Careful experiments by Graham and Poulton,3 conducted in Friedrich Muller's clinic in Munich, have shown that in man a body temperature of 40.20, brought about by the influence of a steam bath, does not of itself cause an increase in the metabolism of body protein. Three different diets were taken. In experiments I and II the caloric value of the diet was high, with excess of carbohydrate and only a minimal quantity of protein. Diets III and IV were composed chiefly of protein and fat; one with ample calories and high in protein, the other with insufficient calories and only a moderate amount of protein. The results of the experiments may be thus epitomized:

3 Graham and Poulton: "Quarterly Journal of Medicine," 1912, vi, 82.

In these experiments the abnormally high body temperature was maintained for several hours, and yet there was never any increase in the breakdown of body protein due to the hyperthermia.

It has already been recited (see p. 317) how Kocher, working in the same clinic, found that a walk of 60 kilometers with a consequent doubling of the heat production was without effect upon the protein metabolism even when the output of urinary nitrogen was at a minimal level.

It is evident from these experiments that neither high body temperature nor largely increased heat production has any effect upon the minimal "wear and tear" quota of protein metabolism. The destruction of protein by toxic processes in fever is, therefore, independent of the two factors enumerated, as will be seen later.

If certain portions of the brain be punctured, and particularly the region of the corpora striata, a high fever sets in. Here again there is an increased output of carbon dioxid and a rise in protein metabolism. This phenomenon has been recently investigated by Hirsch, Muller, and Roily,1 and by Roily2 alone. They find that after the "heat puncture" of the corpora striata the liver, blood, and skin become warmer than the muscles, although normally the muscles are warmer than the skin. They find that the heat puncture is effective even in curarized animals, where the muscles are free from nerve stimuli. Roily finds, however, that the heat puncture is ineffective if the liver of the rabbit has been previously freed from glycogen by strychnin convulsions. Under these circumstances there is no rise in temperature nor concomitant rise in protein metabolism. The inference is that the fever in question is due to nerve impulses which increase the metabolism of carbohydrate in the liver. In infectious fever there is little glycogen in the organism, but that the fever in this case is due to other causes than the rapid combustion of carbohydrates was shown by Roily, who infected a rabbit, which had been freed from glycogen as above described, with a culture of pneumo-cocci and obtained as great a rise in temperature and protein metabolism as would have occurred had the tissues of the rabbit been rich in carbohydrates. The rise in temperature after puncture of the corpora striata may be termed neurogenic fever, and it is like the glycosuria following Claude Bernard's puncture, in that its mechanism is no more invoked in true infectious fever than are the nerve centers in diabetes mellitus (p. 446).

Freund3 finds that simple heat puncture in the rabbit is still effective after cutting the cord at the level of the second dorsal nerve. It is interesting that this phenomenon of heat puncture, with its increased carbohydrate combustion and an elevation of body temperature between 0.70 and 1.760 in rabbits and in dogs, is without influence upon the hydrogen ion concentration of the blood.1

1 Hirsch, Muller, and Roily: "Deutsches Archiv fur klin. Med.," 1903, lxxv, 264.

2 Rolly: Ibid., 1903, lxxviii, 250.

3 Freund, H.: "Archiv fur exp. Path, und Pharm.," 1913, lxxii, 304.

If the extent of metabolism in infectious fevers be investigated the following state of affairs is discovered. The course taken by the metabolism in toxic fevers is, as a rule, (1) a slight rise in protein metabolism, even before the fever sets in; (2) increased metabolism with heat retention and increased protein destruction; (3) heat production and heat elimination become equal, with the body at a higher temperature level. These factors were illustrated in the experiments of May2 on fasting rabbits injected with a culture of erysipelas of the pig and in the following experiments of Staehelin.

Staehelin3 infected a dog by inoculating him with 1.5 c.c. of dog's blood containing surra trypanosomes which are active flagellate parasites. Fever set in on the sixth day after the inoculation and the dog died on the twenty-fifth day. The metabolism due to the infection rose to 88.9 calories per kilogram on the tenth day after inoculation as against a normal of 59.8, an increase of 48 per cent. On this febrile day 26 per cent, of the total energy was yielded by protein; the body lost 2.8 grams of nitrogen, which indicated a high toxic waste. However, all the increase in the heat production did not come from increased protein metabolism, but the fat destruction was also increased, and Staehelin speaks of a toxic waste of fat. He also remarks that the dog remained perfectly quiet during the period of the experiment, but he does not say whether thermal influences which could result in chill were completely excluded. However, he came to the conclusion that in this fever caused by trypanosomes the metabolism was higher than could be explained by the overwarming of the body.

During the last days of life the body temperature fell and with it the amount of the metabolism. The following table gives a partial record of the daily metabolism in this dog:

1 Quagliariello: "Biochemische Zeitschrift," 1912, xliv, 162.

2May: "Zeitscheift fur Biologie," 1894, xxx, 1.

3 Staehelin: "Archiv fur Hygiene," 1904,1, 77.

Metabolism In Fever Induced By Surra Trypanosomes

Long before these experiments Wood1 had found an average increase of 23 per cent, (calculated by Welch) in the heat production of fasting dogs after inducing fever; and he also found that mere ingestion of food by a normal dog would cause a greater heat production than fever itself.

Traube,2 who was the first modern scientific clinician, attributed the cause of fever to a cramp-like constriction of the peripheral arterioles, which prevented the proper distribution of the blood at the surface and therefore hindered the normal cooling of the body. Since Traube's writings on the subject were published the cause of fever has been attributed not to greater heat production, but to a disturbance in the mechanism of the regulation of heat loss. On recalling the fact that the metabolism of a fasting dog may be raised from 100 calories in fasting to 189 calories after giving meat (see p. 234) without any change of body temperature, it becomes evident that the increased heat production in fever cannot alone be the cause of the high body temperature. In fact, as has already been set forth, the rise in the body temperature from failure of the physical regulation may of itself explain the increase in heat production.

1 Wood: "Fever," Smithsonian Contributions to Knowledge, Washington, 1880.

2 Traube: "Allgemeine medizinische Central-Zeitung," 1863, xxxii, 410,426, 810.