Veterinary Medical Care
Veterinary medical care is an essential part of an animal care and use program. Adequate veterinary care consists of effective programs for
Surveillance, diagnosis, treatment, and control of disease, including zoonosis control.
Management of protocol-associated disease, disability, or other sequelae.
Anesthesia and analgesia.
Surgery and postsurgical care.
Assessment of animal well-being.
A veterinary care program is the responsibility of the attending veterinarian, who is certified (see ACLAM, Appendix B) or has training or experience in laboratory animal science and medicine or 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 veterinarian on problems associated with animal health, behavior, and well-being. The veterinarian must provide guidance to investigators and all personnel involved in the care and use of animals to ensure appropriate handling, immobilization, sedation, analgesia, anesthesia, and euthanasia. The attending veterinarian must provide guidance or oversight to surgery programs and oversight of postsurgical care.
ANIMAL PROCUREMENT AND TRANSPORTATION
All animals must be acquired lawfully, and the receiving institution should make reasonable attempts to ensure that all transactions involving animal procurement are conducted in a lawful manner. If dogs and cats are obtained from USDA Class B dealers or pounds, the animals should be inspected to see whether they can be identified, as through the presence of tattoos or subcutaneous transponders. Such identification might indicate that an animal was a pet, and ownership should be verified. Attention should be given to the population status of the taxon under consideration; the threatened or endangered status of species is provided and updated annually by the Fish and Wildlife Service (DOI 50 CFR 17). The use of purpose-bred research animals testing objectives. might be desirable if it is consistent with research, teaching, and
Potential vendors should be evaluated for the quality of animals supplied by them. As a rule, vendors of purpose-bred animals (e.g., USDA Class A dealers) regularly provide information that describes the genetic and pathogen status of their colonies or individual animals. This information is useful for deciding on acceptance or rejection of animals, and similar data should be obtained on animals received by interinstitutional or intrainstitutional transfer (such as transgenic mice).
All transportation of animals, including intrainstitutional transportation, should be planned to minimize transit time and the risk of zoonoses, protect against environmental extremes, avoid overcrowding, provide food and water when indicated, and protect against physical trauma. Some transportation-related stress is inevitable, but it can be minimized by attention to those factors. Each shipment of animals should be inspected for compliance with procurement specifications and signs of clinical disease and should be quarantined and stabilized according to procedures appropriate for the species and the circumstances. Coordination of ordering and receiving with animal care personnel is important to ensure that animals are received properly and that appropriate facilities are available for housing.
Several documents provide details on transportation, including the AWRs and the International Air Transport Association Live Animal Regulations (IATA 1995). In addition, import of primates is regulated by the Public Health Service (CFR Title 42) with specific guidelines for tuberculin testing (CDC 1993). There are special requirements for importing and transporting African green, cynomolgus, and rhesus monkeys (FR 1990; CDC 1991).
Disease prevention is an essential component of comprehensive veterinary medical care. Effective preventive-medicine programs enhance the research value of animals by maintaining healthy animals and minimizing nonprotocol sources
of variation associated with disease and inapparent infection. These programs consist of various combinations of policies, procedures, and practices related to quarantine and stabilization and the separation of animals by species, source, and health status.
Quarantine, Stabilization, and Separation
Quarantine is the separation of newly received animals from those already in the facility until the health and possibly the microbial status of the newly received animals have been determined. An effective quarantine minimizes the chance for introduction of pathogens into an established colony. The veterinary medical staff should have 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 regulations applicable to zoonoses (Butler and others 1995). Effective quarantine procedures should be used for nonhuman primates to help limit exposure of humans to zoonotic infections. Filoviral and mycobacterial infections in nonhuman primates have recently necessitated specific guidelines for handling nonhuman primates (CDC 1991, 1993). Information from vendors on animal quality should be sufficient to enable a veterinarian to determine the length of quarantine, to define the potential risks to personnel and animals within the colony, to determine whether therapy is required before animals are released from quarantine, and, in the case of rodents, to determine whether cesarean rederivation or embryo transfer is required to free the animals of specific pathogens. Rodents might not require quarantine if data from the vendor or provider are sufficiently current and complete to define the health status of the incoming animals and if the potential for exposure to pathogens during transit is considered. When quarantine is indicated, animals from one shipment should be separated from animals from other shipments (not necessarily from each other) to preclude transfer of infectious agents between groups.
Regardless of the duration of quarantine, newly received animals should be given a period for physiologic, psychologic, and nutritional stabilization before their use. The length of time for stabilization will depend on the type and duration of animal transportation, the species involved, and the intended use of the animals. The need for a stabilization period has been demonstrated in mice, rats, guinea pigs, and goats; it is probably required for other species as well (Drozdowicz and others 1990; Jelinek 1971; Landi and others 1982; Prasad and others 1978; Sanhouri and others 1989; Tuli and others 1995; Wallace 1976).
Physical separation of animals by species is recommended to prevent interspecies disease transmission and to eliminate anxiety and possible physiologic and behavioral changes due to interspecies conflict. Such separation is usually accomplished by housing different species in separate rooms; however, cubicles, laminar-flow units, cages that have filtered air or separate ventilation,
and isolators might be suitable alternatives. In some instances, it might be acceptable to house different species in the same room, for example, if two species have a similar pathogen status and are behaviorally compatible. Some species can have subclinical or latent infections that can cause clinical disease if transmitted to another species. A few examples might serve as a guide in determining the need for separate housing by species:
Bordetella bronchiseptica characteristically produces only subclinical infections in rabbits, but severe respiratory disease might occur in guinea pigs (Manning and others 1984).
As a rule, New World (South American), Old World African, and Old World Asian species of nonhuman primates should be housed in separate rooms. Simian hemorrhagic fever (Palmer and others 1968) and simian immunodeficiency virus (Hirsch and others 1991; Murphey-Corb and others 1986), for example, cause only subclinical 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. Squirrel monkeys (Saimiri sciureus), for example, might be latently infected with Herpesvirus tamarinus, which can be transmitted to and cause a fatal epizootic disease in owl monkeys (Aotus trivirgatus) (Hunt and Melendez 1966) and some species of marmosets and tamarins (Saguinus oedipus, S. nigricollis) (Holmes and others 1964; Melnick and others 1964).
Intraspecies separation might be essential when animals obtained from multiple sites or sources, either commercial or institutional, differ in pathogen status, e.g., sialodacryoadenitis virus in rats, mouse hepatitis virus, Pasteurella multocida in rabbits, for Cercopithecine herpesvirus 1 (formerly Herpesvirus simiac) 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, this should occur daily, but more-frequent observations might be warranted, such as during postoperative recovery or when animals are ill or have a physical deficit. There might also be situations in which daily observations of each animal is impractical, for example, when animals are housed in large outdoor settings. Professional judgment should be used to ensure that the frequency and character of observation minimize risks to individual animals.
It is imperative that appropriate methods be in place for disease surveillance and diagnosis. Unexpected deaths and signs of illness, distress, or other deviations from normal in animals should be reported promptly to ensure appropriate
and timely delivery of veterinary medical care. Animals that show signs of a contagious disease should be isolated from healthy animals in the colony. If an entire room of animals is known or believed to be exposed to an infectious agent (e.g., Mycobacterium tuberculosis in nonhuman primates), the group should be kept intact during the process of diagnosis, treatment, and control.
Methods of disease prevention, diagnosis, and therapy should be those currently accepted in veterinary practice. Diagnostic laboratory services facilitate veterinary medical care and can include gross and microscopic pathology, clinical pathology, hematology, microbiology, clinical chemistry, and serology. The choice of medication or therapy should be made by the veterinarian in consultation with the investigator. The selected treatment plan should be therapeutically sound and, when possible, should cause no undesirable experimental variable.
Subclinical microbial, particularly viral, infections (see Appendix A ) occur frequently in conventionally maintained rodents but also can occur in facilities designed and maintained for production and use of pathogen-free rodents if a component of the microbial barrier is breached. Examples of infectious agents that can be subclinical but induce profound immunologic changes or alter physiologic, pharmacologic, or toxicologic responses are Sendai virus, Kilham rat virus, mouse hepatitis virus, lymphocytic choriomeningitis virus, and Mycoplasma pulinonis (NRC 199 la,b). Scientific objectives of a particular protocol, the consequences of infection within a specific strain of rodent, and the adverse effects that infectious agents might have on other protocols in a facility should determine the characteristics of rodent health-surveillance programs and strategies for keeping rodents free of specific pathogens.
The principal method for detecting viral infections is serologic testing. Other methods of detecting microbial infections, such as bacterial culturing and histopathology and DNA analysis using the polymerase chain reaction (PCR), should be used in combinations that are most suitable for specific requirements of clinical and research programs. Transplantable tumors, hybridomas, cell lines, and other biologic materials can be sources of murine viruses that can contaminate rodents (Nicklas and others 1993). The mouse-antibody-production (MAP), rat-antibody-production (RAP), and hamster-antibody-production (HAP) tests are effective in monitoring for viral contamination of biologic materials (de Souza and Smith 1989; NRC 1991c) and should be considered.
Appropriate attention to presurgical planning, personnel training, aseptic and surgical technique, animal well-being, and animal physiologic status during all phases of a protocol will enhance the outcome of surgery (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 and others 1993).
A continuing and thorough assessment of surgical outcomes should be performed to ensure that appropriate procedures are followed and timely corrective changes instituted. Modification of standard techniques might be desirable or even required (for instance, in rodent or field surgery), but it should not compromise the well-being of the animals. In the event of modification, assessment of outcomes should be even more intense and might have to incorporate criteria other than obvious clinical morbidity and mortality.
Presurgical planning should include input from all members of the surgical team, including the surgeon, anesthetist, veterinarian, surgical technicians, animal care staff, and investigator. The surgical plan should identify personnel, their roles and training needs, and equipment and supplies required for the procedures planned (Cunliffe-Beamer 1993); the location and nature of the facilities in which the procedures will be conducted; and preoperative animal-health assessment and postoperative care (Brown and Schofield 1994). If a nonsterile part of an animal, such as the gastrointestinal tract, is to be surgically exposed or if a procedure is likely to cause immunosuppression, preoperative antibiotics might be appropriate (Klement and others 1987). However, the use of antibiotics should never be considered as a replacement for aseptic procedures.
It is important that persons have had appropriate training 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 (Chaffee 1974; Wingfield 1979). People performing and assisting in surgical procedures in a research setting often have a wide range of educational backgrounds and might require various levels and kinds of training before they participate in surgical procedures on animals. For example, persons trained in human surgery might need training in inter species variations in anatomy, physiology, and the effects of anesthetic and analgesic drugs, or in postoperative requirements. Training guidelines for research surgery commensurate with a person's background are available (ASR 1989) to assist institutions in developing appropriate training programs. The PHS Policy and the AWRs place responsibility with the IACUC for determining that personnel performing surgical procedures are appropriately qualified and trained in the procedures to be performed.
In general, surgical procedures are categorized as major or minor and in the laboratory setting can be further divided into survival and nonsurvival. Major survival surgery penetrates and exposes a body cavity or produces substantial impairment of physical or physiologic functions (such as laparotomy, thoracotomy, craniotomy, joint replacement, and limb amputation). Minor survival surgery does not expose a body cavity and causes little or no physical impairment (such as wound suturing; peripheral-vessel cannulation; such routine farm animal
procedures as castration, dehorning, and repair of prolapses; and most procedures routinely done on an "outpatient" basis in veterinary clinical practice).
Minor procedures are often performed under less-stringent conditions than major procedures but still require aseptic technique and instruments and appropriate anesthesia. Although laparoscopic procedures are often performed on an "outpatient" basis, appropriate aseptic technique is necessary if a body cavity is penetrated.
In nonsurvival surgery, an animal is euthanatized before recovery from anesthesia. It might not be necessary to follow all the techniques outlined in this section if nonsurvival surgery is performed; however, at a minimum, the surgical site should be clipped, the surgeon should wear gloves, and the instruments and surrounding area should be clean (Slattum and others 1991).
Emergency situations sometimes require immediate surgical correction under less than ideal conditions. For example, if an animal maintained outdoors needs surgical attention, movement to a surgical facility might pose an unacceptable risk to the animal or be impractical. Such situations often require more-intensive aftercare and might pose a greater risk of postoperative complications. The appropriate course of action requires veterinary medical judgment.
Aseptic technique is used to reduce microbial contamination to the lowest possible practical level (Cunliffe-Beamer 1993). No procedure, piece of equipment, or germicide alone can achieve that objective (Schonholtz 1976). Aseptic technique requires the input and cooperation of everyone who enters the operating suite (Belkin 1992; McWilliams 1976). The contribution and importance of each practice varies with the procedure. Aseptic technique includes preparation of the patient, such as hair removal and disinfection of the operative site (Hofmann 1979); preparation of the surgeon. such as the provision of decontaminated surgical attire, surgical scrub, and sterile surgical gloves (Chamberlain and Houang 1984; Pereira and others 1990; Schonholtz 1976); sterilization of instruments, supplies, and implanted materials (Kagan 1992b); and the use of operative techniques to reduce the likelihood of infection (Ayliffe 1991; Kagan 1 992a; Ritter and Marmion 1987; Schofield 1994; Whyte 1988).
Specific sterilization methods should be selected on the basis of physical characteristics of materials to be sterilized (Schofield 1994). Autoclaving and gas sterilization are common effective methods. Sterilization indicators should be used to identify materials that have undergone proper sterilization (Berg 1993). Liquid chemical sterilants should be used with adequate contact times, and instruments should be rinsed with sterile water or saline before use. Alcohol is neither a sterilant nor a high-level disinfectant (Rutala 1990).
In general, unless an exception is specifically justified as an essential component of the research protocol and approved by the IACUC, nonrodent aseptic surgery should be conducted only in facilities intended for that purpose. Most bacteria are carried on airborne particles or fomites, so surgical facilities should be maintained and operated in a manner that ensures cleanliness and minimizes
unnecessary traffic (AORN 1982; Bartley 1993). In some circumstances, it might be necessary to use an operating room for other purposes. In such cases, it is imperative that the room be returned to an appropriate level of cleanliness before its use for major survival surgery.
Careful surgical monitoring and timely attention to problems increase the likelihood of a successful surgical outcome. Monitoring includes checking of anesthetic depth and physiologic function and assessment of clinical signs and conditions. Maintenance of normal body temperature minimizes cardiovascular and respiratory disturbances caused by anesthetic agents (Dardai and Heavner 1987) and is of particular importance.
The species of animal influences the components and intensity of the surgical program. The relative susceptibility of rodents to surgical infection has been debated; available data suggest that subclinical infections can cause adverse physiologic and behavioral responses (Beamer 1972; Bradfield and others 1992; Cunliffe-Beamer 1990; Waynforth 1980, 1987) that can affect both surgical success and research results. Some characteristics of common laboratory-rodent surgery-such as smaller incision sites, fewer personnel in the surgical team, manipulation of multiple animals at one sitting, and briefer procedures-as opposed to surgery in larger species, can make modifications in standard aseptic techniques necessary or desirable (Brown 1994; Cunliffe-Beamer 1993). Useful suggestions for dealing with some of the unique challenges of rodent surgery have been published (Cunliffe-Beamer 1983, 1993).
Generally, farm animals maintained for biomedical research should undergo surgery with procedures and in facilities compatible with the guidelines set forth in this section. However, some minor and emergency procedures that are commonly performed in clinical veterinary practice and in commercial agricultural settings may be conducted under less-stringent conditions than experimental surgical procedures in a biomedical-research setting. Even when conducted in an agricultural setting, these procedures require the use of appropriate aseptic technique, sedatives, analgesics, anesthetics, and conditions commensurate with the risk to the animal's health and well-being. But they might not require the intensive surgical settings, facilities, and procedures outlined here.
Presurgical planning should specify the requirements of postsurgical monitoring, care, and record-keeping, including the personnel who will perform these duties. The investigator and veterinarian share responsibility for ensuring that postsurgical care is appropriate. An important component of postsurgical care is observation of the animal and intervention as required during recovery from anesthesia and surgery. The intensity of monitoring necessary will vary with the species and the procedure and might be greater during the immediate anesthetic-recovery period than later in postoperative recovery. During the anesthetic-recovery period, the animal should be in a clean, dry area where it can be observed often by trained personnel. Particular attention should be given to thermoregulation, cardiovascular and respiratory function, and postoperative pain or discom-
fort during recovery from anesthesia. Additional care might be warranted, including administration of parenteral fluids for maintenance of water and electrolyte balance (FBR 1987), analgesics, and other drugs; care for surgical incisions; and maintenance of appropriate medical records.
After anesthetic-recovery, monitoring is often less intense but should include attention to basic biologic functions of intake and elimination and behavioral signs of postoperative pain, monitoring for postsurgical infections, monitoring of the surgical incision, bandaging as appropriate, and timely removal of skin sutures, clips, or staples (UFAW 1989).
PAIN, ANALGESIA, AND ANESTHESIA
An integral component of veterinary medical care is prevention or alleviation of pain associated with procedural and surgical protocols. Pain is a complex experience that typically results from stimuli that damage tissue or have the potential to damage tissue. The ability to experience and respond to pain is widespread in the animal kingdom. A painful stimulus prompts withdrawal and evasive action. Pain is a stressor and, if not relieved, can lead to unacceptable levels of stress and distress in animals. The proper use of anesthetics and analgesics in research animals is an ethical and scientific imperative. Recognition and Alleviation of Pain and Distress in Laboratory Animals (NRC 1992) is a source of information about the basis and control of pain (see also Appendix A).
Fundamental to the relief of pain in animals is the ability to recognize its clinical signs in specific species (Hughes and Lang 1983; Soma 1987). Species vary in their response to pain (Breazile 1987; Morton and Griffiths 1985; Wright and others 1985), 50 criteria for assessing pain in various species differ. Some species-specific behavioral manifestations of pain or distress are used as indicators, for example, vocalization, depression or other behavioral changes, abnormal appearance or posture, and immobility (NRC 1992). It is therefore essential that personnel caring for and using animals be very familiar with species-specific (and individual) behavioral, physiologic, and biochemical indicators of well-being (Dresser 1988; Dubner 1987; Kitchen and others 1987). In general, unless the contrary is known or established it should be assumed that procedures that cause pain in humans also cause pain in animals (IRAC 1985).
The selection of the most appropriate analgesic or anesthetic should reflect professional judgment as to which best meets clinical and humane requirements without compromising the scientific aspects of the research protocol. Preoperative or intraoperative administration of analgesics might enhance postsurgical analgesia. The selection depends on many factors, such as the species and age of the animal, the type and degree of pain, the likely effects of particular agents on specific organ systems, the length of the operative procedure, and the safety of an agent for an animal, particularly if a physiologic deficit is induced by a surgical or other experimental procedure. Such devices as precision vaporizers and respirators
increase the safety and choices of inhalation agents for use in rodents and other small species.
Some classes of drugs-such as sedatives, anxiolytics, and neuromuscular blocking agents-are not analgesic or anesthetic and thus do not relieve pain; however, they might be used in combination with appropriate analgesics and anesthetics. Neuromuscular blocking agents (e.g., pancuronium) are sometimes used to paralyze skeletal muscles during surgery in which general anesthetics have been administered (Klein 1987). When these agents are used during surgery or in any other painful procedure, many signs of anesthetic depth are eliminated because of the paralysis. However, autonomic 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. If paralyzing agents are to be used, it is recommended that the appropriate amount of anesthetic be first defined on the basis of results of a similar procedure that used the anesthetic without a blocking agent (NRC 1992).
In addition to anesthetics, analgesics, and tranquilizers, nonpharmacologic control of pain is often effective (NRC 1992; Spinelli 1990).
Neuromuscular blocking drugs, as noted earlier, do not provide relief from pain. They are used to paralyze skeletal muscles while an animal is fully anesthetized. They might be used in properly ventilated conscious animals for specific types of nonpainful, well-controlled neurophysiologic studies. However, it is imperative that any such proposed use be carefully evaluated by the IACUC to ensure the well-being of the animal because 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 1992; Van Sluyters and Oberdorfer 1991).
Euthanasia is the act of 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 1993 Report of the AVMA Panel on Euthanasia (AVMA 1993 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; nonreversibility; time required to induce unconsciousness; species and age limitations; compatibility with research objectives; and safety of and emotional effect on personnel.
Euthanasia might be 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. Protocols should include criteria for initiating euthanasia, such as degree of a physical or behavioral deficit or tumor size, that will enable a prompt
decision to be made by the veterinarian and the investigator to ensure that the end point is humane and the objective of the protocol is achieved.
Euthanasia should be carried out in a manner that avoids animal distress. In some cases, vocalization and release of pheromones occur during induction of unconsciousness. For that reason, other animals should not be present when euthanasia is performed (AVMA 1993).
The selection of specific agents and methods for euthanasia will depend on the species involved and the objectives of the protocol. Generally, inhalant or noninhalant chemical agents (such as barbiturates, nonexplosive inhalant anesthetics, and CO2) are preferable to physical methods (such as cervical dislocation, decapitation, and use of a penetrating captive bolt). However, scientific considerations might preclude the use of chemical agents for some protocols. All methods of euthanasia should be reviewed and approved by the IACUC.
It is essential that euthanasia be performed by personnel who are skilled in methods for the species in question and that it be performed in a professional and compassionate manner. Death should be confirmed by personnel who can recognize cessation of vital signs in the species being euthanatized. Euthanatizing animals is psychologically difficult for some animal care, veterinary, and research personnel, particularly if they are involved in performing euthanasia repetitively or if they have become emotionally attached to the animals being euthanatized (Arluke 1990; NRC 1992; Rollin 1986; Wolfle 1985). When delegating euthanasia responsibilities, supervisors should be aware of this as a potential problem for some employees or students.
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