain management should always be provided. Opioid and nonsteroidal antiinflammatory drugs are the analgesic medications of choice, but others should be considered (e.g., local anesthetic agents). This article provides an update of the current literature regarding anesthesia and analgesia in rabbits and rodents. Copyright 2012 Elsevier Inc. All rights reserved. Key words: anesthesia; lagomorphs; monitoring; pain management; perioperative care; rodents
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n the United States and Europe, rabbits and rodents are common household pets, with rabbits being the third most popular mammalian pet in the United Kingdom (http://www.rabbitwelfare. co.uk). As a companion animal grows in popularity, there appears to be a concurrent increase in the client expectations of the veterinary care provided. Anesthesia in exotic pets is required for a number of diagnostic and surgical procedures. Furthermore, in certain species sedation or anesthesia may be required to perform a thorough physical examination. Analgesia is an important aspect of exotic pet medicine, and it is likely that pain is undertreated in these patients.1 A recent survey evaluating the anesthetic mortality in small animal practice showed an increased risk associated with anesthesia in rabbits and other small exotic mammal species compared with dogs and cats.2 The overall risk of anestheticrelated death was 1.4% in rabbits, 3.8% in guinea pigs, and varied between 1.7% and 3.7% for other small exotic mammal species. As expected, diseased animals had a higher mortality rate than healthy patients. The following factors were brought forth in the study as reasons for the increased mortality observed in exotic mammal species when compared with dogs and cats: ● ●
Stress on induction Increased risk of hypothermia associated with the higher surface area to volume ratio
● ● ● ●
Subclinical respiratory infections with Pasteurella multocida in rabbits Perioperative diseases involving respiratory, digestive, and fluid balance disorders Fewer veins that are easily accessible for catheterization Endotracheal intubation is technically demanding.
This article will provide current information regarding the use of anesthesia and analgesia in rabbits and rodents with a special emphasis on the above-mentioned increased risk factors. PREANESTHETIC PREPARATIONS A thorough patient history and physical examination are required before any procedure in which
From the Clinic for Zoo Animals, Exotic Pets and Wildlife, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland. Address correspondence to: Sandra Wenger, Dr. med. vet., MSc, Dip. ECVAA, Clinic for Zoo Animals, Exotic Pets and Wildlife, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, 8057 Zürich, Switzerland. E-mail: [email protected]. © 2012 Elsevier Inc. All rights reserved. 1557-5063/12/2101-$30.00 doi:10.1053/j.jepm.2011.11.010
Journal of Exotic Pet Medicine 21 (2012), pp 7–16
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TABLE 1. Sedatives and pre-medicants used in rabbits and rodents, doses are given in mg/kg unless otherwise indicated Drug
Rabbit
Acepromazine*
0.25 – 1 IM, SC, IV10
Acepromazine ⫹ Butorphanol Midazolam Fentanyl/Fluanisone (Hypnorm®) Medetomidine Medetomidine ⫹ Butorphanol
0.5 ⫹ 0.5 IM, SC5 0.5 – 2 IV, IM5 0.15 – 0.3 ml/kg IM5 0.1 – 0.5 IM, SC5
Guinea Pig 0.5 – 1 IM, SC10
Chinchilla 0.5 – 1 IM,
SC10
0.5 – 2 IM15 0.4 – 2 IM15 0.5 – 1 0.110
Mouse/Gerbil SC10
Rat
0.5 – 1 IM, may induce seizures in gerbils
0.5 – 1 IM, SC10
2 – 3 IM15 0.2 – 1 ml/kg IM10 0.110
2.5 SC, IM15 0.2 – 3 ml/kg IM 0.08 – 0.210 0.08 ⫹ 0.115
Abbreviations: IV, Intravenously; IM, Intramuscularly; SC, Subcutaneously. *Long duration of action, may cause vasodilation.
anesthesia is involved. Respiratory infections are commonly diagnosed in pet rabbits and rodents.3,4 Animals exhibiting signs of nasal discharge and increased respiAnimals ratory sounds or effort should be exhibiting signs considered at increased risk for an anesthetic procedure. Other comof nasal mon findings in pet exotic mamdischarge and mals that reduce the patient’s ability to withstand the stress associincreased ated with general anesthesia respiratory include dehydration, anorexia, and obesity. Whenever possible, these sounds or effort abnormal physical conditions should be should be corrected before anesthesia is performed. Administration of considered at fluids intravenously or subcutaneincreased risk ously assists in stabilizing dehydrated patients. for an Rabbits and rodents are prey speanesthetic cies and are easily stressed when placed in unfamiliar surroundings. procedure. It is favorable if these animals are hospitalized in a quiet environment away from other species treated at veterinary hospitals (e.g., dogs, cats, and ferrets). In the hospital, pet exotic mammals appear to feel more secure if provided hide boxes, chewing material (e.g., cardboard), and an adequate nesting material. The veterinarian should consider the psychological benefits of allowing companions of the patient to share the hospital cage, if possible, as a means of stress reduction. All animals should be accurately weighed to ensure correct drug and fluid calculations. Be8
cause rabbits and rodents are not able to vomit, withholding food or water for prolonged periods of time before anesthesia is not required. Food can be removed approximately 1 hour before anesthesia induction to reduce the presence of food within the oral cavity. After induction, the oral cavity should be checked for the existence of food material and cleaned with cotton swabs, if necessary. Guinea pigs often retain food in their oral cavity for long periods of time. Premedicating the patient with a sedative is often recommended; this allows for a smooth anesthetic induction (Table 1). Midazolam provides adequate effective sedation for approximately 1 hour when used in rabbits and rodents. When administered intramuscularly or intravenously to rabbits, guinea pigs, and other rodents, midazolam provides adequate sedation for diagnostic procedures (e.g., radiographs, ultrasonography).4,5 There are minimal cardiorespiratory side effects associated with this drug, therefore its use is not limited to healthy animals. Midazolam can also be combined with opioid compounds such as butorphanol to provide additional analgesia. Research findings indicate that midazolam enhances the analgesic properties of dexmedetomidine in the rat.6 Consequently, it appears that midazolam can be combined with other alpha-2agonists to provide adequate sedation and analgesia in small mammals. The combination of fentanyl/fluanisone is another frequently used sedative in rabbits and guinea pigs, and produces profound sedation and analgesia.5,7 Because of the vasodilatory effects of the fentanyl/fluanisone combination,
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placement of intravenous catheters is relatively easy, even in very small rabbits. Anticholinergic drugs such as atropine and glycopyrrolate are not routinely administered as premedication, but are administered to patients that develop bradycardia during the procedure. Atropine and glycopyrrolate reduce bronchial and salivary secretions, but may also increase the viscosity of these secretions.8 Many rabbits possess atropinesterase and therefore glycopyrrolate is the anticholinergic of choice in rabbits.9 Preoxygenation of the patient before anesthetic induction will improve oxygen saturation and is especially useful in animals with respiratory or cardiac disease.
were being intubated.12 An inciEndotracheal dence of 6% laryngospasm was reintubation can ported, and all rabbits with laryngospasm were found to be in the be performed in ketamine-medetomidine group. rabbits, but is Laryngeal masks have been used successfully in rabbits weighing more more than 3 kg (Figs 2 and 3). The challenging laryngeal mask should provide a good fit to the patient and be easrelative to dogs ily inserted, resulting in an adeand cats. quate seal.13,14 Although laryngeal masks can be used for intermittent positive-pressure ventilation, gastric tympanism may develop, especially at a peak inspiratory pressure of 14 cm H2O.8
INDUCTION AND MAINTENANCE Anesthetic circuits recommended for use for rabbit and small rodent patients should have low dead space and low resistance (e.g., Bain circuit or Ayre’s T-piece). Intubation in rodents is not easily performed in most cases, therefore anesthesia is often maintained with a tight-fitting facemask connected to the breathing system (Fig 1).10 Endotracheal intubation can be performed in rabbits, but is more challenging relative to dogs and cats. When intubating rabbits, one can use a blind technique by listening for breath sounds or by visualizing the larynx with a laryngoscope or endoscope.5 To perform both techniques, the rabbit is placed in sternal position, and the neck is hyperextended to facilitate intubation. Because rabbits are prone to laryngospasm, local anesthetics should be applied to the larynx before intubation.11 In one study, the combination of ketamine-midazolam was compared with ketamine-medetomidine to assess quality of anesthetic induction in rabbits that
FIGURE 1. Anesthesia is maintained in this rat with isoflurane using a tight-fitting mask connected to the breathing system. The advantage of the Darval breathing circuit (AAS UK Limited, Checkendon, UK) is that the waste gas outlet and fresh gas inlet are connected directly to the facemask. This allows efficient scavenging and minimizes dead space.
Rodents The recommended inhalation agents for rodents are isoflurane or sevoflurane. Inhalation anesthesia can be used alone or as an adjunct to injectable anesthetic agent(s) administered for induction. Midazolam injected subcutaneously will decrease excitability of the patient during induction.4 The gas anesthetic agent is administered, with oxygen, either into an induction chamber or through a mask. The main advantages of inhalation anesthesia include ease of induction and maintenance, the ability to rapidly alter anesthetic depth, simultaneous administration of oxygen, and rapid recovery.10 Most inhalation anesthetic agents do not provide analgesia, therefore additional drug therapy is needed for painful procedures. Injectable anesthesia alone is a practical option when access to the head and neck is required to perform the procedure. Commonly used injectable anesthetic combinations are provided in Table 2. In small rodents, injectable anesthetic drugs are usually administered by a single intraperitoneal, intramuscular, or subcutaneous injection; therefore dosing to effect is not possible during induction.5 Ketamine is frequently combined with medetomidine or xylazine for shortterm immobilization and surgical anesthesia.10,15 Intramuscular injection of ketamine has been associated with self-mutilation in some species. The combination of medetomidine, midazolam, and fentanyl has been used successfully in chinchillas, guinea pigs, rats, mice, and hamsters.10 In chinchillas, medetomidine-midazolam-fentanyl provided surgical tolerance similar to the medetomdine-ketamine combination, but resulted in a shorter duration of effectiveness.16 One main
Wenger/Journal of Exotic Pet Medicine 21 (2012), pp 7–16
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2 – 515 5 – 10 IM10 20 –
4010 3 – 610 3 (only sedation)15
Abbreviations: IM, Intramuscularly; IP, Intraperitoneally; IV, Intravenously; SC, Subcutaneously. *Antagonization with atipamezole, flumazenil/sarmazenil, naloxone/buprenorphine/butorphanol. †Partial antagonization with naloxone, buprenorphine or butorphanol.
0.15 ⫹ 2 ⫹ 0.005 IM15
0.5 ⫹ 5 ⫹ 0.05 IP (M) 0.15 ⫹ 7.5 ⫹ 0.03 SC (G)15 7.5 – 2610 20 – 30 ⫹ 10 Xylazine10 0.05 ⫹ 1 ⫹ 0.0216
75 ⫹ 0.515 5 – 10 ⫹ 0.25 – 0.510 50 – 75 ⫹ 0.25 – 115 5 ⫹ 0.0615 5 – 15 ⫹ 0.5 – 115
40 ⫹ 0.515 5 – 15 ⫹ 0.5 – 110 1 ml/kg ⫹ 27 0.2 ⫹ 1 ⫹ 0.025 IM15 15 – 20 ⫹ 0.25 – 0.512,18 15 – 25 ⫹ 1 – 312 0.2 ml/kg IM ⫹ 0.5 – 2 IV7 0.2 ⫹ 1 ⫹ 0.0215
Ketamine ⫹ Medetomidine Ketamine ⫹ Midazolam Hypnorm ⫹ Midazolam† Medetomidine ⫹ Midazolam ⫹ Fentanyl* Propofol Tiletamine/Zolazepam
Mouse/Gerbil Chinchilla Guinea Pig
Rat
1 0
Rabbit
FIGURE 3. This laryngeal mask (I-gel; Intersurgical, Berkshire, UK) is made from a medical-grade thermoplastic elastomer and creates a noninflatable, anatomic seal.
Drug
advantage of using medetomidine, midazolam, and fentanyl is the complete reversibility of anesthesia with flumazenil, atipamezole, and naloxone. Therefore, the period of recovery is significantly shortened resulting in a reduced risk of hypoglycemia and hypothermia. Guinea pigs and chinchillas are prone to anorexia if hypothermic. If painful procedures are being performed, one must understand that the analgesic effects of the anesthetic combination will also be negated if reversal drugs are used; therefore additional analgesic therapy is required. Midazolam combined with fentanyl/fluanisone produces neuroleptanalgesia with adequate skeletal muscle relaxation in mice, rats, gerbils, hamsters, and guinea pigs.7 Anesthesia can be prolonged up to 6 to 8 hours in the rat
TABLE 2. Injectable anesthetics used in rabbits and rodents, doses are given in mg/kg unless otherwise indicated
FIGURE 2. This laryngeal mask (Portex Soft Seal Laryngeal Mask; Smiths Medical Schweiz AG, Dübendorf, Switzerland) uses air to provide an adequate seal of the pharyngeal and laryngeal structures.
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by the administration of small doses of an extemporaneous preparation of fentanyl/fluanisone (0.1 mL/kg intramuscularly, Hypnorm; Vetapharma Ltd, Leeds, UK). The solution is prepared by mixing 1 part Hypnorm, 1 part midazolam (5 mg/mL), and 2 parts water for injection. The dose administered intraperitoneally varied between 2.7 mL/kg in the rat and 13.3 mL/kg in the mouse. The author has used this combination of fentanyl/fluanisone and midazolam successfully in guinea pigs, administered via the subcutaneous route. Rabbits Induction of anesthesia in rabbits using only gas anesthetic agents may be detrimental alone because all commonly available inhalation anesthetic compounds are associated with struggling and breath-holding. During this prolonged period of apnea, bradycardia, hypercapnia, and hypoxemia may occur.17 If gas anesthetic agents are used for induction, it is best to premedicate the rabbit with midazolam, fentanyl/fluanisone, or acepromazine to reduce stress associated with the procedure.5 Nevertheless, premedicating rabbit patients does not prevent breath-holding or stress during induction. A balanced anesthetic protocol with a combination of injectable drugs is the preferred method for rabbit induction. In healthy patients, a combination of 10 to 15 mg/kg ketamine and 0.15 to 0.25 mg/kg medetomidine applied subcutaneously can be used to induce a surgical plane of anesthesia.12,18,19 Intramuscular injections are often associated with discomfort, flinching, and kicking.12,19 Several studies have shown a similar induction time after subcutaneous and intramuscular administration of ketamine and medetomidine.18,19 Compared with the intramuscular route, there is markedly less resistance by the patient to the subcutaneous route, and the latter is, in the author’s opinion, the preferred method of administration. Anesthesia with medetomidine and ketamine results in hypoxemia, thus oxygen should be provided while the animal is unconscious. Any drug combination in which medetomidine is used produces moderate peripheral vasoconstriction. The constriction of a patient’s blood vessels increases the difficulty of intravenous catheter placement. For additional analgesia, opioid drugs (e.g., butorphanol, buprenorphine) are recommended.19 To prolong or deepen anesthesia,
inhalation anesthetic agents can be used, or approximately one third of the original dose of the injectable drug combination can be repeated. Medetomidine can be reversed with atipamezole with reported doses for atipamezole varying between 1 and 5 times the medetomidine dose.20,21 One research investigation showed that the optimal atipamezole dosage to achieve reversal is equal to, or double, the dose of medetomidine. At these dosages, mean recovery time was shortened with no side effects being observed.20 Another option for injectable anesthesia is fentanyl/fluanisone combined with midazolam or diazepam. Fentanyl/fluanisone is injected intramuscularly, then after a 5- to 10-minute delay, followed with an intravenous administration of midazolam or diazepam.7 This injectable drug combination produces a surgical plane of anesthesia lasting approximately 30 to 45 minutes. If necessary, the effects of the drugs described above can be enhanced or the anesthetic effects prolonged with the administration of isoflurane, or additional doses of fentanyl/fluanisone. Rabbits administered this combination of drugs develop moderate respiratory depression and hypoxia, consequently supplemental oxygen is recommended. Recovery can be prolonged (up to 3 hours) but can be shortened by administration of a mixed agonist/antagonist opioid drug such as butorphanol or buprenorphine, and flumazenil/sarmazenil.22 Naloxone completely reverses the effects of respiratory depression, but the analgesic effect induced by the opioid agonist fentanyl will also be lost. Recently, alfaxalone has been evaluated for use as an anesthetic induction agent in rabbits.23 In this research investigation, alfaxalone provided at an intravenous dose of 2 to 3 mg/kg was suitable for anesthesia induction and endotracheal intubation was accomplished in all rabbits.23 All rabbits in the study exhibited a short period of apnea that lasted between 10 and 120 seconds.23 When using alfaxalone to induce rabbits for anesthesia, preoxygenation is recommended for all patients before initiating the procedure. Recovery was relatively rapid; therefore, rabbits anesthetized with alfaxalone can be discharged from the hospital the day of the procedure. Propofol is a commonly used anesthetic induction agent in rabbits. An intravenous bolus of propofol with or without premedication will produce sufficient relaxation for intubation.24 Propofol often causes apnea even when administered
Wenger/Journal of Exotic Pet Medicine 21 (2012), pp 7–16
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slowly over 60 seconds. Hypoxemia and hypotension are common adverse side effects observed with propofol use in rabbits. Only light anesthesia is produced with propofol, therefore it is not as useful when trying to maintain a surgical plane of anesthesia over an extended period of time.25 MONITORING, RECOVERY, AND POSTOPERATIVE CARE When a patient is anesthetized, cardiorespiratory parameters, body temperature, and depth of anesthesia should be closely monitored. The rabbit’s respiratory rate For one to and rhythm, in most cases, are vicorrectly assess sually observed. When the animal is intubated, capnography can be changes used to measure end-tidal carbon indicative of dioxide levels and assess ventilation. Heart rates can be measured pain and via auscultation, electrocardiogram, distress, an Doppler probes, or pulse oximeters. In larger animals, arterial blood understanding pressure can be measured directly of normal via the central auricular artery, or indirectly with oscillometric limb species behavior cuffs. A rectal thermometer should is essential. be used to accurately measure body temperature during the procedure. The pedal withdrawal reflex is useful to assess depth of anesthesia and is lost when a surgical plane of anesthesia is achieved.10 In a small animal survey of anesthesia-related mortality, more than half of all anesthetic-related mortalities occurred in the postoperative period. Thus, close monitoring, particularly in the first 3 hours of the postoperative period, is recommended.2 Heart rate and respiratory rate must be measured at regular intervals during recovery from anesthesia. Body temperature should be monitored and maintained by external heating (e.g., warming blanket, convective heating unit), if necessary, until the animal is fully recovered. Anesthesia, stress associated with hospitalization, and pain can have adverse effects on a rabbit’s gastrointestinal motility. Therefore, it is important to monitor feeding and fecal output. Assisted feeding and administration of gastrointestinal motility enhancers (e.g., ranitidine, metoclopramide, cisapride) may be necessary if the patient reduces its feed intake.26 Because pain is an important cause of anorexia, a provision for adequate pain medication is essential. 1 2
ANALGESIA IN RABBITS AND RODENTS Pain Assessment Pain assessment in rabbits and rodents is more challenging than in domestic species (e.g., cats, dogs). In exotic small mammals, behavioral signs of pain are more subtle, and clinicians are often unfamiliar with the normal behaviors of exotic pet species. As prey species, rabbits and rodents are inclined to hide their painful condition to maintain a normal appearance, thereby avoiding predation. The presence of an observer may result in complete immobility with no apparent pain-related behaviors.5 For one to correctly assess changes indicative of pain and distress, an understanding of normal species behavior is essential. Common clinical signs associated with pain in rabbits and rodents include reduced food intake, decreased motor and social activity, altered posture and gait, and licking or chewing at the painful location on their body.27-35 Anorexia is a vital sign of pain and can be a sequel to decreased bowel motility and nausea. More extensive descriptions of clinical signs related with pain are summarized in Table 3. Management of Pain It is crucial to recognize pain as early as possible so that it can be adequately treated before the onset of adverse disease effects. In rabbits, anorexia exceeding 1 to 2 days can rapidly lead to potentially life-threatening gastrointestinal stasis.26 Pain can contribute to immunosuppression, and the subsequent risk of infection must be appreciated in small exotic mammal species, including rabbits in which subclinical respiratory disease is common. An effective pain management plan should include drugs of different classes using a multimodal approach. Commonly used analgesics are provided in Table 4. As with domestic animals, the concept of preemptive analgesia should be considered, and adequate pain medication provided before or just after anesthetic induction.36 Providing soft food (e.g., with dental disease), bandaging, and other types of nursing care may also be indicated as adjunctive therapy to analgesic medication. Nonsteroidal Antiinflammatory Drugs The most frequently used nonsteroidal antiinflammatory drugs (NSAIDs) in rabbits and ro-
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TABLE 3. Signs of pain in rabbits and rodents ● ● ● ● ● ● ● ● ●
Decreased or no appetite (can be a side effect of opioid administration) Increased water intake and urination (often seen in rabbits with dental disease) Aggression in a normally docile animal Altered breathing pattern Altered posture and gait Over-grooming, lack of grooming or licking, chewing or pulling of hair at the painful site Reduced level of spontaneous activity such as digging or exploring the cage Decreased social activity in animals housed in groups, isolation Polyphagia of bedding material that may progress to self-mutilation in small rodents
dents include meloxicam, carprofen, and ketoprofen.37,38 Pharmacokinetic studies have shown that rabbits have lower plasma peak concentrations of meloxicam after oral administration, and metabolize meloxicam faster than dogs, humans, or rats.39 In rabbits, an initial oral dose of 1 mg/kg meloxicam, followed by 0.5 mg/kg/d, may be necessary to achieve adequate analgesia after surgery. Oral doses of meloxicam may not be sufficient to completely control pain after abdominal surgery (e.g., ovariohysterectomy). Therefore, multimodal analgesic treatment should be considered when significant pain is involved (i.e., combining NSAIDs with an opioid drug).31 Clinical experience indicates that doses of 0.3 to 0.6 mg/kg meloxicam can be used safely with no adverse clinical side effects and can be administered on a long-term basis to rabbits.5 Although oral meloxicam doses as low as 0.2 mg/kg have antiinflammatory effects in rats, clin-
● ● ● ● ● ● ● ● ●
Production of fewer, smaller or no fecal droppings Half-closed or squinting eyes, pale (in albino mice or rodent) or bulging eyes (in guinea pigs) Immobility or reluctance to move, slow postural adjustments Pressing abdomen on the floor, tucked appearance to abdomen or hunched posture Reduced weight bearing on affected limb Decreased interest in surroundings, huddling, or hiding in a corner and lethargy Twitching and wincing Piloerection, rough hair coat in small rodents Porphyrin secretions in rodents (ocular/nares)
ical experience indicates that doses ⬍1 to 2 mg/kg do not adequately alleviate pain after surgery.33,40,41 The oral form of meloxicam is honey flavored. It is palatable to most small exotic mammals and is a convenient method for a pet owner to continue managing pain at home. Opioid Drugs Opioid drugs are effective analgesic agents for the control of acute or chronic visceral pain. Butorphanol, buprenorphine, and fentanyl are regularly used in small exotic mammal patients and are well tolerated.42,43 In rabbits, buprenorphine, butorphanol, nalbuphine, and pentazocine provided analgesic effects.44 Although elevated doses of buprenorphine had little effect on the maximum degree of analgesia, it did prolong the duration of the drug’s effect. The onset of analgesia with buprenorphine was rapid (only 30 minutes after intravenous administration) and appears to
TABLE 4. Analgesics used in rabbits and rodents, doses are given in mg/kg Drug
Rabbit
Buprenorphine* Butorphanol† Morphine‡ Meloxicam Carprofen
0.01 – 0.05 IV, SC5 0.1 – 0.5 IV, SC5 2 – 5 SC, IM10 0.3 – 1.5 SC, PO7,39 1.5 – 4 SC, PO5
Guinea Pig
Chinchilla
0.02 – 0.05 SC10 0.01 – 0.05 SC10 0.2 – 2 SC10 0.2 – 2 SC10 10 2 – 5 SC 1 – 2 SC, PO10 4 SC, PO10 4 SC, PO10
Mouse/Gerbil
Rat
0.05 – 0.1 SC10 1 – 2 SC10 2.5 SC10 1 – 5 SC, PO10 5 – 10 SC, PO10
0.01 – 0.05 SC, IV10 0.5 – 2 SC10 0.5 – 5 SC, IM10 1.0 SC, PO10 1 – 5 SC, PO10
Abbreviations: IV, Intravenously; PO, Orally; SC, Subcutaneously. *Long duration of action, if sedation occurs then the dose cab be reduced, may be given orally in the rabbit. †Weaker analgesic than buprenorphine, short duration of action. ‡Side effects: respiratory depression, sedation, reduced gastrointestinal motility.
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have excellent transmucosal absorption. Transmucosal administration of buprenorphine is an uncomplicated method for pet owners to give pain medication at home over a several-day time period without having to give injections. Butorphanol had a rapid onset of action, but increased dose rates did not produce increased levels of analgesia.44 In rabbits and small mammals, the main adverse side effects of opioids are drowsiness and respiratory depression.36,42 In addition to respiratory depression in rabbits, intravenous administration of morphine also causes hypertension, bradycardia, and hyperglycemia.45 In healthy, conscious rabbits, buprenorphine administration decreases respiratory rate and produces mild hypoxemia after subcutaneous and intravenous administration.36,42 Although potential adverse effects of opioid drugs should be considered, the degree of depression seems unlikely to be of clinical importance. Buprenorphine or butorphanol can be used to reverse the respiratory depression and sedation produced by fentanyl/fluanisone.22 Opioids can reduce gastrointestinal motility in rabbits, but this does not appear to be clinically relevant, because in most cases, unalleviated pain is a primary cause of gastrointestinal stasis.29 In mice medicated with buprenorphine, less food intake and weight loss can occur during the postoperative period.46 Pica and gastric distension have been observed in rats receiving high doses of buprenorphine (0.5 mg/kg subcutaneously).47 If the rat patient is showing signs of pica, the bedding material should be temporarily removed to prevent gastric obstruction.38 Transdermal administration of fentanyl results in variable plasma levels. Rabbits tolerate fentanyl transdermal patches well, but hair regrowth may hinder dermal absorption of fentanyl after 24 hours. Conversely, the application of a depilatory agent can cause early and rapid absorption of fentanyl, thereby leading to unwanted sedation and lack of sustained therapeutic plasma concentration levels over the 3-day treatment period.48 Transdermal fentanyl has been used experimentally in hairless guinea pigs and rats.49,50 Most small exotic mammals are not well suited for the use of fentanyl patches because of their diminutive size. Tramadol is a centrally acting analgesic drug that is becoming popular within the zoological medicine field. It is both a weak opioid agonist with selectivity for the mu-receptor, and a weak inhibitor of the reuptake of norepinephrine and serotonin.51 Several pharmacokinetic experiments 1 4
using tramadol have been performed in rodents and rabbits. In one study, the administration of tramadol 10 mg/kg intraperitoneally abolished postoperative hyperalgesia in rats when compared with saline solution or parecoxib.52 Another scientific investigation using rats found that oral tramadol doses as low as 0.45 mg/kg may provide analgesia.53 In a study with rabbits, the investigators concluded that administering oral tramadol at a dose of 11 mg/kg is unlikely to provide analgesia for a clinically acceptable length of time because of low plasma tramadol concentrations.54 LOCAL ANESTHETIC AGENTS Local and regional anesthetic techniques provide good analgesia during the perioperative period. Lidocaine and bupivacaine are commonly used local anesthetics and can be applied topically, via tissue infiltration, intraarticularly, regional nerve block, or by epidural injection. Creams containing local anesthetics, for example EMLA 5% cream (Emla; Astrazeneca, Zug, Switzerland), can be applied topically to the skin before placing intravenous catheters. It is advantageous to clip the hair before applying the EMLA cream. Incisional line blocks and wound infiltration are simple, cost-effective means to provide analgesia for surgical procedures. Important nerve blocks for dental surgery include infraorbital, mental, mandibular, and maxillary nerve blocks.43 Intratesticular injection of local anesthetics can be performed to provide additional analgesia for neutering.55 Epidural analgesia has been described in guinea pigs and rabbits.43,56,57 The extent of the sensory, motor, and autonomic blockade through an epidural injection depends on the dose and volume of drug administered. The lumbosacral space is the preferred site of an epidural injection because of the relatively large space between L7 and S1. The dural sac in rabbits extends into the sacrum, and injection into the lumbosacral space may result in subdural injections.58 Volumes of local anesthetic agent used for epidural injection vary between 0.1 and 0.2 mL/kg. CONCLUSION Rabbits and rodents are frequently anesthetized for various diagnostic and surgical procedures. Inhalation anesthesia using a facemask is commonly used for anesthesia in small rodents. Injectable anesthetic agents in combination with
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inhalation anesthesia are routinely used in rabbits and larger rodents. Adequate pain management needs to be addressed, when necessary, for all small exotic mammal patients. Signs of pain are often more subtle in these species and may be more difficult to recognize. Opioid analgesics and NSAIDs are commonly used, but other analgesic options (e.g., local anesthetic drugs) should also be considered.
REFERENCES 1. Lascelles BD, Capner CA, Waterman-Pearson AE: Current British attitudes to perioperative analgesia for cats and small mammals. Vet Rec 145:601-604, 1999 2. Brodbelt DC, Blissitt KJ, Hammond RA, et al: The risk of death: the confidential enquiry into perioperative small animal fatalities. Vet Anaesth Anal 35:365-373, 2008 3. Meredith A: Respiratory disorders, in Meredith A, Flecknell P (eds): BSAVA Manual of Rabbit Medicine and Surgery (ed 2). Gloucester, UK, BSAVA Press, pp 67-74, 2006 4. Johnson-Delaney C: Guinea pigs, chinchillas, degus and duprasi, in Meredith A, Johnson-Delaney C (ed): BSAVA Manual of Exotic Pets (ed 5). Glouchester, UK, BSAVA Press, pp 28-62, 2010 5. Flecknell P: Anaesthesia and perioperative care, in Meredith A, Flecknell P (eds): BSAVA Manual of Rabbit Medicine and Surgery (ed 2). Gloucester, UK, BSAVA Press, pp 154-165, 2006 6. Boehm CA, Carney EL, Tallarida RJ, et al: Midazolam enhances the analgesic properties of dexmedetomidine in the rat. Vet Anaesth Anal 37:550-556, 2010 7. Flecknell PA, Mitchell M: Midazolam and fentanyl-fluanisone: assessment of anaesthetic effects in laboratory rodents and rabbits. Lab Anim 18:143-146, 1984 8. Bateman L, Ludders JW, Gleed RD, et al: Comparison between facemask and laryngeal mask airway in rabbits during isoflurane anesthesia. Vet Anaesth Anal 32:280288, 2005 9. Stormont C, Suzuki Y: Atropinesterase and cocainesterase of rabbit serum: localization of the enzyme activity in isozymes. Science 167:200, 1970 10. Longley LA: Anaesthesia of Exotic Pets. Philadelphia, PA, Saunders/Elsevier, 2008 11. Wixson SK: Anesthesia and analgesics, in Manning PJ, Ringler DH, Newcomer CE (eds): The Biology of the Laboratory Rabbit. Millbrae, CA, Academic Press, pp 87-109, 1994 12. Grint NJ, Murison PJ: A comparison of ketamine-midazolam and ketamine-medetomidine combinations for induction of anaesthesia in rabbits. Vet Anaesth Anal 35: 113-121, 2008 13. Cruz ML, Sacchi T, Luna SPL: Use of a laryngeal mask for airway maintenance during inhalation anaesthesia in rabbits. Vet Anaesth Analg 27:115-116, 2000 14. Kazakos GM, Anagnostou T, Savvas I, et al: Use of laryngeal mask airway in rabbits: placement and efficacy. Lab Anim Europe 7:41-49, 2000 15. Erhardt W, Haberstroh J: Speziesspezifische Anästhesie, in Erhardt W, Henke J, Haberstroh J (eds): Anästhesie & Analgesie beim Klein- und Heimtier sowie bei Vögeln, Reptilien, Amphibien und Fischen. Stuttgart, Germany, Schattauer, pp 629-663, 2004
16. Henke J, Baumgartner C, Röltgen I, et al: Anaesthesia with midazolam/medetomidine/fentanyl in chinchillas (Chinchilla lanigera) compared to anaesthesia with xylazine/ketamine and medetomidine/ketamine. J Vet Med 51:259-264, 2004 17. Hedenqvist P, Orr HE, Roughan JV, et al: Induction of anesthesia with desflurane and isoflurane in the rabbit. Lab Anim 35:172-179, 2001 18. Hedenqvist P, Orr HE, Roughan JV, et al: Anaesthesia with ketamine/medetomidine in the rabbit: influence of route of administration and the effect of combination with butorphanol. Vet Anaesth Anal 29:14-19, 2002 19. Williams AM, Wyatt JD: Comparison of subcutaneous and intramuscular ketamine-medetomidine with and without reversal by atipamezole in Dutch belted rabbits (Oryctolagus cuniculus). J Am Assoc Lab Anim Sci 46:16-20, 2007 20. Kim MS, Jeong SM, Park JH, et al: Reversal of medetomidine-ketamine combination anesthesia in rabbits by atipamezole. Exp Anim 53:423-428, 2004 21. Carpenter J: Exotic Animal Formulary (ed 3). St. Louis, MO, Elsevier/Saunders, 2005 22. Flecknell PA, Liles JG, Wootton RJ: Reversal of fentanyl/ fluanisone neuroleptanalgesia in the rabbit using mixed agonist/antagonist opioids. Lab Anim 23:147-155, 1989 23. Grint NJ, Smith HE, Senior JM: Clinical evaluation of alfaxalone in cyclodextrin for the induction of anaesthesia in rabbits. Vet Rec 163:395-396, 2008 24. Aeschbacher G, Webb AI: Propofol in rabbits. 1. Determination of an induction dose. Lab Anim Sci 43:324-327, 1993 25. Aeschbacher G, Webb AI: Propofol in rabbits. 2. Longterm anaesthesia. Lab Anim Sci 43:328-335, 1993 26. Davies RR: Digestive system, in Meredith A, Flecknell P (eds): BSAVA Manual of Rabbit Medicine and Surgery (ed 2). Gloucester, UK, BSAVA Press, pp 74-84, 2006 27. Bradley TA: Normal behavior and the clinical implications of abnormal behavior in guinea pigs. Vet Clin N Am Exot Anim Pract 4:681-696, 2001 28. Bradley Bays T, Lightfoot T, Mayer J: Exotic Pet Behavior: Birds, Reptiles, and Small Mammals. Philadelphia, PA, Saunders/Elsevier, 200 29. Cooper CS, Metcalf-Pate KA, Barat CE, et al: Comparison of side effects between buprenorphine and meloxicam used postoperatively in Dutch belted rabbits (Oryctolagus cuniculus). J Am Assoc Lab Anim Sci 48:279-285, 2009 30. Farabollini F, Giordano G, Carli G: Tonic pain and social behavior in male rabbits. Behav Brain Res 31:169-175, 1988 31. Leach MC, Allweiler S, Richardson C, et al: Behavioural effects of ovariohysterectomy and oral administration of meloxicam in laboratory housed rabbit. Res Vet Sci 87: 336-347, 2009 32. Roughan JV, Flecknell PA: Behavioural effects of laparotomy and analgesic effects of ketoprofen and carprofen in rats. Pain 90:65-74, 2001 33. Roughan JV, Flecknell PA: Evaluation of a short duration behaviour-based post-operative pain scoring system in rats. Eur J Pain 7:397-406, 2003 34. Roughan JV, Flecknell PA: Behavioural assessment of postoperative pain and analgesic effects of carprofen in the domestic rabbit. Proc 8th World Congr Vet Anesth, Knoxville, TN, p 143, 2003 35. Vermeirsch H, Biermans R, Salmon PL, et al: Evaluation of pain behavior and bone destruction in two arthritic models in guinea pig and rat. Pharmacol Biochem Behav 87: 349-359, 2007
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36. Shafford HL, Schadt JC: Respiratory and cardiovascular effects of buprenorphine in conscious rabbits. Vet Anaesth Analg 35:326-332, 2008 37. Barter LS: Rabbit analgesia. Vet Clin N Am Exot Anim Pract 14:93-104, 2011 38. Miller AL, Richardson CA: Rodent analgesia. Vet Clin N Am Exot Anim Pract 14:81-92, 2011 39. Turner PV, Chen HC, Taylor WM: Pharmacokinetics of meloxicam in rabbits after single and repeat oral dosing. Comp Med 56:63-67, 2006 40. Busch U, Schmid J, Heinzel G, et al: Pharmacokinetics of meloxicam in animals and the relevance to humans. Drug Metab Dispos 26:576-584, 1998 41. Laird JMA, Herrero JF, Garcia de la Rubia P, et al: Analgesic activity of the novel COX-2 preferring NSAID, meloxicam in mono-arthritic rats: central and peripheral components. Inflamm Res 46:203-210, 1997 42. Flecknell PA: Analgesia of small mammals. Vet Clin N Am Exot Anim Pract 4:47-56, 2001 43. Lichtenberger M, Ko J: Anesthesia and analgesia for small mammals and birds. Vet Clin N Am Exot Anim Pract 10:293-315, 2007 44. Flecknell PA, Liles JH: Assessment of the analgesic action of opioid agonist-antagonists in the rabbit. Vet Anaesth Analg 17:24-29, 1990 45. May CN, Ham IW, Heslop KE, et al: Intravenous morphine causes hypertension, hyperglycaemia and increases sympatho-adrenal outflow inconscious rabbits. Clin Sci 75 71-77, 1988 46. Goecke JC, Awad H, Lawson JC, et al: Evaluating postoperative analgesia in mice using telemetry. Comp Med 55: 37-44, 2005 47. Clark JA, Myers PH, Goelz JE, et al: Pica behaviour associated with buprenorphine administration in the rat. Lab Anim 47:300-303, 1997 48. Foley PL, Henderson AL, Bisonette EA, et al: Evaluation of
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fentanyl transdermal patches in rabbits: blood concentrations and physiologic response. Comp Med 51: 239-244, 2001 Cichewicz DL, Welch SP, Smith FL: Enhancement of fentanyl and buprenorphine antinociception by transdermal delta9-tetrahydrocannabinol. Eur J Pharmacol 525:74-82, 2005 Vanbever R, Langers G, Montmayeur S, et al: Transdermal delivery of fentanyl: rapid onset of analgesia using electroporation. J Control Release 50:225-235, 1998 Scott LJ, Perry CM: Tramadol: a review of its use in perioperative pain. Drugs 60:139-76, 2000 Kamermann P, Koller A, Loram L: Postoperative administration of the analgesic tramadol, but not the selective cyclooxygenase-2 inhibitor parecoxib, abolishes postoperative hyperalgesia in a new model of postoperative pain in rats. Pharmacology 80:244-8, 2007 Granados-Sato V, Arguelles CF: Synergic antinociceptive interaction between tramadol and gabapentin after local, spinal and systemic administration. Pharmacology 74: 200-208, 2005 Souza MJ, Greenacre CB, Cox SK: Pharmacokinetics of oral tramadol in the domestic rabbit. Am J Vet Res 69:979-82, 2008 Schützenhofer G, Tacke S, Wehrend A: Die Kastration des männlichen Kaninchens unter besonderer Berücksichtigung der Anästhesie. Tieraerztl Prax 37:200-208, 2009 Eisele PH, Kaaekuahiwi MA, Canfield DR, et al: Epidural catheter placement for testing of obstetrical analgesics in female guinea pigs. Lab Anim Sci 44:586 – 490, 1994 Hopcroft SC: A technique for the simultaneous bilateral removal of the adrenal glands in guinea pigs. Using a new type of safe anaesthetic. Exp Med Surg 24:12, 1996 Greenaway JB, Partlow GD, Gonsholt Nl, et al: Anatomy of the lumbosacral spinal cord in rabbits. J Am Anim Hosp Assoc 37:27-34, 2001
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Abstract Rabbits and rodents are popular pets and are often presented to veterinarians for evaluation and medical treatment. Anesthesia in exotic pets is required for many diagnostic and surgical procedures and is associated with a higher perioperative risk in rabbits and rodents when compared with dogs and cats. Inhalation anesthetic agents are commonly used as the sole source of anesthesia in small rodents, whereas injectable agents in combination with inhalation anesthesia are often used for rabbits and larger rodents. Analgesia is an important component of exotic pet medicine. Although it may be difficult to recognize signs of pain in companion exotic mammals, adequate pain management should always be provided. Opioid and nonsteroidal antiinflammatory drugs are the analgesic medications of choice, but others should be considered (e.g., local anesthetic agents). This article provides an update of the current literature regarding anesthesia and analgesia in rabbits and rodents. Copyright 2012 Elsevier Inc. All rights reserved. Key words: anesthesia; lagomorphs; monitoring; pain management; perioperative care; rodents
I
n the United States and Europe, rabbits and rodents are common household pets, with rabbits being the third most popular mammalian pet in the United Kingdom (http://www.rabbitwelfare. co.uk). As a companion animal grows in popularity, there appears to be a concurrent increase in the client expectations of the veterinary care provided. Anesthesia in exotic pets is required for a number of diagnostic and surgical procedures. Furthermore, in certain species sedation or anesthesia may be required to perform a thorough physical examination. Analgesia is an important aspect of exotic pet medicine, and it is likely that pain is undertreated in these patients.1 A recent survey evaluating the anesthetic mortality in small animal practice showed an increased risk associated with anesthesia in rabbits and other small exotic mammal species compared with dogs and cats.2 The overall risk of anestheticrelated death was 1.4% in rabbits, 3.8% in guinea pigs, and varied between 1.7% and 3.7% for other small exotic mammal species. As expected, diseased animals had a higher mortality rate than healthy patients. The following factors were brought forth in the study as reasons for the increased mortality observed in exotic mammal species when compared with dogs and cats: ● ●
Stress on induction Increased risk of hypothermia associated with the higher surface area to volume ratio
● ● ● ●
Subclinical respiratory infections with Pasteurella multocida in rabbits Perioperative diseases involving respiratory, digestive, and fluid balance disorders Fewer veins that are easily accessible for catheterization Endotracheal intubation is technically demanding.
This article will provide current information regarding the use of anesthesia and analgesia in rabbits and rodents with a special emphasis on the above-mentioned increased risk factors. PREANESTHETIC PREPARATIONS A thorough patient history and physical examination are required before any procedure in which
From the Clinic for Zoo Animals, Exotic Pets and Wildlife, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland. Address correspondence to: Sandra Wenger, Dr. med. vet., MSc, Dip. ECVAA, Clinic for Zoo Animals, Exotic Pets and Wildlife, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, 8057 Zürich, Switzerland. E-mail: [email protected]. © 2012 Elsevier Inc. All rights reserved. 1557-5063/12/2101-$30.00 doi:10.1053/j.jepm.2011.11.010
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TABLE 1. Sedatives and pre-medicants used in rabbits and rodents, doses are given in mg/kg unless otherwise indicated Drug
Rabbit
Acepromazine*
0.25 – 1 IM, SC, IV10
Acepromazine ⫹ Butorphanol Midazolam Fentanyl/Fluanisone (Hypnorm®) Medetomidine Medetomidine ⫹ Butorphanol
0.5 ⫹ 0.5 IM, SC5 0.5 – 2 IV, IM5 0.15 – 0.3 ml/kg IM5 0.1 – 0.5 IM, SC5
Guinea Pig 0.5 – 1 IM, SC10
Chinchilla 0.5 – 1 IM,
SC10
0.5 – 2 IM15 0.4 – 2 IM15 0.5 – 1 0.110
Mouse/Gerbil SC10
Rat
0.5 – 1 IM, may induce seizures in gerbils
0.5 – 1 IM, SC10
2 – 3 IM15 0.2 – 1 ml/kg IM10 0.110
2.5 SC, IM15 0.2 – 3 ml/kg IM 0.08 – 0.210 0.08 ⫹ 0.115
Abbreviations: IV, Intravenously; IM, Intramuscularly; SC, Subcutaneously. *Long duration of action, may cause vasodilation.
anesthesia is involved. Respiratory infections are commonly diagnosed in pet rabbits and rodents.3,4 Animals exhibiting signs of nasal discharge and increased respiAnimals ratory sounds or effort should be exhibiting signs considered at increased risk for an anesthetic procedure. Other comof nasal mon findings in pet exotic mamdischarge and mals that reduce the patient’s ability to withstand the stress associincreased ated with general anesthesia respiratory include dehydration, anorexia, and obesity. Whenever possible, these sounds or effort abnormal physical conditions should be should be corrected before anesthesia is performed. Administration of considered at fluids intravenously or subcutaneincreased risk ously assists in stabilizing dehydrated patients. for an Rabbits and rodents are prey speanesthetic cies and are easily stressed when placed in unfamiliar surroundings. procedure. It is favorable if these animals are hospitalized in a quiet environment away from other species treated at veterinary hospitals (e.g., dogs, cats, and ferrets). In the hospital, pet exotic mammals appear to feel more secure if provided hide boxes, chewing material (e.g., cardboard), and an adequate nesting material. The veterinarian should consider the psychological benefits of allowing companions of the patient to share the hospital cage, if possible, as a means of stress reduction. All animals should be accurately weighed to ensure correct drug and fluid calculations. Be8
cause rabbits and rodents are not able to vomit, withholding food or water for prolonged periods of time before anesthesia is not required. Food can be removed approximately 1 hour before anesthesia induction to reduce the presence of food within the oral cavity. After induction, the oral cavity should be checked for the existence of food material and cleaned with cotton swabs, if necessary. Guinea pigs often retain food in their oral cavity for long periods of time. Premedicating the patient with a sedative is often recommended; this allows for a smooth anesthetic induction (Table 1). Midazolam provides adequate effective sedation for approximately 1 hour when used in rabbits and rodents. When administered intramuscularly or intravenously to rabbits, guinea pigs, and other rodents, midazolam provides adequate sedation for diagnostic procedures (e.g., radiographs, ultrasonography).4,5 There are minimal cardiorespiratory side effects associated with this drug, therefore its use is not limited to healthy animals. Midazolam can also be combined with opioid compounds such as butorphanol to provide additional analgesia. Research findings indicate that midazolam enhances the analgesic properties of dexmedetomidine in the rat.6 Consequently, it appears that midazolam can be combined with other alpha-2agonists to provide adequate sedation and analgesia in small mammals. The combination of fentanyl/fluanisone is another frequently used sedative in rabbits and guinea pigs, and produces profound sedation and analgesia.5,7 Because of the vasodilatory effects of the fentanyl/fluanisone combination,
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placement of intravenous catheters is relatively easy, even in very small rabbits. Anticholinergic drugs such as atropine and glycopyrrolate are not routinely administered as premedication, but are administered to patients that develop bradycardia during the procedure. Atropine and glycopyrrolate reduce bronchial and salivary secretions, but may also increase the viscosity of these secretions.8 Many rabbits possess atropinesterase and therefore glycopyrrolate is the anticholinergic of choice in rabbits.9 Preoxygenation of the patient before anesthetic induction will improve oxygen saturation and is especially useful in animals with respiratory or cardiac disease.
were being intubated.12 An inciEndotracheal dence of 6% laryngospasm was reintubation can ported, and all rabbits with laryngospasm were found to be in the be performed in ketamine-medetomidine group. rabbits, but is Laryngeal masks have been used successfully in rabbits weighing more more than 3 kg (Figs 2 and 3). The challenging laryngeal mask should provide a good fit to the patient and be easrelative to dogs ily inserted, resulting in an adeand cats. quate seal.13,14 Although laryngeal masks can be used for intermittent positive-pressure ventilation, gastric tympanism may develop, especially at a peak inspiratory pressure of 14 cm H2O.8
INDUCTION AND MAINTENANCE Anesthetic circuits recommended for use for rabbit and small rodent patients should have low dead space and low resistance (e.g., Bain circuit or Ayre’s T-piece). Intubation in rodents is not easily performed in most cases, therefore anesthesia is often maintained with a tight-fitting facemask connected to the breathing system (Fig 1).10 Endotracheal intubation can be performed in rabbits, but is more challenging relative to dogs and cats. When intubating rabbits, one can use a blind technique by listening for breath sounds or by visualizing the larynx with a laryngoscope or endoscope.5 To perform both techniques, the rabbit is placed in sternal position, and the neck is hyperextended to facilitate intubation. Because rabbits are prone to laryngospasm, local anesthetics should be applied to the larynx before intubation.11 In one study, the combination of ketamine-midazolam was compared with ketamine-medetomidine to assess quality of anesthetic induction in rabbits that
FIGURE 1. Anesthesia is maintained in this rat with isoflurane using a tight-fitting mask connected to the breathing system. The advantage of the Darval breathing circuit (AAS UK Limited, Checkendon, UK) is that the waste gas outlet and fresh gas inlet are connected directly to the facemask. This allows efficient scavenging and minimizes dead space.
Rodents The recommended inhalation agents for rodents are isoflurane or sevoflurane. Inhalation anesthesia can be used alone or as an adjunct to injectable anesthetic agent(s) administered for induction. Midazolam injected subcutaneously will decrease excitability of the patient during induction.4 The gas anesthetic agent is administered, with oxygen, either into an induction chamber or through a mask. The main advantages of inhalation anesthesia include ease of induction and maintenance, the ability to rapidly alter anesthetic depth, simultaneous administration of oxygen, and rapid recovery.10 Most inhalation anesthetic agents do not provide analgesia, therefore additional drug therapy is needed for painful procedures. Injectable anesthesia alone is a practical option when access to the head and neck is required to perform the procedure. Commonly used injectable anesthetic combinations are provided in Table 2. In small rodents, injectable anesthetic drugs are usually administered by a single intraperitoneal, intramuscular, or subcutaneous injection; therefore dosing to effect is not possible during induction.5 Ketamine is frequently combined with medetomidine or xylazine for shortterm immobilization and surgical anesthesia.10,15 Intramuscular injection of ketamine has been associated with self-mutilation in some species. The combination of medetomidine, midazolam, and fentanyl has been used successfully in chinchillas, guinea pigs, rats, mice, and hamsters.10 In chinchillas, medetomidine-midazolam-fentanyl provided surgical tolerance similar to the medetomdine-ketamine combination, but resulted in a shorter duration of effectiveness.16 One main
Wenger/Journal of Exotic Pet Medicine 21 (2012), pp 7–16
9
2 – 515 5 – 10 IM10 20 –
4010 3 – 610 3 (only sedation)15
Abbreviations: IM, Intramuscularly; IP, Intraperitoneally; IV, Intravenously; SC, Subcutaneously. *Antagonization with atipamezole, flumazenil/sarmazenil, naloxone/buprenorphine/butorphanol. †Partial antagonization with naloxone, buprenorphine or butorphanol.
0.15 ⫹ 2 ⫹ 0.005 IM15
0.5 ⫹ 5 ⫹ 0.05 IP (M) 0.15 ⫹ 7.5 ⫹ 0.03 SC (G)15 7.5 – 2610 20 – 30 ⫹ 10 Xylazine10 0.05 ⫹ 1 ⫹ 0.0216
75 ⫹ 0.515 5 – 10 ⫹ 0.25 – 0.510 50 – 75 ⫹ 0.25 – 115 5 ⫹ 0.0615 5 – 15 ⫹ 0.5 – 115
40 ⫹ 0.515 5 – 15 ⫹ 0.5 – 110 1 ml/kg ⫹ 27 0.2 ⫹ 1 ⫹ 0.025 IM15 15 – 20 ⫹ 0.25 – 0.512,18 15 – 25 ⫹ 1 – 312 0.2 ml/kg IM ⫹ 0.5 – 2 IV7 0.2 ⫹ 1 ⫹ 0.0215
Ketamine ⫹ Medetomidine Ketamine ⫹ Midazolam Hypnorm ⫹ Midazolam† Medetomidine ⫹ Midazolam ⫹ Fentanyl* Propofol Tiletamine/Zolazepam
Mouse/Gerbil Chinchilla Guinea Pig
Rat
1 0
Rabbit
FIGURE 3. This laryngeal mask (I-gel; Intersurgical, Berkshire, UK) is made from a medical-grade thermoplastic elastomer and creates a noninflatable, anatomic seal.
Drug
advantage of using medetomidine, midazolam, and fentanyl is the complete reversibility of anesthesia with flumazenil, atipamezole, and naloxone. Therefore, the period of recovery is significantly shortened resulting in a reduced risk of hypoglycemia and hypothermia. Guinea pigs and chinchillas are prone to anorexia if hypothermic. If painful procedures are being performed, one must understand that the analgesic effects of the anesthetic combination will also be negated if reversal drugs are used; therefore additional analgesic therapy is required. Midazolam combined with fentanyl/fluanisone produces neuroleptanalgesia with adequate skeletal muscle relaxation in mice, rats, gerbils, hamsters, and guinea pigs.7 Anesthesia can be prolonged up to 6 to 8 hours in the rat
TABLE 2. Injectable anesthetics used in rabbits and rodents, doses are given in mg/kg unless otherwise indicated
FIGURE 2. This laryngeal mask (Portex Soft Seal Laryngeal Mask; Smiths Medical Schweiz AG, Dübendorf, Switzerland) uses air to provide an adequate seal of the pharyngeal and laryngeal structures.
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by the administration of small doses of an extemporaneous preparation of fentanyl/fluanisone (0.1 mL/kg intramuscularly, Hypnorm; Vetapharma Ltd, Leeds, UK). The solution is prepared by mixing 1 part Hypnorm, 1 part midazolam (5 mg/mL), and 2 parts water for injection. The dose administered intraperitoneally varied between 2.7 mL/kg in the rat and 13.3 mL/kg in the mouse. The author has used this combination of fentanyl/fluanisone and midazolam successfully in guinea pigs, administered via the subcutaneous route. Rabbits Induction of anesthesia in rabbits using only gas anesthetic agents may be detrimental alone because all commonly available inhalation anesthetic compounds are associated with struggling and breath-holding. During this prolonged period of apnea, bradycardia, hypercapnia, and hypoxemia may occur.17 If gas anesthetic agents are used for induction, it is best to premedicate the rabbit with midazolam, fentanyl/fluanisone, or acepromazine to reduce stress associated with the procedure.5 Nevertheless, premedicating rabbit patients does not prevent breath-holding or stress during induction. A balanced anesthetic protocol with a combination of injectable drugs is the preferred method for rabbit induction. In healthy patients, a combination of 10 to 15 mg/kg ketamine and 0.15 to 0.25 mg/kg medetomidine applied subcutaneously can be used to induce a surgical plane of anesthesia.12,18,19 Intramuscular injections are often associated with discomfort, flinching, and kicking.12,19 Several studies have shown a similar induction time after subcutaneous and intramuscular administration of ketamine and medetomidine.18,19 Compared with the intramuscular route, there is markedly less resistance by the patient to the subcutaneous route, and the latter is, in the author’s opinion, the preferred method of administration. Anesthesia with medetomidine and ketamine results in hypoxemia, thus oxygen should be provided while the animal is unconscious. Any drug combination in which medetomidine is used produces moderate peripheral vasoconstriction. The constriction of a patient’s blood vessels increases the difficulty of intravenous catheter placement. For additional analgesia, opioid drugs (e.g., butorphanol, buprenorphine) are recommended.19 To prolong or deepen anesthesia,
inhalation anesthetic agents can be used, or approximately one third of the original dose of the injectable drug combination can be repeated. Medetomidine can be reversed with atipamezole with reported doses for atipamezole varying between 1 and 5 times the medetomidine dose.20,21 One research investigation showed that the optimal atipamezole dosage to achieve reversal is equal to, or double, the dose of medetomidine. At these dosages, mean recovery time was shortened with no side effects being observed.20 Another option for injectable anesthesia is fentanyl/fluanisone combined with midazolam or diazepam. Fentanyl/fluanisone is injected intramuscularly, then after a 5- to 10-minute delay, followed with an intravenous administration of midazolam or diazepam.7 This injectable drug combination produces a surgical plane of anesthesia lasting approximately 30 to 45 minutes. If necessary, the effects of the drugs described above can be enhanced or the anesthetic effects prolonged with the administration of isoflurane, or additional doses of fentanyl/fluanisone. Rabbits administered this combination of drugs develop moderate respiratory depression and hypoxia, consequently supplemental oxygen is recommended. Recovery can be prolonged (up to 3 hours) but can be shortened by administration of a mixed agonist/antagonist opioid drug such as butorphanol or buprenorphine, and flumazenil/sarmazenil.22 Naloxone completely reverses the effects of respiratory depression, but the analgesic effect induced by the opioid agonist fentanyl will also be lost. Recently, alfaxalone has been evaluated for use as an anesthetic induction agent in rabbits.23 In this research investigation, alfaxalone provided at an intravenous dose of 2 to 3 mg/kg was suitable for anesthesia induction and endotracheal intubation was accomplished in all rabbits.23 All rabbits in the study exhibited a short period of apnea that lasted between 10 and 120 seconds.23 When using alfaxalone to induce rabbits for anesthesia, preoxygenation is recommended for all patients before initiating the procedure. Recovery was relatively rapid; therefore, rabbits anesthetized with alfaxalone can be discharged from the hospital the day of the procedure. Propofol is a commonly used anesthetic induction agent in rabbits. An intravenous bolus of propofol with or without premedication will produce sufficient relaxation for intubation.24 Propofol often causes apnea even when administered
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slowly over 60 seconds. Hypoxemia and hypotension are common adverse side effects observed with propofol use in rabbits. Only light anesthesia is produced with propofol, therefore it is not as useful when trying to maintain a surgical plane of anesthesia over an extended period of time.25 MONITORING, RECOVERY, AND POSTOPERATIVE CARE When a patient is anesthetized, cardiorespiratory parameters, body temperature, and depth of anesthesia should be closely monitored. The rabbit’s respiratory rate For one to and rhythm, in most cases, are vicorrectly assess sually observed. When the animal is intubated, capnography can be changes used to measure end-tidal carbon indicative of dioxide levels and assess ventilation. Heart rates can be measured pain and via auscultation, electrocardiogram, distress, an Doppler probes, or pulse oximeters. In larger animals, arterial blood understanding pressure can be measured directly of normal via the central auricular artery, or indirectly with oscillometric limb species behavior cuffs. A rectal thermometer should is essential. be used to accurately measure body temperature during the procedure. The pedal withdrawal reflex is useful to assess depth of anesthesia and is lost when a surgical plane of anesthesia is achieved.10 In a small animal survey of anesthesia-related mortality, more than half of all anesthetic-related mortalities occurred in the postoperative period. Thus, close monitoring, particularly in the first 3 hours of the postoperative period, is recommended.2 Heart rate and respiratory rate must be measured at regular intervals during recovery from anesthesia. Body temperature should be monitored and maintained by external heating (e.g., warming blanket, convective heating unit), if necessary, until the animal is fully recovered. Anesthesia, stress associated with hospitalization, and pain can have adverse effects on a rabbit’s gastrointestinal motility. Therefore, it is important to monitor feeding and fecal output. Assisted feeding and administration of gastrointestinal motility enhancers (e.g., ranitidine, metoclopramide, cisapride) may be necessary if the patient reduces its feed intake.26 Because pain is an important cause of anorexia, a provision for adequate pain medication is essential. 1 2
ANALGESIA IN RABBITS AND RODENTS Pain Assessment Pain assessment in rabbits and rodents is more challenging than in domestic species (e.g., cats, dogs). In exotic small mammals, behavioral signs of pain are more subtle, and clinicians are often unfamiliar with the normal behaviors of exotic pet species. As prey species, rabbits and rodents are inclined to hide their painful condition to maintain a normal appearance, thereby avoiding predation. The presence of an observer may result in complete immobility with no apparent pain-related behaviors.5 For one to correctly assess changes indicative of pain and distress, an understanding of normal species behavior is essential. Common clinical signs associated with pain in rabbits and rodents include reduced food intake, decreased motor and social activity, altered posture and gait, and licking or chewing at the painful location on their body.27-35 Anorexia is a vital sign of pain and can be a sequel to decreased bowel motility and nausea. More extensive descriptions of clinical signs related with pain are summarized in Table 3. Management of Pain It is crucial to recognize pain as early as possible so that it can be adequately treated before the onset of adverse disease effects. In rabbits, anorexia exceeding 1 to 2 days can rapidly lead to potentially life-threatening gastrointestinal stasis.26 Pain can contribute to immunosuppression, and the subsequent risk of infection must be appreciated in small exotic mammal species, including rabbits in which subclinical respiratory disease is common. An effective pain management plan should include drugs of different classes using a multimodal approach. Commonly used analgesics are provided in Table 4. As with domestic animals, the concept of preemptive analgesia should be considered, and adequate pain medication provided before or just after anesthetic induction.36 Providing soft food (e.g., with dental disease), bandaging, and other types of nursing care may also be indicated as adjunctive therapy to analgesic medication. Nonsteroidal Antiinflammatory Drugs The most frequently used nonsteroidal antiinflammatory drugs (NSAIDs) in rabbits and ro-
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TABLE 3. Signs of pain in rabbits and rodents ● ● ● ● ● ● ● ● ●
Decreased or no appetite (can be a side effect of opioid administration) Increased water intake and urination (often seen in rabbits with dental disease) Aggression in a normally docile animal Altered breathing pattern Altered posture and gait Over-grooming, lack of grooming or licking, chewing or pulling of hair at the painful site Reduced level of spontaneous activity such as digging or exploring the cage Decreased social activity in animals housed in groups, isolation Polyphagia of bedding material that may progress to self-mutilation in small rodents
dents include meloxicam, carprofen, and ketoprofen.37,38 Pharmacokinetic studies have shown that rabbits have lower plasma peak concentrations of meloxicam after oral administration, and metabolize meloxicam faster than dogs, humans, or rats.39 In rabbits, an initial oral dose of 1 mg/kg meloxicam, followed by 0.5 mg/kg/d, may be necessary to achieve adequate analgesia after surgery. Oral doses of meloxicam may not be sufficient to completely control pain after abdominal surgery (e.g., ovariohysterectomy). Therefore, multimodal analgesic treatment should be considered when significant pain is involved (i.e., combining NSAIDs with an opioid drug).31 Clinical experience indicates that doses of 0.3 to 0.6 mg/kg meloxicam can be used safely with no adverse clinical side effects and can be administered on a long-term basis to rabbits.5 Although oral meloxicam doses as low as 0.2 mg/kg have antiinflammatory effects in rats, clin-
● ● ● ● ● ● ● ● ●
Production of fewer, smaller or no fecal droppings Half-closed or squinting eyes, pale (in albino mice or rodent) or bulging eyes (in guinea pigs) Immobility or reluctance to move, slow postural adjustments Pressing abdomen on the floor, tucked appearance to abdomen or hunched posture Reduced weight bearing on affected limb Decreased interest in surroundings, huddling, or hiding in a corner and lethargy Twitching and wincing Piloerection, rough hair coat in small rodents Porphyrin secretions in rodents (ocular/nares)
ical experience indicates that doses ⬍1 to 2 mg/kg do not adequately alleviate pain after surgery.33,40,41 The oral form of meloxicam is honey flavored. It is palatable to most small exotic mammals and is a convenient method for a pet owner to continue managing pain at home. Opioid Drugs Opioid drugs are effective analgesic agents for the control of acute or chronic visceral pain. Butorphanol, buprenorphine, and fentanyl are regularly used in small exotic mammal patients and are well tolerated.42,43 In rabbits, buprenorphine, butorphanol, nalbuphine, and pentazocine provided analgesic effects.44 Although elevated doses of buprenorphine had little effect on the maximum degree of analgesia, it did prolong the duration of the drug’s effect. The onset of analgesia with buprenorphine was rapid (only 30 minutes after intravenous administration) and appears to
TABLE 4. Analgesics used in rabbits and rodents, doses are given in mg/kg Drug
Rabbit
Buprenorphine* Butorphanol† Morphine‡ Meloxicam Carprofen
0.01 – 0.05 IV, SC5 0.1 – 0.5 IV, SC5 2 – 5 SC, IM10 0.3 – 1.5 SC, PO7,39 1.5 – 4 SC, PO5
Guinea Pig
Chinchilla
0.02 – 0.05 SC10 0.01 – 0.05 SC10 0.2 – 2 SC10 0.2 – 2 SC10 10 2 – 5 SC 1 – 2 SC, PO10 4 SC, PO10 4 SC, PO10
Mouse/Gerbil
Rat
0.05 – 0.1 SC10 1 – 2 SC10 2.5 SC10 1 – 5 SC, PO10 5 – 10 SC, PO10
0.01 – 0.05 SC, IV10 0.5 – 2 SC10 0.5 – 5 SC, IM10 1.0 SC, PO10 1 – 5 SC, PO10
Abbreviations: IV, Intravenously; PO, Orally; SC, Subcutaneously. *Long duration of action, if sedation occurs then the dose cab be reduced, may be given orally in the rabbit. †Weaker analgesic than buprenorphine, short duration of action. ‡Side effects: respiratory depression, sedation, reduced gastrointestinal motility.
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have excellent transmucosal absorption. Transmucosal administration of buprenorphine is an uncomplicated method for pet owners to give pain medication at home over a several-day time period without having to give injections. Butorphanol had a rapid onset of action, but increased dose rates did not produce increased levels of analgesia.44 In rabbits and small mammals, the main adverse side effects of opioids are drowsiness and respiratory depression.36,42 In addition to respiratory depression in rabbits, intravenous administration of morphine also causes hypertension, bradycardia, and hyperglycemia.45 In healthy, conscious rabbits, buprenorphine administration decreases respiratory rate and produces mild hypoxemia after subcutaneous and intravenous administration.36,42 Although potential adverse effects of opioid drugs should be considered, the degree of depression seems unlikely to be of clinical importance. Buprenorphine or butorphanol can be used to reverse the respiratory depression and sedation produced by fentanyl/fluanisone.22 Opioids can reduce gastrointestinal motility in rabbits, but this does not appear to be clinically relevant, because in most cases, unalleviated pain is a primary cause of gastrointestinal stasis.29 In mice medicated with buprenorphine, less food intake and weight loss can occur during the postoperative period.46 Pica and gastric distension have been observed in rats receiving high doses of buprenorphine (0.5 mg/kg subcutaneously).47 If the rat patient is showing signs of pica, the bedding material should be temporarily removed to prevent gastric obstruction.38 Transdermal administration of fentanyl results in variable plasma levels. Rabbits tolerate fentanyl transdermal patches well, but hair regrowth may hinder dermal absorption of fentanyl after 24 hours. Conversely, the application of a depilatory agent can cause early and rapid absorption of fentanyl, thereby leading to unwanted sedation and lack of sustained therapeutic plasma concentration levels over the 3-day treatment period.48 Transdermal fentanyl has been used experimentally in hairless guinea pigs and rats.49,50 Most small exotic mammals are not well suited for the use of fentanyl patches because of their diminutive size. Tramadol is a centrally acting analgesic drug that is becoming popular within the zoological medicine field. It is both a weak opioid agonist with selectivity for the mu-receptor, and a weak inhibitor of the reuptake of norepinephrine and serotonin.51 Several pharmacokinetic experiments 1 4
using tramadol have been performed in rodents and rabbits. In one study, the administration of tramadol 10 mg/kg intraperitoneally abolished postoperative hyperalgesia in rats when compared with saline solution or parecoxib.52 Another scientific investigation using rats found that oral tramadol doses as low as 0.45 mg/kg may provide analgesia.53 In a study with rabbits, the investigators concluded that administering oral tramadol at a dose of 11 mg/kg is unlikely to provide analgesia for a clinically acceptable length of time because of low plasma tramadol concentrations.54 LOCAL ANESTHETIC AGENTS Local and regional anesthetic techniques provide good analgesia during the perioperative period. Lidocaine and bupivacaine are commonly used local anesthetics and can be applied topically, via tissue infiltration, intraarticularly, regional nerve block, or by epidural injection. Creams containing local anesthetics, for example EMLA 5% cream (Emla; Astrazeneca, Zug, Switzerland), can be applied topically to the skin before placing intravenous catheters. It is advantageous to clip the hair before applying the EMLA cream. Incisional line blocks and wound infiltration are simple, cost-effective means to provide analgesia for surgical procedures. Important nerve blocks for dental surgery include infraorbital, mental, mandibular, and maxillary nerve blocks.43 Intratesticular injection of local anesthetics can be performed to provide additional analgesia for neutering.55 Epidural analgesia has been described in guinea pigs and rabbits.43,56,57 The extent of the sensory, motor, and autonomic blockade through an epidural injection depends on the dose and volume of drug administered. The lumbosacral space is the preferred site of an epidural injection because of the relatively large space between L7 and S1. The dural sac in rabbits extends into the sacrum, and injection into the lumbosacral space may result in subdural injections.58 Volumes of local anesthetic agent used for epidural injection vary between 0.1 and 0.2 mL/kg. CONCLUSION Rabbits and rodents are frequently anesthetized for various diagnostic and surgical procedures. Inhalation anesthesia using a facemask is commonly used for anesthesia in small rodents. Injectable anesthetic agents in combination with
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inhalation anesthesia are routinely used in rabbits and larger rodents. Adequate pain management needs to be addressed, when necessary, for all small exotic mammal patients. Signs of pain are often more subtle in these species and may be more difficult to recognize. Opioid analgesics and NSAIDs are commonly used, but other analgesic options (e.g., local anesthetic drugs) should also be considered.
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