Peptone Shock Research Articles

Fibrinolysis in Peptone and Anaphylactic Shock in the Dog

FIBRINOLYSIS in peptone and anaphylactic shock can be demonstrated either directly, by estimation of flbrinogen in samples taken after the injection of the respective agent, or by adding protamine in order to counteract the effect of the heparin which is discharged into the blood stream. We have shown1 that even the addition of an excess of a powerful preparation of human thrombin is unable to correct the decrease in fibrinogen, which can be estimated by the method of Cullen and Van Slyke2. Since thrombin was able to correct the inhibitory effect of heparin added in amounts such as those appearing in anaphylactic shock, we conclude that a drop in fibrinogen actually occurs during anaphylactic and peptone shock. Moreover, in the case of peptone shock, fibrinolysis can be directly observed, since in several cases the blood clots very quickly and the coagulum redissolves after a few hours. Apparently, Nolf3 was the first to describe this flbrinolytic effect as occurring after peptone injection, in animals in which the liver had been removed or the circulation reduced to the upper part of the body, by ligaturing the thoracic aorta and inferior vena cava, just above the diaphragm. It is now clear that in Nolf's experiments, the removal of the liver prevented the discharge of heparin, since it has been proved that heparin comes from the liver in peptone and anaphylactic shock4.

The Behaviour of Platelets in Anaphylactic and Peptone Shock

Summary Platelet counts have been made in dogs which showed typical anaphylactic shock judged by the blood pressure tracing. Within two to ten minutes after the injection of the antigen in sensitive animals the platelet count reached a level of from 2½ to 20 per cent of the count before injection. The majority of these counts in shock were less than 50,000/mm3 and all showed clumping of the platelets to the extent of from 40 to 90 per cent. Injection of heparin before the antigen did not prevent the low count or the clumping. The low platelet counts also occurred when anaphylactic shock was obtained in the anaesthetized liverless animal. The decreased coagulability of the blood in the liverless dog in anaphylactic shock appears to be due to the lack of platelets in the circulating blood. In canine anaphylaxis the platelet count is of value in indicating sensitivity in mild or doubtful cases. Peptone in a dose of 0.3 g/kilo produced a reaction in dogs very similar to anaphylactic shock in its effect not only on blood pressure but also on the platelets.

Role Played by Leucocytes, Platelets and Plasma Trypsin in Peptone Shock in the Dog

ConclusionsFrom the results described in this paper, it appears evident that peptone produces shock in the dog by a mechanism very similar to that leading to anaphylactic shock. Participation of the white blood elements (leucocytes and platelets) in the discharge of histamine and heparin from liver cells is definitely suggested by the fact that the severity of the shock is closely connected with the incapacity of those blood elements to return to blood stream, and also by experiments with isolated liver, in which it became apparent that peptone is unable by itself to release those substances from liver cells, and that the presence and retention of blood elements (leucocytes and platelets) is an indispensable step leading to the discharge of those substances. That the final mediator for the release of these substances is activated plasma trypsin is strongly suggested by the fact that platelets contain a kinase for plasma trypsin and that there actually occurs activation of this enzyme, as shown by fibrinol...

Observations on Spontaneous and Induced Refractoriness to Peptone Shock in Dogs

Abstract The intravenous injection of proteose solutions into dogs results in a reaction (commonly referred to as “peptone shock”) which is virtually indistinguishable in symptomatology from that of an anaphylactic reaction produced by the injection of specific antigen into a previously sensitized animal. The two reactions are similar in their symptomatology, and in the underlying mechanisms by which the prominent symptoms are produced. In both reactions the vascular crisis is due to a release of histamine (1, 2), and the incoagulability of the blood, to a release of heparin (3, 4). An anaphylactic reaction, when not fatal, is followed by a refractory state, usually referred to as a desensitization. This is considered to be highly characteristic of anaphylaxis and is often used as a criterion of differentiation from apparently similar reactions. While there is no decisive proof as to the mechanism of anaphylactic desensitization, it is rather generally considered to be due to a binding or saturation of sessile antibodies with antigen.

Inhibitory Effect of Heparin upon Histamine Release by Trypsin, Antigen, and Proteose.

Anaphylactic, trypsin, and peptone shock are closely related phenomena. The prominent symptoms are similar and the intravenous injection of antigen, trypsin, or proteose into intact animals has been shown to result in the liberation of significant amounts of histamine.1-3 It has also been shown that the addition of antigen, trypsin, or proteose to rabbits' blood (rendered incoagulable with heparin) leads to the release of histamine from cells to plasma.4-9 It is possible that the mechanisms of the release are the same in each case. A study of the effect of various agents in inhibiting or augmenting the release of histamine by the above substances suggests itself as a means of determining whether similar mechanisms are involved. Inasmuch as rabbits' blood can be divided into samples which can be considered identical in every respect, this tissue seems to provide an ideal medium for such studies.It has been shown that heparin is capable of inhibiting the proteolysis of various substrates by trypsin,10, 11 a...

Peptone shock in rabbits: Gotzl, F. R., and Dragstedt, C. A.: J. Pharmacol. & Exper. Therap. 74: 33, 1942

Peptone shock in rabbits: Gotzl, F. R., and Dragstedt, C. A.: J. Pharmacol. & Exper. Therap. 74: 33, 1942

Liver Histamine During Peptone Shock in Dogs

ConclusionPeptone shock in the dog is accompanied by a reduction in the liver histamine which is roughly parallel to the degree of the shock reaction. The amount of histamine liberated from the liver is substantially adequate to account for the degree of shock as determined by the systemic blood pressure.

Peptone Shock in Fetal Dogs and its Significance in the Metabolism of Histamine

It has previously been shown1, 2 that “peptone” shock in dogs, which is produced by the intravenous injection of proteoses, is accompanied by and due to the liberation of histamine from the tissues of the injected animals. The source of, and the reasons for, the storage of histamine in the tissues are only incompletely understood. It seemed, therefore, of interest to determine whether histamine is present in the tissues of fetal animals, and if it is present, to determine whether it can readily be liberated with resulting shock reactions such as occur in adult animals. The studies of Code3 indicate that the traces of histamine which are normally present in the blood of dogs occur in the cellular elements and not in the plasma. This would imply that the histamine normally circulating in the blood of a pregnant dog would not be accessible to the fetus. As there is no opportunity for the formation of histamine within the fetus by bacterial decomposition of histidine in the fetal intestine, it may be presumed...

Vitamin C and peptone shock in dogs: Dragstedt, C. A., Eyer, S. W., and De Arellano, M. R.: Proc. Soc. Exper. Biol. & Med. 38: 641, 1938

Vitamin C and peptone shock in dogs: Dragstedt, C. A., Eyer, S. W., and De Arellano, M. R.: Proc. Soc. Exper. Biol. & Med. 38: 641, 1938

Vitamin C and Peptone Shock in Dogs

Vitamin C and Peptone Shock in Dogs

Relationship Between Peptone Shock and Anaphylactic Shock

We have recently reported that the intravenous injection into dogs of a solution of peptone produces shock indirectly by leading to the liberation of a vasodepressor substance, identified as histamine, from the tissues. Thus the mechanism of peptone shock is apparently similar to that of anaphylactic shock. Biedl and Kraus pointed out the remarkable similarities between these conditions. They also reported that peptone shock desensitizes an animal to anaphylactic shock and vice versa. They concluded that the fundamental mechanism concerned in these reactions was identical. They interpreted the reactions as indicating that peptone contains some active substance, such as Popielski's vasodilatin, which can produce shock directly, and that in the anaphylactic experiment a mother substance is formed as the result of the sensitization which then discharges this active peptone constituent when the shocking injection of antigen is made. Subsequent investigators have had variable results in attempting to influence an anaphylactic reaction by the prior administration of peptone. Hill and Martin in their review summarize the reports as follows: “In short, there is some, but not striking evidence that peptone may inhibit shock within certain defined limits.” In view of our demonstration that both peptone shock and anaphylactic shock are reactions that are brought about indirectly by the liberation of histamine from the tissues of the shocked animal, the relationship between these reactions has considerable significance. For example, the question whether desensitization is related to a depletion or exhaustion of the mobilizable store of histamine in the tissues is subject to direct approach by such a study. The present investigation, therefore, was undertaken in the effort to determine whether or not one reaction would desensitize to the alternative reaction.

EFFECT OF PARENTERALLY ADMINISTERED PEPTONE

The possibility of supplying the nitrogen requirements of the body parenterally led us to investigate the effect of protein split products given by this route. For many years reports have appeared in the literature on various phases of the phenomenon which has been designated peptone shock. These have included elaborate chemical studies and physiologic observations made after the parenteral and oral administration of certain protein split products. This work has all been carried out with crude products of protein digestion. In consequence the results obtained have been variable and often contradictory. REVIEW OF THE LITERATURE In 1913 Henriques and Andersen1described experiments in which they maintained goats in positive nitrogen balance by means of intravenous injections. The authors achieved this by administering a solution containing completely digested (trypsin-erepsin) meat, dextrose, sodium acetate, sodium chloride, potassium chloride, calcium chloride and magnesium chloride by continuous intravenous drip. They concluded that protein

THE THERAPEUTICS OF THE INTRAVENOUS DRIP

rapid introduction of pharmacologically active or inert chemicals, drugs and biologic fluids may frequently give rise to immediate and far-reaching nonspecific sequelae, at times serious and occasionally fatal.1This syndrome (speed shock) includes circulatory and respiratory symptoms, together with alterations in the blood. The reaction is immediate and may include or closely simulate such apparently unrelated phenomena as the anaphylactoid reaction,2nitritoid and hemoclastic crises, post-transfusion reactions,3peptone shock, and the sudden death that has been described following injections.4 These untoward reactions may be avoided by the slow continuous intravenous drip.5The clinical application of this principle is by no means new and has been emphasized by many clinicians.6 We have already described a convenient apparatus for the practical clinical application of the drip.7A central room for the preparation of these sets was established at the Mount

Anaphylactic Shock and Mechanical Obstruction of the Hepatic Veins in the Dog

Summary Mechanical obstruction of the hepatic veins of the dog produces a fall in arterial blood pressure similar to, but not so marked as, that which occurs in anaphylactic shock. The injection of the homologous serum into a sensitized dog while the hepatic veins are mechanically obstructed does not cause an additional fall in blood pressure that can be attributed to the onset of anaphylactic shock. Peptone, on the other hand, does induce a further fall in pressure under these conditions as a result of peripheral dilatation. When the homologous serum is injected into a sensitized dog with the hepatic veins mechanically obstructed and, after an interval of from one to three minutes, the hepatic veins are released either indefinitely, or for fifteen to twenty seconds and then reconstricted, the ensuing fall in blood pressure is, in most animals, greater than that induced by the obstruction alone. Fifteen to twenty seconds is sufficient time for enough of the injected serum in the circulating blood of a sensitized dog to pass through the liver to initiate anaphylactic shock. It is suggested that in anaphylactic shock in the dog very little blood escapes from the liver into the vena cava. It is further suggested that in anaphylactic shock in the dog there is a peripheral dilatation such as occurs after injections of peptone. But before this peripheral effect is induced the injected serum must pass through the liver of the sensitized animal, while in peptone shock this is not necessary.

THE EFFECT OF PEPTONE ON THE PERIPHERAL CIRCULATION

1. Injection of a solution of peptone directly into the artery of the leg of a dog is followed by an abrupt increase in leg volume. This is of short duration and is quickly followed, usually in less than (1/2) minute, by a decrease in the volume of the limb below that previous to the injection. 2. The phases of the leg volume curve bear a fairly definite relation to the changes in arterial pressure. 3. These results, therefore, indicate that the long continued low arterial pressure in peptone shock, and probably in anaphylactic shock, may be hastened but is not maintained by peripheral dilatation, and suggest that there is an impounding of the blood in some other part of the body.

Hepatic Reactions in Anaphylaxis

Summary Marked fall in arterial blood pressure is produced by intravenous injections of peptone into dehepatized dogs. Canine peptone shock and canine anaphylactic shock therefore cannot be regarded as physiologically identical reactions. Recovery from peptone shock does not take place in dehepatized dogs.

Hepatic Reactions in Anaphylaxis

Summary The dominant factor increasing resistance to blood flow through the liver during canine peptone shock is a suddenly increased permeability of the sinusoidal endothelium. This produces an explosive hepatic edema accompanied by swelling of the parenchymatous cells, increasing local tissue pressure sufficient to cause passive sinusoidal vasoconstriction and passive constriction of the hepatic veins. The sudden loss of fluid from the sinusoidal blood increases local blood viscosity sufficient to cause temporary sinusoidal stasis, and even stasis in the narrowed hepatic veins. A minor factor contributing to this increased resistance, is sinusoidal narrowing from leucocytic deposits. We have no evidence thus far that active hepatic vasoconstriction is a factor in this reaction.

Hepatic Reactions in Anaphylaxis

Summary The net weight of the liver exclusive of the weight of the contained blood is increased as much as 95 per cent during the early stages of canine peptone shock.

Hepatic Reactions in Anaphylaxis

Summary The portal blood pressure increases about 7 mm. Hg during the first forty-five seconds of peptone shock. The pressure then gradually falls, reaching normal in from eight to twelve minutes. Perfusions of isolated livers show an increased resistance to perfusion flow as a result of the action of peptone or of peptone-blood mixtures. The resistance reaches a maximum during the second minute, and then gradually decreases, being restored to approximately normal by the tenth minute. Mechanically increased resistance to hepatic outflow sufficient to raise the portal blood pressure 10 mm. Hg, the maximum rise during peptone shock, does not cause the hepatic-intestinal cyanosis characteristic of the peptone reaction, nor the characteristic fall in carotid blood pressure. Theories of peptone shock based solely on the hepatic mechanical factor are, therefore, no longer tenable.

Hepatic Reactions in Anaphylaxis

Summary Unneutralized Witte's peptone, tested by perfusion methods on isolated canine tissues, gives mechanical reactions in the following parts: Isolated liver: Marked increase in perfusion resistance, reaching its maximum by the end of one minute, with partial or complete recovery by the end of eight minutes. Isolated lungs: Reactions similar to those in the isolated liver. The reactions, however, are more pronounced, with practically no tendency to recovery by the end of eight minutes. Isolated intestines: Slight decrease in perfusion resistance, reaching its maximum by the end of one minute, with partial recovery by the end of eight minutes. Isolated hind quarters: Reactions similar to these in the isolated intestines, but with less tendency to recovery by the end of eight minutes. Isolated heart: Reactions intermediary between those in the isolated liver and the isolated hind quarters. The combined effect of these mechanical reactions is conceivably sufficient to account for the characteristic clinical picture of peptone shock.