As a noxious factor, we used an intravenous injection of killed microbes or of a colloidal suspension of a metal. Within a few minutes, a group of changes occurred. They were revealed through a series of analyses made at very short intervals. (Note 1) The changes were found to affect most of the blood constituents. The most characteristic change in our opinion is a leucopenia which especially affects the granulocytes. With it, there is a lowering of serum antitryptic power; a decrease of serum albumin; appearance of degradated proteins, esterase and amylase; increase of free fatty acids; and a lowering of coagulability with reduced clot retraction. Clinically, these changes are accompanied by hypothermia and hypotension.

Together they represent what we will call the "negative phase" of the immediate response.

This group of changes represents, in fact, only the first part of a diphasic phenomenon. The negative phase is usually followed by a second and opposite one which we call the "positive phase" of this immediate response. It results from the tendency of the body to correct, and even over correct, the changes occurring in the first phase. After hypothermia and hypotension, hyperthermia and slight hypertension follow. At the same time, the number of granulocytes increases, as does the antitryptic power of serum and its albumin content. The serum appears richer in free sterols. Blood coagulability and clot retraction also increase. After moving rapidly to a peak, all these values return slowly to normal. The existence of two phases can be recognized in all the changes occurring in hemo shock. (Fig. 75)

Fig. 75. Diphasic response in the defense. The intravenous injections to a normal individual of a foreign material such as of a suspension of killed microbes or of a colloidal metal induces a typical response which corresponds to the hemoshock. A diphasic curve seen in most of the analyses characterizes the occurring variations. The curve presented corresponds to the total number of the blood leucocytes. A parallel diphasic curve is seen for other blood analyses such as clot retraction, albumin content of the serum, and antitryptic values of the serum. Similar diphasic curves, but opposite in sense, are seen for blood coagulation time, amount of amylase and esterase in the serum, amount of K + in the serum, and for the amounts of proteoses and peptones.

Diphasic response in the defense

In trying to correlate the multiple changes taking place, it is the lysis of leucocytes, especially granulocytes, which can be considered of primary importance in the development of hemo shock. This is evident from the relationship between granulocytopenia and the intensity of the diphasic phenomenon. The administration of morphine or other opium derivatives to an individual, prior to the application of the noxious factor, will reduce or suppress the granulocytopenia together with all the manifestations. (Note 2) Intensive physical exercise concomitant with the application of the noxious factor will increase the granulocytopenia parallel with all the manifestations of hemo shock. (Note 3)

According to our hypothesis, lysis leads to liberation of proteolytic enzymes which may be present as such or may be present in precursor form in the leucocytes. And it is the intervention of these enzymes which reduces the antitryptic power of the blood and, by digesting blood constituents, lowers the amount of albumin present in the serum, and induces a parallel increase of products of protein hydrolysis. The increase in amylase as well as in esterase present in blood is related to the other hydro lytic enzymes liberated in this phase, and is also probably correlated with leucolysis. The esterase acts hydrolytically upon the neutral fats present and this would explain, at least in part, the liberation of free fatty acids seen in this phase. In the changes corresponding to the first phase, digestive effect of these enzymes upon the blood constituents can be recognized as being one of the most important intervening factors.

We confirmed the correlation between these changes and leucolysis not only through their parallel variations, as mentioned above, but also through in vitro experiments. Lysis of leucocytes resulted in liberation of hydrolytic enzymes. An exudate rich in granulocytes was obtained by injecting sterile broth, or an aleuron suspension, into the pleura of rabbits. To this exudate, removed through pleural puncture, a small amount of a colloidal silver protein preparation (Collargol 0.1%) was added and the preparation maintained at 38°C. This was seen to induce the appearance of vacuoles in the leucocytes, following the phagocytosis of silver grains. The vacuoles were observed to grow rapidly to huge dimensions followed by bursting of the leucocytes. (Fig. 76)

Analysis of the pleural fluid treated in this manner has shown the same change as those seen in the first phase of hemo shock: lowering of antitryptic power with a decrease in albumin content, increase in products formed by partial digestion of proteins, appearance of amylase and esterase, and an increase of free fatty acids. There were also the same nuclear "shadows" as encountered in large amounts in the circulating blood at this phase. The increase of the potassium content of serum seen in this phase, and the increase found also in the supernatant part following centrifuga tion of the exudate to which Collargol had been added, represents a further confirmation of the role of leucolysis in this first phase. These data enabled us to consider that the mechanism through which the blood tries to combat the intervention of a noxious agent corresponds, in the first phase, primarily to a lysis of granulocytes followed by hydrolytic digestion.

Fig. 76. Drawing of the changes induced by a colloidal suspension of silver proteinase upon leucocytes. The leucocytes were obtained by injecting broth intrapleurally to rabbits. Silver proteinate was added to the suspension of leucocytes and the changes observed in a microscope heated chamber maintained at 38°C. The phagocytosis of the silver proteinate leads first to the appearance of this substance as intracellular granules, followed by the formation of vacuoles. As these grow to a huge size the cells burst. The nucleus remains as nuclear shadow.

Drawing of the changes induced by a colloidal suspension of silver proteinase upon leucocytes

The second phase, which would correspond to efforts to correct the exaggerated effects of the first digestive phase, involves largely a mobilization of reserves of those blood constituents which were altered during the first digestive phase. The spleen pours a part of its stored blood into the circulation. The richness of spleen in reticuloendothelial cells explains the liberation of sterols which is seen during this second phase. This is recognized by the fact that, at this time, the spleen efferent blood is richer in sterols than the afferent blood. Other constituents come from intercellular and lymphatic spaces. This mobilization, characterizing the second phase of hemo shock, appears to be achieved in large part mechanically, through a direct intervention of the vegetative nervous system inducing the contraction of the smooth muscular fibers, as seen during chill, which marks the beginning of this second phase. Fever which follows, is in part, due to the sterols liberated largely by the reticuloendothelial system.

If this hemo shock, in spite of its frequently violent clinical manifestations, resolves the effects of the noxious intervention upon the blood, it can be considered to be, to a certain degree, a physiological response. It amounts to an exaggeration of the oscillatory mechanism through which the characteristic constants of the blood are maintained. By employing the hydrolytic enzymes stored in the leucocytes, the blood tries to resolve the influence exercised by the noxious factor, digesting and thus breaking down either the factor itself or the results of its direct intervention. Acting upon blood constituents, the noxious agent often induces the appearance of micelles bigger than those normally circulating. The fatty acids liberated by hydrolytic enzymes would insure, in the first place, a higher boundary permeability, thus permitting the passage through the capillaries of substances otherwise barred. At the same time the fatty acids bind the antigen in a lipidic complex.

In the second phase, the organism tries to repair damages caused by the exaggerated digestive process or by the intervention of fatty acids. If the organism is able to resolve through a successful diphasic reaction the changes induced by the noxious agent, it returns to normal.