THE NATURE OF FATIGUE i8 7 



partly with the absence of the essential carbohydrate or other food 

 stuff, and partly with the presence of /?-oxybutyric acid. It is probable 

 that future research will add still others to the class of fatigue sub- 

 stances, especially to those which are accompaniments of disease. 

 Fatigue is one of the most common features of disease, and espe- 

 cially of diseases that are characterized by an upset of the chemical 

 balance of the body. In such cases a considerable increase in the 

 quantity of some intermediate metabolic product may conceivably lead 

 to fatigue phenomena. 



A few years ago, in studying experimentally the action of fatigue 

 substances on muscle, I came upon an unexpected result. Fatigue 

 substances in small quantity have a physiological action which is 

 exactly the reverse of that of the same substances in larger quantity — 

 instead of depressing or fatiguing protoplasm, they act so as to augment 

 its activity. In other words, they increase its irritability, so that a 

 given stimulus is capable of eliciting a greater response than it could 

 elicit without the aid of the fatigue substances. Graphic records of 

 the contractions of muscles under the influence of very small quantities 

 of carbon dioxide, lactic acid or* other fatigue substances, show how 

 potent this augmenting action may be (Fig. 5). I believe that in this 

 action we have the long-sought explanation of the treppe. In the early 

 stages of muscular work the fatigue substances are present in small 

 quantity, in later stages in large quantity. Correspondingly in the 

 early stages there is augmentation or treppe; in the later stages there is 

 depression or fatigue. 



Thus far I have confined myself largely to a consideration of fatigue 

 as exhibited by muscles, where the phenomena are best known and can 

 be studied most accurately. There is every reason to believe, however, 

 that the main principles of muscular fatigue are demonstrable in the 

 other tissues and organs of the body — that in them also fatigue is 

 characterized, physically, by a diminution in working power and, chem- 

 ically, by both the destruction of energy-yielding substances and the 

 appearance of toxic metabolic products. Diminution of working power 

 is manifested in very different ways by diverse tissues. Glands in 

 fatigue seem to secrete less than when fresh, and it may be that the 

 action of digestive juices is diminished. The kidneys may be deranged, 

 so that their epithelium is unable wholly to prevent the passage of 

 albumin from the blood to the urine. A fatigued heart is dilated, its 

 beats are quickened and may become irregular, and its diastole, or 

 resting period, may become abbreviated. Fatigue often results in an 

 abnormally high bodily temperature, constituting a fatigue fever. The 

 •chemical phenomena of fatigue in the various organs and tissues, apart 

 from the muscles, is almost wholly unstudied, and there is great need 

 of a careful analysis of the entire subject. 



The fatigue of the nervous system is of great general interest, yet 



