4 PHYSIOLOGY OF INDUCED HYPOTHERMIA 



reversible thermal denaturation is absent, is typical of many cellular processes and 

 enzymic reactions. In these the logarithm of the rate increases linearly with the 

 reciprocal of the absolute temperature until irreversible thermal denaturation ensues 

 more or less abruptly at a temperature near or above the upper physiological limit. 

 Since the reversible thermal denaturation is absent, inhibitors (Type I) act primarily 

 by combining with the prosthetic group, competing with the substrate at this site. 

 As a result, their potency tends to increase progressively with a lowering of the 

 temperature. 



Serum cholinesterase exemplifies the above type of process. In the absence of an 

 inhibitor the rate of the cholinesterase of dog or human blood serum varies with 

 temperature in accordance with the Arrhenius relation, beginning to show some 

 irreversible denaturation above 30° C. (Bach, ct ah, 1951; Robert, ct al, 1951). 

 When an inhibitor such as quinine is present, the inhibition at low temperatures is 

 much greater and the temperature coefilicient is increased accordingly. It is significant, 

 however, that if a series of quinine derivatives is compared the degree of tempera- 

 ture sensitivity varies widely, the inhibition of certain members being independent 

 of temperature over the physiological range (Lawler, Brown, unpublished). An 

 anticholinesterase with the latter characteristics would be particularly useful in the 

 regulation of induced hypothermia. 



The foregoing physicochemical considerations are sufficient to illustrate the types 

 of reactions underlying cellular processes and to show the manner in which they are 

 influenced by temperature and chemical agents. In induced hypothermia, under con- 

 ditions of a natural circulation, the chemicals subject to experimental control are 

 drugs and such substances as might be used in an attempt to sustain the electrolyte 

 balance. In relation to their use, the above discussion may serve to emphasize the 

 fact that one group of substances (Type I) combines with the prosthetic group of 

 the enzyme and is usually potentiated by a lowering in temperature, but it is possi- 

 ble to have inhibitors that act independently of temperature. The additional fact is 

 that enzymes which exhibit a reversible thermal denaturation are also inhibited by 

 substances such as ether and narcotics (Type II), the inhibition tending to decrease 

 with a lowering of the temperature. This could be a disturbing factor in hypothermia 

 but could be eliminated if anesthetics acting independently of temperature could be 

 employed. 



In turning to a consideration of cellular processes, such as excitability, rhyth- 

 micity, contractility and secretion which may be the target of metabolites and other 

 agents in hypothermia, it may be stated that they reflect the behavior of enzymatic 

 systems in their temperature dependence. This is shown in the case of the cardiac 

 rhythm which Landau and Marsland (1952) have found to be controlled by a proc- 

 ess showing a temperature and pressure dependence resembling in its main char- 

 acteristics the luminescence reaction. The contractility of auricular strips of the 

 turtle also shows a dependence on events which increase with temperature to an 

 optimum and then decrease, the latter decrease, as in the case of luminescence, 

 being reversed by high pressure. 



The major problem with which we are faced in dealing with such complex cellu- 

 lar processes is insufficient knowledge on which to decide whether the potentiation 

 of some processes results from tlic inhil)iti()n of a recovery process or an increased 



