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.

Multidimensional Risk

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.

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