Personal Experiences with Clinical Pain Management, Study Design, Mitigation of Scientific Confounders, and Long-term Gains to the Researchers and Public
Advanced Veterinary Applications
It is truly an honor to be invited here to the National Academy of Sciences and to have the opportunity to be associated with all of you. As a newcomer to this arena, you might say that I am well qualified and have come of age on the front line in mammoth research programs where I have collaborated with scientists to reduce distress in animal models within scientific constraints of the protocols.
EXPERIMENTAL EFFECTS ON ANIMALS
Animal models of human disease and physiology are becoming exceedingly complex. Experimentation is not neatly packaged. Pain and “altered states” of physiology leading to distress can be acute or chronic in duration and any combination. It is a mistake to state, as many have, that animals do not suffer during experimentation simply because they have not been observed to suffer. Lack of observation is particularly relevant because only small numbers of programs, if any, provide more than 8 hours of care over the workday. It is also a mistake to dwell on costs associated with increased provisions for monitoring and intervention programs because the relative savings are well known in terms of higher animal yields, smaller interanimal variability due to management of stressors, and shorter time from bench-to-bedside human trials. Thus, quality pain management programs result in more observations during experimentation and public assurances that are immeasurable.
Results of Cumulative Minor Events
It is my clinical opinion that most animals in research suffer from cumulative and minor events that, when combined, amount to distress. In other words, the animal is not feeling well enough to normally ambulate, eat, or drink. It then becomes a bit dehydrated, a downward trend develops, and more serious stressors result. Thus, early detection provides the greatest gain in terms of control of variables and pain and distress management. Current endpoints such as weight loss and low body temperature are instituted long after distress and stress or pain are encountered and are useless to refinements that are either pragmatic or beneficial. Viewed prospectively, however, a variable such as weight can be very useful for finding that particular instance when results become negative. Time is therefore essential in pain management if one hopes to reach beyond a paper program and create one of substance. The importance of time is more dramatic in smaller animals as metabolic rate is known to be roughly 10 times higher in mice than man. Other species fall somewhere between. The best way to describe this early detection of weight loss and other variables contributing to physiological stress is to describe the following example.
An excellent example of multidimensional risk is that of canine myocardial ischemia (Banai and others 1991, 1994; Lazarous and others 1996; Rajanayagam and others 2000; Shou and others 1997; Unger and others 1990, 1991, 1993a,b; 1994). The dog patient received a left lateral thoracotomy incision to create a left anterior descending coronary artery event. In this example, I shall discuss veterinary support surrounding a decade of research involving hundreds of canine patients on which human trials were eventually predicated. The instrumentation utilized to constrict arteries over a 3-week period of time is a silastic balloon ameroid placed over the artery and tunneled through the ribs into the subcutaneous space. The dog, pig, or rat (as are today's models) is then recovered overnight with oxygen, warmth, analgesics, and antibiotics; it also must receive constant monitoring for ventricular arrythmias, infection, electrolyte imbalance, and glucose disturbances. The model then undergoes the additional stress of serial MRI or angiographic episodes under general anesthesia. Then add the additional experiment whereby the investigator wishes to administer viral-mediated gene therapy using adenoviral vascular endothelial growth factor, and have a singular experiment within a multidimensional risk project. The risks to distress include infection, dehydration, electrolyte disturbances, arrythmias and angina, poor wound healing, and increased catabolic demand at a time when animals do not feel particularly well.
Within this one model, you may look at one possible risk such as infection or septicemia. Septic animals undergo an initial systemic inflammatory response.
The body is then riddled with the events associated with hyperdynamic shock, leaky blood vessels, pulmonary edema, and glucose and electrolyte disturbances. Such events must be detected within hours to provide symptomatic relief as well as to stabilize the experiment. Therefore, an 8-hour or singular monitoring scheme is worthless to the animal, the model, and, ultimately, extrapolation to public medicine and benefit.
PROVISION OF NECESSARY IMPROVEMENT
In 1989, when I first joined NIH, this model received only a few hours of intensive care and was put back in a kennel. The mortality rate was 55%. During my first 5 years there, I had supportive program directors who encouraged the augmentation or magnification of veterinary presence. I made steady improvements, which included acquisition of an overnight technical staff, clinical chemistry and complete blood count analyzers that gave results instantly at the cageside, and the provision of scoring systems that augmented analgesic administration. Survival rates increased to 95%. Deaths were always associated with sudden ischemia and closure of the ameroid rather than with other complications.
I was very proud of this progress and other changes, and the scientists noted a more expensive short-term solution with long-term benefit. Over the next 5 years, I continued to make similar improvements across all species and all projects. Although the scientists initially viewed this as expensive, they eventually understood the benefit.
Scheme of Veterinary Care
In my view, the way to achieve this outcome is to suggest a scheme more like a good veterinary teaching hospital or private clinic for animals in these risk groups. We thus need small teams to cover large amounts of ground and high rodent density housing for less risky groups in an effort to discover outliers. Such management is accomplished by the hiring of clinically astute veterinarians and roaming technical teams.
The emergence of large numbers of genetically altered rodents can also be monitored in this manner by central dispersion of teams of technologists under the line command of clinical veterinarians. Successful monitoring has already been achieved in some places and was recently described in Lab Animal (Hampshire and others 2000a,b).
Shifting Responsibility for Performance Standards
Additionally, it is not reasonable to expect today's scientist to be clinically knowledgeable or experienced about veterinary medicine; therefore the development and line accountability of such teams of clinical veterinarians and technologists
are absolute requirements for accomplishing this task. In the context of research budgets, this approach is easily achieved by a shift from engineering standards toward greater emphasis on veterinary performance standards. However responsible, the scientists can be unrealistically expected to understand or have time to fully manage such key animal populations. There must be responsibility, collaboration, and authority of clinical veterinary staff.
ESTABLISHMENT OF PREREVIEW
Finally, part of ILAR's directive today was to provide guidance to USDA's inclusion of alternative searches in Policy 11. I have not heard anyone call this a similarities search, but having performed such searches, I believe the existing directive does not enhance science or animal care. The current policy and enactment drive away scientists rather than enlisting their cooperation because it is described and viewed as a barrier rather than an opportunity. A better solution is to require a prereview in which the attending veterinary staff search human and animal-similar literature for the purposes of seeking answers to confounding variables, stress and pain outcomes, and case management of human or animal-similar patients.
Alternatives, in my opinion, are most beneficial when viewed as refinements to animal care and study design. If such a search were undertaken prospectively for these purposes, compliance with responsible use of animals would often develop naturally.
SCIENTIFIC JOURNALS AS FACILITATORS
I must mention literature because methods that describe adequate animal care and monitoring are frequently not part of scientific journal reporting. Many investigators argue that their science does not need refinement because the methods they are utilizing have been reproduced time and again according to proven methods. Many will also try to pool controls from previous work in which no pain and distress management schemes were utilized. I contend, however, that many methods are missing from such papers. A preponderance of papers reviewed, do not mention analgesic programs and leave the reader to wonder if compliance really existed at all.
One must understand that the recalcitrant scientist will continue to ignore Policy 11 directives but will still cater to the scientific journals under today's “publish or perish” conduct. If the majority of exemplary publications were also to include a section specifically describing pain and distress monitoring, duration, and intervention criteria, the mainstay of scientists would also conform to that standard. A commensurate education in Policy 11 guidelines and journal management would be very useful for achieving this goal.
I have attempted to describe a pain classification system that is substantive when viewed retrospectively. It assumes strong veterinary action in prereview, the design of a pilot, and retrospective adjustment of protocols not only so that accurate reporting is performed, but also so that the public can be made more aware of which relief measures were meaningful. This system of veterinary collaboration, pilot design, and retrospective refinements and reporting affords more efficient experimental conduct with more accurate reporting of results and animal pain classification.
Banai S., M.T. Jaklitsch, W. Casscells, M. Shou, S. Shrivastav, R. Correa, S.E. Epstein, and E.F.Unger. 1991. Effects of acidic fibroblast growth factor on normal and ischemic myocardium. Circ Res 69: 76-85.
Banai S., M.T. Jaklitsch, M. Shou, D.F. Lazarous, M. Scheinowitz, S. Biro, S.E. Epstein, and E.F.Unger. 1994. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 89: 2183-2189.
Hampshire V.A., C. McNickle, and J.A. Davis. 2000a. Red-carpet rodent care: Making the most of dollars and sense in the animal facility. Lab Anim 29: 40-45.
Hampshire V.A., C. McNickle, and J.A. Davis. 2000b. Technical team approaches to rodent care: Cost savings, reduced risk, and improved stewardship. Lab Anim 29: 35-39.
Rajanayagam M.A., M. Shou, V. Thirumurti, D.F. Lazarous, A.A. Quyyumi, L. Goncalves, J. Stiber, S.E. Epstein, and E.F. Unger. 2000. Intracoronary basic fibroblast growth factor enhances myocardial collateral perfusion in dogs. J Am Coll Cardiol 35: 519-526.
Shou M., V. Thirumurti, S. Rajanayagam, D.F. Lazarous, E. Hodge, J.A. Stiber, M. Pettiford, E.Elliott, S.M. Shah, and E.F. Unger. 1997. Effect of basic fibroblast growth factor on myocardial angiogenesis in dogs with mature collateral vessels. J Am Coll Cardiol 29: 1102-1106.
Unger E.F., S. Banai, M. Shou, M.T. Jaklitsch, E. Hodge, R. Correa, M. Jaye, and S.E. Epstein. 1993a. A model to assess interventions to improve collateral blood flow: Continuous administration of agents into the left coronary artery in dogs. Cardiovasc Res 27: 785-791.
Unger E.F., S. Banai, M. Shou, D.F. Lazarous, M.T. Jaklitsch, M. Scheinowitz, R. Correa, C.Klingbeil, and S.E. Epstein. 1994. Basic fibroblast growth factor enhances myocardial collateral flow in a canine model. Am J Physiol 299(Pt 2): H1588-H1595.
Unger E.F., C.D. Sheffield, and S.E. Epstein. 1990. Creation of anastomoses between an extracardiac artery and the coronary circulation. Proof that myocardial angiogenesis occurs and can provide nutritional blood flow to the myocardium. Circulation 82: 1449-1466.
Unger E.F., C.D. Sheffield, and S.E. Epstein. 1991. Heparin promotes the formation of extracardiac to coronary anastomoses in a canine model. Am J Physiol 260(Pt 2): H1625-H1634.
Unger E.F., M. Shou, C.D. Sheffield, E. Hodge, M. Jaye, and S.E. Epstein. 1996. Extracardiac to coronary anastomoses support regional left ventricular function in dogs. Am J Physiol 264(Pt 2): H1567-1574.