Review of Cold Injury Research Grant
Christopher D. Smith, M.D., F.A.C.E.P.
Dr. Matthew Wolf and colleagues are performing cold-injury experiments at the University of South Carolina School of Medicine. Based on an examination of the proposal for this research, "Effects of Cold and Cold Injury on Transcapillary fluid exchange in extremities," there appears to be serous scientific problems with their approach. In their proposal, the investigators comment that cold injury's effects on soldiers' feet are incompletely understood. The importance to the military, they maintain, is demonstrated by the "cold injury deaths" in the Falkland Islands, where "combat groups were 100% affected" by cold-related injuries. They also note the "almost 100% casualties in the Napoleonic war."
Added to the absurdity of citing the Napoleonic war as evidence of current necessity is the failure to define cold injury. The researchers speak of "this condition" as if it were a single entity. There are, however, several distinct clinical conditions that fall under the general heading of cold injury. These include hypothermia (a decrease in core temperature below 35 degrees centigrade), trench foot (severe superficial damage to an extremity resulting from exposure to moisture and cold for a period of days), pernio (superficial ulcerations resulting from prolonged exposure to dry cold) and frostbite (freezing cold injury). Each of these entities differs in its pathophysiology, treatment, prognosis, and prevention.(1)
Wolf et al.'s research involves perfusing severed cats' legs at low temperatures (6-8 degrees centigrade) with a solution of cooled saline and 2-4% red blood cells. The investigators use this unnatural blood cell concentration (too low to be compatible with life) because a more normal 30-40% blood cell concentration previously resulted in hemolysis, which adversely affected their data collection. This blood cell concentration, about one-tenth normal, is too low to permit normal metabolism. The physiological parameters they are studying, such as leg weight gain, will be adversely influenced by the leg tissues' decreased metabolic activity and the markedly diminished colloid osmotic pressure of the artificial perfusate. While this protocol yields "cleaner" data, its extreme artificiality leaves little likelihood that it could have clinical relevance.
The researchers also add isoproterenol, a drug that affects vascular permeability, to "establish normal permeability." The investigators thus adjust their artificial model so that it will better correspond to known permeability data. But permeability is what they are supposedly investigating. Their manipulations, therefore, make their data on tissue permeability uninterpretable.
This "model" does not correspond to any known human cold injury. The experiments do not simulate hypothermia because blood cooled to 6-8 degrees centigrade would be lethal; they do not model trench foot or pernio because the investigators are evaluating immediate effects, not the results of prolonged exposure; and they do not resemble frostbite because freezing temperatures are not being used. Therefore, the investigators' claim that this research will benefit military personnel "on the ground, in warships and in the extreme cold conditions faced by high altitude pilots and personnel in space" is unfounded.
The researchers state, "There is no alternative to the use of animals as this research is involved with studying the physiology of whole organs." Yet, in their own section entitled "Scientific Significance," they cite Lewis' experiments on his own hand and Brown's experiments on the human forearm. It is not necessary to sever an organ in order to study it.
While the protocol does not even closely resemble any known human condition, can one argue that it has "basic science" value? This, too, is highly unlikely, given the model's inability to yield interpretable data. Furthermore, the researchers have expressed a proprietary attitude not in keeping with a desire to disseminate scientific information. They claim that the need to regard the model as militarily sensitive requires that the ideas underlying it be treated as privileged information. They even go so far as to state, "It would be unethical to offer these ideas to the general scientific community for competitive bidding in order to obtain a research contract to do the work" (emphasis theirs). How is it unethical to share ideas on possible treatments for environmentally caused injury? The contradiction between claims of clinical relevance or basic scientific merit and this secretive approach indicates a desire to avoid the peer review process of other funding agencies.
Reference
1. Heller B: Frostbite, in Tintinalli JE, Krome RL, Ruiz E (eds): Emergency Medicine a Comprehensive Study Guide. New York, McGraw-Hill, 1988, pp 745-747.