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4 Veterinary Care V eterinary care is an essential part of an animal care and use Program. The primary focus of the veterinarian is to oversee the well-being and clinical care of animals used in research, testing, teaching, and production. This responsibility extends to monitoring and promoting ani- mal well-being at all times during animal use and during all phases of the animal’s life. Well-being is determined by considering physical, physiologic, and behavioral indicators, which vary by species. The number, species, and use of animals housed in an institution may influence the complexity of the veterinary care program, but a veterinary program that offers a high quality of care and ethical standards must be provided, regardless of the number of animals or species maintained. An adequate veterinary care program consists of assessment of animal well-being and effective management of • animal procurement and transportation • preventive medicine (including quarantine, animal biosecurity, and surveillance) • clinical disease, disability, or related health issues • protocol-associated disease, disability, and other sequelae • surgery and perioperative care • pain and distress • anesthesia and analgesia • euthanasia. 105

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106 GUIdE FOR ThE CARE ANd USE OF LAbORATORy ANIMALS The veterinary care program is the responsibility of the attending vet- erinarian (AV), who is certified or has training or experience in laboratory animal science and medicine or is otherwise qualified in the care of the species being used. Some aspects of the veterinary care program can be conducted by persons other than a veterinarian, but a mechanism for direct and frequent communication should be established to ensure that timely and accurate information is conveyed to the responsible veterinarian about issues associated with animal health, behavior, and well-being, and that appropriate treatment or euthanasia is administered. The AV should provide guidance to investigators and all personnel involved in the care and use of animals to ensure appropriate husbandry, handling, medical treatment, immobilization, sedation, analgesia, anesthesia, and euthanasia. In addi- tion, the AV should provide guidance and oversight to surgery programs and perioperative care involving animals. ANIMAL PROCUREMENT AND TRANSPORTATION Animal Procurement All animals must be acquired lawfully, and the receiving institution should ensure that all procedures involving animal procurement are con- ducted in a lawful manner. Before procuring animals, the principal investi- gator should confirm that there are sufficient facilities and expertise to house and manage the species being acquired. Procurement of animals should be linked to the prior approval of animal use and number by the IACUC (see Chapter 2, Protocol Review). If dogs and cats are obtained from random sources, such as shelters or pounds, the animals should be inspected for tattoos or identification devices such as subcutaneous transponders (NRC 2009b); such identification might indicate that an animal was a pet, and if so, ownership should be verified. Attention should also be given to the pop- ulation status of the species under consideration; the threatened or endan- gered status of species is updated annually by the Fish and Wildlife Service (DOI 2007). Appropriate records and other forms of documentation should be maintained for animals acquired by an institution for its investigators. Potential vendors should be evaluated for the quality of animals they supply. As a rule, vendors of purpose-bred animals (e.g., USDA Class A dealers) regularly provide information that describes the genetic and patho- gen status of their colonies or individual animals and relevant clinical his- tory (e.g., vaccination status and anthelminthic administration). The use of purpose-bred and preconditioned animals is therefore preferable when con- sistent with the research, teaching, and testing objectives. In general, ani- mals used for scientific purposes should not be obtained from pet stores or pet distributors due to the unknown or uncontrolled background of animals

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10 VETERINARy CARE from these sources and the potential for introducing health risks to personnel and other facility animals. Breeding colonies should be established based on need and managed according to principles of animal reduction such as cryopreservation for rodent stocks or strains (Robinson et al. 2003). Transportation of Animals Transportation of animals is governed by a number of US regulatory agencies and international bodies. The Animal Welfare Regulations (USDA 1985) set standards for interstate and export/import transportation of regu- lated species; the International Air Transport Association (IATA) updates the Live Animals Regulations annually and IATA member airlines and many countries agree to comply with these regulations to ensure the safe and humane transport of animals by air (IATA 2009). The Centers for Disease Control and Prevention and USDA enforce regulations to prevent the intro- duction, transmission, or spread of communicable diseases and regulate the importation of any animal or animal product capable of carrying a zoonotic disease. The US Fish and Wildlife Service regulates importation/exportation of wild vertebrate and invertebrate animals and their tissues. As the national authority arm of the Convention on International Trade in Endangered Spe- cies of Wild Fauna and Flora (CITES), the US Fish and Wildlife Service also regulates movement of CITES-listed species that are captive bred, includ- ing nonhuman primates (DOI 2007). Institutions should contact appropri- ate authorities to ensure compliance with any relevant statutes and other animal transportation requirements that must be met for animals to cross international boundaries, including those not of the country of final des- tination. The NRC publication Guidelines for the humane Transportation of Research Animals provides a comprehensive review of this topic (NRC 2006); additional references on transportation of animals are available in Appendix A. Animal transportation may be intrainstitutional, interinstitutional, or between a commercial or noncommercial source and a research facility. For wildlife, transportation may occur between the capture site and field holding facilities. Careful planning for all types of transportation should occur to ensure animal safety and well-being. The process of transportation should provide an appropriate level of animal biosecurity (see definition on page 109) while minimizing zoonotic risks, protecting against environmen- tal extremes, avoiding overcrowding, providing for the animals’ physical, physiologic, or behavioral needs and comfort, and protecting the animals and personnel from physical trauma (Maher and Schub 2004). Movement of animals within or between sites or institutions should be planned and coordinated by responsible and well-trained persons at the sending and receiving sites to minimize animal transit time or delays in

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108 GUIdE FOR ThE CARE ANd USE OF LAbORATORy ANIMALS receipt. Shipping should be coordinated to ensure that animals arrive dur- ing normal business hours or, if delivery occurs outside of this time, that someone is available to receive them. Defining and delegating responsibil- ity to the appropriate persons, who are knowledgeable about the needs of the species being shipped, will help ensure effective communication and planning of animal transport (AVMA 2002). All animals in transit within and between institutions or jurisdictions should be accompanied by appropriate documentation to minimize delays in shipping and receipt. Documentation may include health certificates, sending and receiving institutions’ addresses and contacts, emergency procedures and veterinary contact information, and agency permits as needed. For noncommercial sources of animals, in particular, it is important for the veterinarian or the veterinarian’s designee to review the health status and other housing and husbandry requirements before authorizing shipment of animals. This action will ensure that effective quarantine practices are implemented for incoming animals and address any special requirements needed to ensure animal well-being (Otto and Tolwani 2002). Special con- siderations may be necessary for transporting animals during certain phases of their life or in certain conditions, such as pregnant, perinatal, and geri- atric animals; animals with preexisting medical conditions (e.g., diabetes mellitus); and animals surgically prepared by the supplier (FASS 2010). Although ensuring animal biosecurity during transportation is always important, it is of particular importance for immunocompromised, geneti- cally modified, and specific pathogen-free rodents (Jacoby and Lindsey 1998). For these animals, reinforced disposable shipping containers with filter-protected ventilation openings and internal food and water sources help ensure that microbial contamination does not occur during transit. Commercial vendors are experienced in animal transport and typically use dedicated transport systems and protocols to minimize microbiologic con- tamination. Noncommercial or interinstitutional transfer of rodents poses a higher risk of microbial contamination since the individuals involved may lack the required knowledge and animal biosecurity capabilities to maintain the animals’ health status. Risks due to in-transit microbial contamination of shipping container surfaces can be reduced by decontaminating the sur- faces before placement of the containers in clean sites of animal facilities (NRC 1996, 2006). Transportation of animals in private vehicles is discour- aged because of potential animal biosecurity, safety, health, and liability risks for the animals, personnel, and institution. For aquatic species and amphibians, special considerations are required for transportation in an aqueous or sufficiently moist environment, and special attention should be given to avoiding temperature extremes for poikilotherms.

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10 VETERINARy CARE In all cases, appropriate loading and unloading facilities should be pro- vided for the safe and secure transfer of animals at an institution. Facilities and procedures should be in place to help ensure that the environment at the site does not pose risks to animal well-being or personnel safety. During times of extreme temperatures animal transport may be detrimental to ani- mal well-being and therefore may not be possible unless an appropriately heated or cooled means of transportation is available (Robertshaw 2004; Schrama et al. 1996). PREVENTIVE MEDICINE Disease prevention is an essential component of comprehensive veteri- nary medical care and biosecurity programs. Effective preventive medicine enhances the research value of animals by maintaining healthy animals and minimizing nonprotocol sources of variation associated with disease and inapparent infection, thus minimizing animal waste and potential effects on well-being. Preventive medicine programs consist of various combinations of policies, procedures, and equipment related to quarantine and stabiliza- tion and the separation of animals by species, source, and health status. Animal biosecurity Animal biosecurity refers to all measures taken to identify, contain, pre- vent, and eradicate known or unknown infections that may cause clinical disease or alter physiologic and behavioral responses or otherwise make the animals unsuitable for research. Animal biosecurity practices should be applied to all species, but they Animal biosecurity includes all are most important when housing measures to control known or large numbers of animals in intensive unknown infections in laboratory animals. housing conditions (e.g., laboratory rodents). Limiting exposure of animals to infectious disease agents requires consideration of physical plant layout and operational practices. Separation of clean and soiled caging and equipment, and sometimes the associated staff, is often fundamental to success. A successful animal biosecurity program incorporates a number of ele- ments: procedures that ensure that only animals of a desired defined health status enter the facility; personnel and materials, especially consumables, that do not serve as fomites; practices that reduce the likelihood of cross contamination if an infectious agent is inadvertently introduced; a com- prehensive ongoing system for evaluating animals’ health status, includ- ing access to all animals; and containment and eradication, if desired, of

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110 GUIdE FOR ThE CARE ANd USE OF LAbORATORy ANIMALS introduced infectious agents. Related components include procedures for evaluating and selecting appropriate animal suppliers (these may include quarantine and determination of animal health status if unknown); treat- ment of animals or their products at entry to minimize disease risks (e.g., surface disinfection of fish eggs); a comprehensive pest control program that may include evaluation of the health status of feral animals; procedures to ensure that all biologics administered to animals are free of contamination; and procedures for intra- and interfacility animal transport (e.g., transport of animals to laboratory and other facilities outside the animal facility can present challenges to animal biosecurity) (Balaban and Hampshire 2001). Additional details pertaining to these topics are available in the sections of Chapter 2 that deal with occupational health and safety. Quarantine and Stabilization Quarantine is the separation of newly received animals from those already in the facility, in a way that prevents potential spread of con- taminants, until the health and possibly the microbial status of the newly received animals have been determined. Transportation can be stressful and may induce recrudescence of subclinical infections harbored by an animal. An effective quarantine program minimizes the risk of introduction of pathogens into an established colony. The veterinary medical staff should implement procedures for evaluating the health and, if appropriate, the pathogen status of newly received animals, and the procedures should reflect acceptable veterinary medical practice and federal and state regu- lations applicable to zoonoses (Butler et al. 1995). Effective quarantine procedures are particularly helpful in limiting human exposure to zoo- notic infections from nonhuman primates, such as mycobacterial infections, which necessitate specific guidelines for handling of these animals (Lerche et al. 2008; Roberts and Andrews 2008). Information from suppliers about animal quality should be sufficient to enable a veterinarian to establish the length of quarantine, define the potential risks to personnel and animals in the colony, determine whether therapy is required before animals are released from quarantine, and, in the case of rodents, determine whether rederivation (cesarean or embryo transfer) is necessary to free the animals of specific pathogens. Rodents may not require quarantine if data from the vendor or provider are sufficiently current, complete, and reliable to define the health status of the incoming animals and if the potential for exposure to pathogens during transit is con- sidered. When quarantine is indicated, animals from one shipment should be handled separately or be physically separated from animals from other shipments to preclude transfer of infectious agents between groups.

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111 VETERINARy CARE Depending on the health status of the colony animals and consistent with the animal biosecurity program in place, rodents or other animals being moved outside an animal facility for procedures (e.g., imaging or behavioral testing) may need to be held separately from their colony of origin until their health status is evaluated. Regardless of whether the animals are quarantined, newly received ani- mals should be given a period for physiologic, behavioral, and nutritional acclimation before their use (Obernier and Baldwin 2006). The length of time for acclimation will depend on the type and duration of animal trans- portation, the species, and the intended use of the animals. For animals not typically housed in research settings, consideration should be given to providing means to assist with their acclimation (e.g., shearing sheep before they are brought indoors). The need for an acclimation period has been demonstrated in mice, rats, guinea pigs, nonhuman primates, and goats, and time for acclimation is likely important for other species as well (Capitanio et al. 2006; Conour et al. 2006; Kagira et al. 2007; Landi et al. 1982; Prasad et al. 1978; Sanhouri et al. 1989; Tuli et al. 1995). Separation by Health Status and Species Physical separation of animals by species is recommended to prevent interspecies disease transmission and to eliminate the potential for anxiety and physiologic and behavioral changes due to interspecies conflict (Arndt et al. 2010). Such separation is usually accomplished by housing different species in separate rooms, but in some instances it may be possible with cubicles, laminar flow units, cages that have filtered air or separate ventila- tion, or isolators. It may also be acceptable to house different species in the same room—for example, two species that have a similar pathogen status and are behaviorally compatible (Pritchett-Corning et al. 2009), or aquatic species, as long as nets and other animal handling devices remain separate between systems. In some species subclinical or latent infections can cause clinical dis- ease if transmitted to another species. A few examples may serve as a guide in determining the need for separate housing by species: • helicobacter bilis can infect rats and mice and may induce clini- cal disease in both species (Haines et al. 1998; Jacoby and Lindsey 1998; Maggio-Price et al. 2002). • As a rule, New World (South and Central American), Old World African, and Old World Asian species of nonhuman primates should be housed in separate rooms. Simian hemorrhagic fever (Renquist 1990) and simian immunodeficiency virus (Hirsch et al. 1991; Murphey-Corb et al. 1986), for example, cause only subclinical

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112 GUIdE FOR ThE CARE ANd USE OF LAbORATORy ANIMALS infections in African species but induce clinical disease in Asian species. • Some species should be housed in separate rooms even though they are from the same geographic region. For example, squirrel monkeys (Saimiri sciureus) and tamarins (Saguinus oedipus) may be latently infected with herpesviruses (herpesirus saimiri and h. tamarinus, respectively), which could be transmitted to and cause a fatal epizootic disease in owl monkeys (Aotus triirgatus) (Barahona et al. 1975; Hunt and Melendez 1966; Murphy et al. 1971). Intraspecies separation may be essential when animals obtained from multiple sites or sources, either commercial or institutional, differ in patho- gen status—for example, with respect to rat theilovirus in rats, mouse hepatitis virus in mice, bacterial gill disease in rainbow trout, Pasteurella multocida in rabbits, Macacine herpesirus 1 (B virus) in macaque species, and Mycoplasma hyopneumoniae in swine. Surveillance, Diagnosis, Treatment, and Control of Disease All animals should be observed for signs of illness, injury, or abnormal behavior by a person trained to recognize such signs. As a rule, such obser- vation should occur at least daily, but more frequent observations may be required, such as during postoperative recovery, when animals are ill or have a physical deficit, or when animals are approaching a study endpoint. Professional judgment should be used to ensure that the frequency and character of observations minimize risks to individual animals and do not compromise the research for which the animals are used. Appropriate procedures should be in place for disease surveillance and diagnosis. Unexpected deaths and signs of illness, distress, or other devia- tions from normal in animals should be reported promptly and investigated, as necessary, to ensure appropriate and timely delivery of veterinary medi- cal care. Animals that show signs of a contagious disease should be isolated from healthy animals. If an entire room or enclosure of animals is known or believed to be exposed to an infectious agent (e.g., Mycobacterium tuber- culosis in nonhuman primates), the group should be kept intact during the process of diagnosis, treatment, and control. Procedures for disease prevention, diagnosis, and therapy should be those currently accepted in veterinary and laboratory animal practice. Health monitoring programs also include veterinary herd/flock health pro- grams for livestock and colony health monitoring programs for aquatic and rodent species. Access to diagnostic laboratory services facilitates veterinary medical care and can include gross and microscopic pathology, hematol- ogy, microbiology, parasitology, clinical chemistry, molecular diagnostics,

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113 VETERINARy CARE and serology. If a disease or infectious agent is identified in a facility or colony, the choice of therapy should be made by the veterinarian in con- sultation with the investigator. If the animal is to remain in the study, the selected treatment plan should be therapeutically sound and, when pos- sible, interfere minimally with the research process. Subclinical microbial infections (see Appendix A, Pathology, Clinical Pathology, and Parasitology) occur frequently in conventionally maintained rodents but can also occur in facilities designed and maintained for produc- tion and use of pathogen-free rodents if the microbial barrier is breached. Examples of infectious agents that can be subclinical but that may induce immunologic changes or alter physiologic, pharmacologic, or toxicologic responses are noroviruses, parvoviruses, mouse hepatitis virus, lymphocytic choriomeningitis virus, and helicobacter spp. (Besselsen et al. 2008; Clif- ford and Watson 2008; NRC 1991a,b,c). Scientific objectives of a particular protocol, the consequences of infection in a specific strain of rodent, the potential for zoonotic disease, and the adverse effects that infectious agents may have on other animals or protocols in a facility should determine the characteristics of rodent health surveillance programs and strategies for keeping rodents free of specific pathogens. The principal methods for detecting microbial infections in animal populations are serologic tests (e.g., flow cytometric bead immunoassays, immunofluorescent assays) but other methods, such as DNA analysis using polymerase chain reaction (PCR), microbial culture, clinical chemistry (e.g., lactate dehydrogenase virus), histopathology, and other validated emerging technologies, can also be used to make or confirm a diagnosis. Transplantable tumors, hybridomas, cell lines, blood products, and other biologic materials can be sources of both murine and human viruses that can contaminate rodents or pose risks to laboratory personnel (Nicklas et al. 1993); rapid and effective assays are available to monitor micro- biologic contamination and should be considered before introducing such material into animals (Peterson 2008). Because health monitoring programs are dependent on the size and com- plexity of the Program, the species involved, and the institutional research focus, it is beyond the scope of the Guide to go into details about health monitoring programs for all species; additional references are in Appendix A (under Disease Surveillance, Diagnosis, and Treatment; Pathology, Clinical Pathology, and Parasitology; and Species-Specific References). CLINICAL CARE AND MANAGEMENT Healthy, well-cared-for animals are a prerequisite for good-quality animal-based science. The structure of the veterinary care program, includ- ing the number of qualified veterinarians, should be appropriate to fulfill the

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114 GUIdE FOR ThE CARE ANd USE OF LAbORATORy ANIMALS program‘s requirements, which will vary by institution, species used, and the nature of the animal use. To be effective in providing clinical care, the veterinarian should be familiar with the species and various uses of animals in the institutional research, teaching, testing, or production programs and have access to medical and experimental treatment records. Medical Management There should be a timely and accurate method for communication of any abnormalities in or concerns about animal health, behavior, and well- being to the veterinarian or the veterinarian’s designee. The responsibility for communicating these concerns rests with all those involved with animal care and use. Reports should be triaged to ensure that animals most in need receive priority attention, and the veterinarian or veterinarian’s designee should perform an objective assessment of the animal(s) to determine an appropriate course of action. Well-planned experiments with clearly delineated scientific and humane endpoints will help to ensure that a contingency plan is in place for prob- lems that may arise during the study (see Chapter 2, Experimental and Humane Endpoints). For animals on research protocols, the veterinarian or veterinarian’s designee should make every effort to discuss any problems with the principal investigator or project director to jointly determine the most appropriate course of treatment or action. Standard operating proce- dures (SOPs) may be developed for recurrent health conditions to expedite treatment. Recurrent or significant problems involving experimental animal health should be communicated to the IACUC, and all treatments and out- comes should be documented (USDA 1997). Emergency Care Procedures must be in place to provide for emergency veterinary care both during and outside of regularly scheduled hours. Such procedures must enable animal care and research staff to make timely reports of animal injury, illness, or death. A veterinarian or the veterinarian’s designee must be available to expeditiously assess the animal’s condition, treat the animal, investigate an unexpected death, or advise on euthanasia. In the case of a pressing health problem, if the responsible person (e.g., investigator) is not available or if the investigator and veterinary staff cannot reach consensus on treatment, the veterinarian must have the authority, delegated by senior administration (see Chapter 2, Institutional Official and Attending Veteri- narian) and the IACUC, to treat the animal, remove it from the experiment, institute appropriate measures to relieve severe pain or distress, or perform euthanasia if necessary.

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115 VETERINARy CARE Recordkeeping Medical records are a key element of the veterinary care program and are considered critical for documenting animal well-being as well as track- ing animal care and use at a facility. A veterinarian should be involved in establishing, reviewing, and overseeing medical and animal use records (Field et al. 2007; Suckow and Doerning 2007). All those involved in ani- mal care and use must comply with federal laws and regulations regarding human and veterinary drugs and treatments. Drug records and storage pro- cedures should be reviewed during facility inspections. SURGERy Successful surgical outcomes require appropriate attention to presurgi- cal planning, personnel training, anesthesia, aseptic and surgical technique, assessment of animal well-being, appropriate use of analgesics, and animal physiologic status during all phases of a protocol involving surgery and postoperative care (see Appendix A, Anesthesia, Pain, and Surgery). The individual impact of those factors will vary according to the complexity of procedures involved and the species of animal used. A team approach to a surgical project often increases the likelihood of a successful outcome by providing input from persons with different expertise (Brown and Schofield 1994; Brown et al. 1993). Surgical outcomes should be continually and thoroughly assessed to ensure that appropriate procedures are followed and timely corrective changes are instituted. Modification of standard techniques may be required (for instance, in aquatic or field surgery), but should not compromise the well-being of the animals. In the event of modification, close assessment of outcomes may have to incorporate criteria other than clinical morbidity and mortality. Such assessments rely on continuing communication among technical staff, investigators, veterinarians, and the IACUC. Training Researchers conducting surgical procedures must have appropriate train- ing to ensure that good surgical technique is practiced—that is, asepsis, gentle tissue handling, minimal dissection of tissue, appropriate use of instruments, effective hemostasis, and correct use of suture materials and patterns (Brown et al. 1993; Heon et al. 2006). Training may have to be tailored to accom- modate the wide range of educational backgrounds frequently encountered in research settings. For example, persons trained in human surgery may need training in interspecies variations in anatomy, physiology, the effects of anesthetic and analgesic drugs, and/or postoperative care requirements.

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122 GUIdE FOR ThE CARE ANd USE OF LAbORATORy ANIMALS Alleviation of chronic pain may be more challenging than postproce- dural pain; commercially available opiate slow-release transdermal patches or implantable analgesic-containing osmotic minipumps may be useful for such relief. Because of wide individual variation in response to analgesics, regardless of the initial plan for pain relief, animals should be closely moni- tored during and after painful procedures and should receive additional drugs, as needed, to ensure appropriate analgesic management (Karas et al. 2008; Paul-Murphy et al. 2004). Nonpharmacologic control of pain may be effective and should not be overlooked as an element of postprocedural or perioperative care for research animals (NRC 2009a; Spinelli 1990). Appropriate nursing support may include a quiet, darkened recovery or resting place, timely wound or bandage maintenance, increased ambient warmth and a soft resting surface, rehydration with oral or parenteral fluids, and a return to normal feeding through the use of highly palatable foods or treats. Most anesthetics cause a dose-dependent depression of physiologic homeostasis and the changes can vary considerably with different agents. The level of consciousness, degree of antinociception (lack of response to noxious stimuli), and status of the cardiovascular, respiratory, muscu- loskeletal, and thermoregulatory systems should all be used to assess the adequacy of the anesthetic regimen. Interpretation and appropriate response to the various parameters measured require training and experience with the anesthetic regimen and the species. Loss of consciousness occurs at a light plane of anesthesia, before antinociception, and is sufficient for purposes of restraint or minor, less invasive procedures, but painful stimuli can induce a return to consciousness. Antinociception occurs at a surgical plane of anes- thesia and must be ascertained before surgery. Individual animal responses vary widely and a single physiologic or nociceptive reflex response may not be adequate for assessing the surgical plane or level of analgesia (Mason and Brown 1997). For anesthesia delivery, precision vaporizers and monitoring equipment (e.g., pulse oximeter for determining arterial blood oxygen saturation levels) increase the safety and choices of anesthetic agents for use in rodents and other small species. For injectable anesthestic protocols, specific reversal agents can minimize the incidence of some side effects related to prolonged recovery and recumbency. Guidelines for the selection and proper use of analgesic and anesthetic drugs should be developed and periodically reviewed and updated as standards and techniques are refined. Agents that provide anesthesia and analgesia must be used before their expiration dates and should be acquired, stored, their use recorded, and disposed of legally and safely. Some classes of drugs such as sedatives, anxiolytics, and neuromus- cular blocking agents may not provide analgesia but may be useful when

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123 VETERINARy CARE used in combination with appropriate analgesics and anesthetics to provide balanced anesthesia and to minimize stress associated with perioperative procedures. Neuromuscular blocking agents (e.g., pancuronium) are some- times used to paralyze skeletal muscles during surgery in which general anesthetics have been administered (Klein 1987); because this paralysis eliminates many signs and reflexes used to assess anesthetic depth, auto- nomic nervous system changes (e.g., sudden changes in heart rate and blood pressure) can be indicators of pain related to an inadequate depth of anesthesia. It is imperative that any proposed use of neuromuscular block- ing drugs be carefully evaluated by the veterinarian and IACUC to ensure the well-being of the animal. Acute stress is believed to be a consequence of paralysis in a conscious state and it is known that humans, if conscious, can experience distress when paralyzed with these drugs (NRC 2008; Van Sluyters and Oberdorfer 1991). If paralyzing agents are to be used, the appropriate amount of anesthetic should first be defined on the basis of results of a similar procedure using the anesthetic without a blocking agent (NRC 2003, 2008, 2009a). EUTHANASIA Euthanasia is the act of humanely killing animals by methods that induce rapid unconsciousness and death without pain or distress. Unless a deviation is justified for scientific or medical reasons, methods should be consistent with the AVMA Guidelines on Euthanasia (AVMA 2007 or later editions). In evaluating the appropriateness of methods, some of the criteria that should be considered are ability to induce loss of consciousness and death with no or only momentary pain, distress, or anxiety; reliability; irre- versibility; time required to induce unconsciousness; appropriateness for the species and age of the animal; compatibility with research objectives; and the safety of and emotional effect on personnel. Euthanasia may be planned and necessary at the end of a protocol or as a means to relieve pain or distress that cannot be alleviated by analgesics, sedatives, or other treatments. Criteria for euthanasia include protocol-spe- cific endpoints (such as degree of a physical or behavioral deficit or tumor size) that will enable a prompt decision by the veterinarian and the inves- tigator to ensure that the endpoint is humane and, whenever possible, the scientific objective of the protocol is achieved (see Chapter 2). Standardized methods of euthanasia that are predictable and control- lable should be developed and approved by the AV and IACUC. Euthanasia should be carried out in a manner that avoids animal distress. Automated systems for controlled and staged delivery of inhalants may offer advantages for species killed frequently or in large numbers, such as rodents (McIntyre et al. 2007). Special consideration should be given to euthanasia of fetuses

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124 GUIdE FOR ThE CARE ANd USE OF LAbORATORy ANIMALS and larval life forms depending on species and gestational age (Artwohl et al. 2006). The selection of specific agents and methods for euthanasia will depend on the species involved, the animal’s age, and the objectives of the proto- col. Generally, chemical agents (e.g., barbiturates, nonexplosive inhalant anesthetics) are preferable to physical methods (e.g., cervical dislocation, decapitation, use of a penetrating captive bolt); however, scientific consid- erations may preclude the use of chemical agents for some protocols. Although carbon dioxide (CO2) is a commonly used method for rodent euthanasia, there is ongoing controversy about its aversive characteristics as an inhalant euthanasia agent. This is an area of active research (Conlee et al. 2005; Danneman et al. 1997; Hackbarth et al. 2000; Kirkden et al. 2008; Leach et al. 2002; Niel et al. 2008) and further study is needed to optimize the methods for CO2 euthanasia in rodents (Hawkins et al. 2006). The acceptability of CO2 as a euthanasia agent for small rodents should be evaluated as new data become available. Furthermore, because neonatal rodents are resistant to the hypoxia-inducing effects of CO2 and require lon- ger exposure times to the agent (Artwohl et al. 2006), alternative methods should be considered (e.g., injection with chemical agents, cervical disloca- tion, or decapitation; Klaunberg et al. 2004; Pritchett-Corning 2009). It is essential that euthanasia be performed by personnel skilled in meth- ods for the species in question and in a professional and compassionate manner. Special attention is required to ensure proficiency when a physi- cal method of euthanasia is used. Death must be confirmed by personnel trained to recognize cessation of vital signs in the species being euthanized. A secondary method of euthanasia (e.g., thoracotomy or exsanguination) can be also used to ensure death. All methods of euthanasia should be reviewed and approved by the veterinarian and IACUC. Euthanizing animals is psychologically difficult for some animal care, veterinary, and research personnel, particularly if they perform euthanasia repetitively or are emotionally attached to the animals being euthanized (Arluke 1990; NRC 2008; Rollin 1986; Wolfle 1985). When delegating euthanasia responsibilities, supervisors should be sensitive to this issue. REFERENCES Anderson LC. 2007. Institutional and IACUC responsibilities for animal care and use education and training programs. ILAR J 48:90-95. ACLAM [American College of Laboratory Animal Medicine]. 2001. Position Statement on Ro- dent Surgery. Available at www.aclam.org/education/guidelines/position_rodentsurgery. html; accessed January 7, 2010. AORN [Association of Operating Room Nurses]. 2006. Recommended practices for traffic patterns in the perioperative practice setting. AORN J 83:681-686. Arluke A. 1990. Uneasiness among laboratory technicians. Lab Anim 19:20-39.

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