Fever (a complex of phenomena in the organism,)

FEVER, a complex of phenomena in the organism, characterized mainly by disturbance of thermoregulation and increased body temperature. From this definition it is evident that the increase in temperature during fever is, strictly speaking, only the main, most demonstrative symptom of the pathological process in question, but by no means exhausts all its content. Indeed, besides disturbance of thermoregulation with the characteristic of increased body temperature, fever is also accompanied by more or less profound disturbances in metabolism, in the cardiovascular and respiratory systems, in secretory and excretory functions, etc. A short-term increase in body temperature, not accompanied by the deviations listed, is not fever in the true sense of the word, but is called simple hyperthermia. Etiology. In the overwhelming majority of cases, fever is of infectious origin. It is necessary, however, to keep in mind the following. First of all, the presence of microbes in the organism is insufficient for the development of fever; it is necessary that either the bacteria themselves or the products they produce pass into the blood and circulate in it. On the other hand, there is no definite correlation between the ability of microbes to cause fever and their pathogenicity; in general, however, most pathogenic bacteria also turn out to have pyrogenic properties; but non-pathogenic microorganisms for a given animal can also cause fever in it when killed. Besides infectious fever, aseptic fevers are also observed, caused by products of both normal and, to an even greater extent, abnormal metabolism, without the aid of microorganisms. Such are, for example, so-called traumatic fevers (after subcutaneous fractures), postoperative fevers, from the absorption of various kinds of exudates, detritus, etc. Do nervous fevers exist besides these? Since there are certain areas in the brain (tuber cinereum, as well as the so-called Aronsonov centers: corpus striatum, nucleus caudatus, thalamus opticus), artificial irritation of which under experimental conditions produces hyperthermia (so-called thermal puncture, and hyperthermia occurs under such conditions after several hours, sometimes lasts for whole days and reaches high degrees), then a priori one must admit the possibility of similar disturbances of heat exchange on the basis of nervous perturbations and moreover of both central and reflex origin. It is necessary, however, to take into account the following: first, nervous increases in temperature of central origin, as observed in hysteria, deserve rather the name of hyperthermia than true fever, although the increase in temperature in such cases can sometimes be quite considerable; second, some cases classified as reflex fevers may in reality be of a more complex, mixed nature. Such are gallstone and urethral fever. (In biliary colic there is always an obstacle to the outflow of bile and almost always also inflammation of the walls of the bile ducts, i.e., conditions exist for the absorption of pathological products, and during difficult catheterization damage to the urethra is possible with subsequent absorption of pathologically altered urine.) Fever can occur with significant muscle tension, for example during convulsions, strong crying in small children, etc. However, as for convulsions, the excessive formation of heat under such conditions may not be accompanied by an increase in temperature as long as thermoregulation functions satisfactorily, and only with the onset of widespread paralysis of nerve centers does the latter become possible. Energy exchange in fever. Mechanism of increase in febrile temperature. The maintenance of temperature at a certain height in all cases, as is known, is determined by the relationship between heat production and heat loss. Both the absolute and relative values of each change compared to the norm in different stages of the febrile process. The following types of febrile curves are distinguished: a) febris continua; having risen to a certain height, the body temperature remains at it throughout the disease without particularly sharp fluctuations, and both its rise and fall can be either sharp or gradual; example: typhoid fever, lobar pneumonia; b) febris remittens; fluctuations in temperature more than 1°; example: some cases of sepsis; c) febris intermittens; alternation of individual short-term attacks of temperature increase and periods of apyrexia; example: malaria; d) febris recurrens; longer intervals between attacks and greater duration of the attacks themselves than in f. intermittens; example: relapsing fever; e) Fever with an irregular temperature curve; so-called febris hectic is a variety of f. intermittens; observed in prolonged tuberculosis and is characterized by alternation of high temperature rises with large remissions of 3-4° with exhausting sweating, apparently on the basis of absorption of tubercular products.-Whatever the type of febrile curve, three stages can be distinguished in it: stadium incrementi-period of temperature rise, stadium fastigii-period of its maximum maintenance, and stadium decrementi-period of temperature decline. Heat production in most cases begins to increase already at the earliest stages of the febrile process, and its increase is particularly sharply expressed when chills are present (muscle contraction); heat loss, however, decreases depending on the spasm of peripheral vessels (pale, 'gooseflesh' skin). In individual cases, however, variations in the ratio of these values are observed: thus, heat loss may be decreased only slightly, and the rise in temperature occurs mainly due to a sharp increase in heat production; but the reverse also happens: heat production is almost not increased or is increased very slightly, and the rise in temperature is caused by a sharp decrease in heat loss. In this case, the spasm of skin vessels is apparently caused by the action of toxic substances on the vasomotor center; the increase in heat production, proven calorimetrically, is caused by irritation of brain areas related to metabolism, and chills-by constriction of peripheral vessels, since we judge the temperature of the surrounding environment by the condition of these very vessels (compare, for example, the decrease in the sense of chill in a state of intoxication depending on the dilation of skin vessels). The contrast between the skin temperature and the internal body temperature should further contribute to the sensation of chills. The latter in turn leads to an increase in the said contrast by increasing heat production (trembling), creating a kind of vicious circle. In the stage of fastigii, both heat production and heat loss are increased compared to the norm (red, 'glowing with heat' skin), but the former is disproportionately greater than the latter, which results in the high maintenance of temperature despite the increase in heat loss. Finally, in the stage of decrementi, there is a decrease in heat production and an increase in heat loss, particularly sharp in critical temperature drop due to increased sweating. The crisis itself finds explanation in some cases from the point of view of immunizing reactions (as for example in relapsing fever), in others, as for example in malaria,-in the biology of the parasite (see Crisis). Metabolism in fever. Nitrogen exchange in fever is sharply increased (50-100-200% and more) compared to the norm in quantitative terms (protein decay is present) and changes in qualitative terms, namely-in the urine of fever patients there is relatively much so-called under-oxidized products, mainly NH₃; as for uric acid, although its quantity increases due to urea, the latter should be interpreted as enhanced decay of nucleins, and not as an expression of under-oxidation of proteins in general, given the origin of uric acid specifically from nucleoproteins. This decay is mainly of toxic origin and to a lesser extent depends on hyperthermia, as shown by comparative observations on feverish animals, on the one hand infected, on the other-only artificially overheated. To an even lesser extent does nitrogen decay depend on undernutrition (consumption of one's own proteins).-Carbohydrate and fat metabolism is also increased, the former due to enhanced conversion of glycogen into sugar with subsequent burning of the latter to end products-CO₂ and H₂O (however, hyperglycemia is often present in the blood), and the increase in fat metabolism makes the emaciation of fever patients understandable. Gas exchange also increases in fever, i.e., the absolute amounts of both absorbed O₂ and excreted CO₂. The latter, however, is not directly related to the height of the fever, and in particular in exhausted patients gas exchange may not be increased. The reason for the phenomenon apparently lies in the increased tone of the muscles, judging by experiments of Zuntz on curarized animals, in which under such conditions no increase in gas exchange was observed despite a fairly significant rise in temperature.. Respiration

the coefficient (-Q^) more often increases depending on not so significant an increase in the amount of absorbed O₂ compared to the excreted CO₂.-Water exchange undergoes various changes at different stages of the febrile process; in the first and second stages, the amount of water in the body is definitely increased depending both on decreased excretion (retention of perspiration, later decrease in kidney function) and on increased formation (increase in oxidative processes, breakdown of more complex molecules into simple ones), while in the third stage a reversal occurs in the opposite direction in terms of cessation of increased water formation and increased excretion, mainly through perspiration and lungs. The just-mentioned fluctuations in water exchange in febrile patients explain the following paradoxical phenomenon: at the height of the disease, body weight is not reduced at all despite poor nutrition and tissue breakdown, while during the recovery period a sharp decrease suddenly occurs. Water retention in the body during F. should be considered as a beneficial phenomenon for the organism, preventing an increase in molecular concentration of tissues, and consequently, disruption of osmotic processes.-Mineral exchange changes in the direction of retention of chlorides in the body, while excretion of potassium, on the contrary, is increased due to destruction of erythrocytes and muscle tissue. Excretion of phosphates as well as salts of H₂SO₄ is also increased. In qualitative terms, it should be noted that albumoses and acetone often appear in the urine as an expression of deviations in protein and fat metabolism (partly, however, also due to starvation). In addition, there is acidosis, compensated by the alkaline reserves of the blood. Symptomatology of F. During F., the functions of various organs and systems are disrupted, especially those of the cardiovascular system, respiration, digestion, kidney function, and the central nervous system. The work of the heart initially increases mainly due to increased contractions depending on irritation of the cardiac nodes by heated blood, as well as on decreased tone of the n. vagi, since in the rabbit, where the tone of the n. vagi does not have such important significance as in other animals, the increase in pulse rate during F. is less pronounced. Later, the work of the heart decreases on the basis of intoxication. As for blood pressure, various changes are observed in individual cases, but most often the situation is as follows: initially, pressure is somewhat elevated due to irritation of the vasomotor center and spasm of peripheral vessels; later it decreases on the basis of both vasodilation and weakening of heart activity. In the ratio of the just-mentioned moments, cases of collapse find their explanation, sometimes observed precisely at the stage of temperature decline (loss of the stimulus-elevated t°-for heart activity). Respiration during F. is increased and elevated in volume due to irritation of the respiratory center by both heated blood and CO₂ in connection with increased oxidative processes. By strengthening respiratory function, the body is to some extent relieved of excess heat, which is especially important in view of difficulties from the skin's perspiration in the initial stage of the process.-From the digestive tract, there is decreased secretion of digestive juices and hypotonia of the intestine; hence-loss of appetite, decreased assimilation, and tendency to constipation. This justifies the empirically established rule: not to overload febrile patients with hard-to-digest food, nor to force-feed them without special indications.-Urination in the first period of F. is usually somewhat increased due to the outflow of blood from the periphery of the body to deeper-lying organs, including the kidneys, but later decreased due to decreased blood pressure, and partly due to damage to the kidneys themselves. The urine becomes more concentrated (water retention in the body); it contains many nitrogenous constituents, especially uric acid salts (Sedimentum lateritium), but also urea, ammonia, and creatinine. The content of urobilin and potassium salts is also increased, while the amount of chlorides decreases (cf. the above). Protein often appears in it due to increased permeability of the renal filter. The central nervous system is affected almost always, but to very varying degrees, ranging from fairly common sensations of heaviness in the head, headache, pains throughout the body, to such phenomena as clouding of consciousness with delirium and hallucinations. The latter is caused by both intoxication and hyperthermia, since the intensity of mental phenomena usually (though not always) goes hand in hand with t°. The symptoms of febrile delirium are quite diverse depending on the underlying disease, height of t°, and individuality of the subject: in some cases, the patient delirs only at night, i.e., while in a semi-conscious state, vaguely perceives the surroundings, talks to himself, mixes real facts with products of his imagination; in other cases, consciousness is affected more deeply: perception of external impressions is distorted by a mass of hallucinations and illusions, which, invading the patient's consciousness, cause marked confusion; in the third category of cases, the patient does not recognize people at all, which is sometimes combined with motor agitation; finally, in even more severe cases, the degree of agitation decreases, but consciousness becomes even more clouded, reaching a state of stupor, coma. Pathological-anatomical changes in F. consist mainly partly to cloudy swelling, partly to dystrophic fatty degeneration of a number of parenchymatous organs. The greatest importance here are changes in the heart as the factor underlying the weakening of its activity'. These changes are again caused by both hyperthermia and intoxication. The latter, however, plays a dominant role.-Nature of pyrogenic substances. Since the main etiological factor of F. are infections, the question of the nature of pyrogenic substances is mainly reduced to determining the nature of bacterial toxins, substances which are thought to be enzymatic in na-

262 tours. However, in view of the fact that bodies of non-pathogenic bacteria also possess pyrogenic properties, and that substances such as sterilized milk also produce the same effect when administered parenterally, it is necessary to attribute pyrogenic properties to substances of a protein nature. Friedberger, in this connection, speaks of a special 'anaphylatoxin'—a poisonous atomocomplex, which is cleaved off from the protein molecule under the action of precipitin and complement on it. In infections, in Friedberger's opinion, the conditions necessary for the formation of such an atomocomplex are always present: namely, the parenteral introduction of bacterioproteins into the organism, the production of antibodies against them, and the presence of complement. The fact that in classical anaphylactic shock there is not hyper-, but, on the contrary, hypothermia, Friedberger explains from a quantitative point of view, namely—the rapid and massive formation of anaphylatoxin in shock and the slow gradual production of it in infections. Be that as it may, the essential point is that in certain cases, a febrile reaction can be caused by other kinds of substances besides proteins and enzymes: thus, in Finkelstein's clinic, a fact of similar action was even established with NaCl * in small children when the latter was administered per os in a known quantity. This fact must probably be interpreted in the sense of the absorption of a part of the introduced NaCl in an unsplit form and the irritation of the thermoregulatory areas of the brain. From this it follows that various substances, capable of acting on the mentioned areas in an irritating manner when entering the blood, can produce a febrile reaction or at least hyperthermia. Theories of F. Attempts to attribute the entire pathogenesis of F. exclusively to a decrease in heat loss (Traube) or (which in essence is very close to the same thing) to a disturbance of perspiration (Leyden) must be recognized as too one-sided, and therefore far from corresponding to reality. Undoubtedly, the disturbance of heat loss in the first stage of the febrile process plays an extremely important role in the origin of febrile hyperthermia, but in the fastigium stage heat loss is not decreased but increased, and yet the body temperature stands at its maximum height. Moreover, in relation to Leyden's point of view, in addition to what has just been said, it should be borne in mind that pilocarpine by no means exerts any significant influence on the course of the febrile process, and on the other hand, in animals with a rudimentary sweat apparatus (dogs), the course of the process differs in no way from its course in other animals.—According to Liebermeister, the febrile organism behaves in relation to the surrounding environment essentially in the same way as a healthy one, and the whole matter lies only in the setting of the temperature by the central nervous regulators at a higher point. This view, besides its insufficient clarity, is also not quite correct in a certain respect. It is true that both to artificial cooling and to artificial overheating, the febrile organism responds essentially with the same reactions from the side of metabolism as a healthy one; however, it is hardly correct to speak of the setting of temperature in F. in the exact meaning of the word in view of its lability: it is known how easily the temperature can be lowered in a febrile person, for example, by cool baths, and how difficult this is to do in a healthy person. Moreover, with such a point of view, the very fact of switching the temperature to a higher level remains unexplained.—A similar point of view, but in a more detailed form, has been developed in recent years by Dresel. According to his opinion, one should admit the existence, firstly, of a special center determining the level of body temperature, further—a center regulating the temperature at this level, and finally—a center subordinate to this regulatory center, receiving impulses from the latter and directly increasing or decreasing heat loss or heat production. However, the doctrine of a single thermoregulatory center, finding favor with some, met with objections from some other authors (Bogolyubets). The 'thermal puncture', as is known, turns out to be a puncture not only in the striated body but also in various other parts of the brain stem, so it is more correct to speak not of a center but of areas, whole territories of the brain, having to do with thermoregulation. Under such conditions, it is allegedly more natural to assume damage not to a hypothetical center but to the conducting pathways of vegetative reflexes connecting the brain with peripheral organs. Moreover, heat exchange is not a special kind of exchange, but only a cumulative expression of the work of a number of systems of the body.—Among other things, the endocrine theory of F. has also been put forward. Indications of the role of endocrine organs in heat exchange can be: the decrease in temperature after thyroidectomy and in myxedema, and conversely, its increase in animals in a state of winter hibernation under the influence of thyroxin injection; adrenalin hyperthermia; hypothermia in hypophysectomized animals; the connection between the pituitary gland and the heat center in regard to their influence on fat exchange (Raab). However, despite the undoubted participation of the internal secretion glands in metabolism and their connection with the autonomic nervous system, as well as the possibility of fluctuations in body temperature to a certain extent depending on the endocrine status, it is hardly possible to speak of the direct regulation by endocrine glands of the relationship between heat loss and heat production. Simple hyperthermia besides the 'thermal puncture' can most easily be experimentally caused by placing an animal in a thermostat with a temperature equal to its body temperature. The phenomena developing in this can be divided into 3 periods: 1) when the animal still copes with the impossibility of conducting heat into the surrounding environment, giving off heat by evaporation and limiting heat production; 2) when the said adaptations prove insufficient and the body temperature begins to rise with acceleration of the pulse, increased respiration and general excitement of the animal; 3) the comatose period, characterized by exhaustion of the nerve centers: first the respiratory, and then the vasomotor. At this time there is an increase in gas exchange, intensification of nitrogenous disintegration, depletion of the body of water, and patho-anatomically—phenomena of degeneration in parenchymatous organs. The toxicity of extracts of organs of animals that died under such conditions speaks for the significant importance of auto-intoxication by products of disturbed intermediate metabolism in such cases. The same is indicated by cases of so-called sunstroke and heatstroke (the direct action of scorching rays of the sun or high external temperature in a confined space), and in most cases the body temperature has not yet reached extreme values.—Under opposite conditions of body cooling leading to hypothermia, one can distinguish 2 periods: 1) when the organism is still able to cope with the decrease in its temperature by means of a number of adaptations [narrowing of skin vessels, decrease in body surface (the animal curls up into a ball), increase in muscle tone (tremor), intensification of oxidative processes] and 2) the period characterized by exhaustion of the said regulatory mechanisms, and the decrease in body temperature in this stage goes hand in hand with a decrease in heat production, slowing of the pulse and respiration, fall in blood pressure and decrease in the respiratory coefficient. Death occurs from paralysis of the heart. On autopsy—degenerative phenomena in parenchymatous organs; on the gastric mucosa—numerous petechial hemorrhages. In humans, hypothermia besides cases of freezing is observed in collapse after a crisis in febrile diseases, after profuse blood loss, in traumatic injuries of the spinal cord, in auto-intoxications of diabetic (coma) or uremic origin, etc. A temperature of 24° in rectum is considered fatal for humans, while some animals can withstand much lower temperatures (hibernating). (See also Anabiosis.) Evaluation of the significance of F. from the point of view of the organism's well-being. F. represents a general reaction of the organism to the invasion into its bloodstream of various substances with so-called pyrogenic, or febrile, properties, and just like inflammation, in a certain sense and under certain conditions it can be beneficial to the organism, but it can also be definitely harmful (compare the effect of high temperature and intoxication on the heart). Hippocrates interpreted F. from the point of view of the doctrine of the 'vis medicatrix naturae', and after a period of indiscriminate enthusiasm for antipyretic views, this one is now also quite widespread. It is true first of all that the intensity of the febrile reaction in many cases serves as an indicator of the strength of the counteraction to the pathogenic factor, and sluggish asthenic forms of F. (sometimes, however, another sense is invested in the just mentioned term, namely—one speaks of an asthenic form of F. not in relation to the temperature reaction, but in the sense of general adynamia) often give a poor prognosis (cases of so-called 'cold diphtheria', cases of febrile pneumonia in uremics, in diabetics, etc.). However, this is by no means always the case, and sometimes the insignificance of the reaction is due not to a lack of counteraction but to the small strength of the infection itself (compare mild cases of typhoid fever).

The assumption has been made that the production of antibodies is stimulated by high temperature and that the phagocytic reaction is enhanced, and that high temperatures are harmful to bacteria; however, the production of antibodies by no means requires hyperthermia and is usually not accompanied by it, phagocytosis can be stimulated only by slight increases in temperature, while high temperature rather inhibits it; finally, only very large hyperthermias (40° and above) can be harmful to bacteria. It is more correct to think that the matter comes down to more energetic breakdown of toxins at high temperature. In any case, the usefulness of fever is very relative: this is already evident in the fact that in many cases a high degree of fever or its duration is fatal to the organism, and in these cases fever can be classified as clearly non-adaptive trait. Therefore, if there is reason to consider fever (like thermoregulation in general) an adaptive trait that developed in the process of evolution, then in any case the idealistic conception of fever as a manifestation of 'vis medicatrix naturae' must be decisively rejected.

G. Sakharov. LICHTGRUN, a light, green, acidic triphenylmethane dye. In microtechnique, L. SF (syn. Sauregrün, Guineagrün) is used, having the structure C₂H_3ч

^0H/\

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c₆н₄ S0₃Na

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S0₃Na I S0₃H (the French designation Vert Lumiere corresponds not to L., but to Methylgrün). Brown powder; easily soluble in water with a green color, less soluble in alcohol. The aqueous solution is decolorized by alkali and takes on a yellow-brown color from hydrochloric acid. In histological technique, it is used as an excellent plasma dye and serves for additional staining after staining with carmine, thionin, safranin. Good results are obtained by staining with an aqueous solution of specimens previously stained with hematoxylin and eosin. Results: protoplasm and muscles-pink, connective tissue and mucus-green. Very good staining is obtained when combining L. and Neutralrot (see).