The course of the early restorative period, we know, also determines to a considerable degree the character of the restoration of the functions of an organism that has suffered clinical death. It is at this time that closely interconnected posthypoxic disturbances of circulation and metabolism occur, leading to severe functional and morphologic changes in organs and tissues.
These complications may progress or develop again, however, even in the presence of good indices of arterial blood pressure. Underlying their development is intoxication of the organism by the products of a posthypoxic metabolic disturbance, in particular of an upsetting of acid-base equilibrium. The hepato-renal insufficiency that develops then in turn aggravates the intoxication of the organism through weakening of the detoxicating ability of these organs and their production of toxic substances.
Thanks to the numerous investigations of this problem, the presence of toxaemia in different states of shock can now be considered a proven fact.
It has been shown in our Laboratory that the blood serum of animals that have survived protracted clinical death also has a toxic effect on mice with a blocked reticuloendothelial system. The toxicity of serum appears in the earliest stages of the postreanimation period: during the restoration of respiration, 30 minutes and an hour after resuscitation.
Some authors attribute great, even decisive importance to a bacterial endotoxin coming from the intestines in the development of irreversibility in terminal states. In fact there is now fairly convincing evidence of the possibility of endotoxaemia developing in various states accompanied with ischaemia of the internal organs. In our Laboratory for Testing Medical and Biological Preparations, bacteria were observed in the blood of animals that had suffered 12 minute’s cardiac arrest; in 80 per cent of the dogs gram-negative bacteria of the intestinal group were identified 30 minutes after reanimation. In addition it was found that, at the end of the first month after resuscitation, the titre of normal E. coli antibodies and the bactericidal capacity of serum in respect of this bacterium increased. These findings can serve as indirect evidence of the circulation of this endotoxin in the blood after resuscitation.
A cause of endotoxaemia in terminal states could be impairment of the barrier function of the intestinal mucosa, or reduction of the absorbent function of the reticuloendothelial system or of the activity of other immunological mechanisms. Our Laboratory has studied the dynamics of the best known indices of non-specific immunity capacity of neutrophils of the peripheral blood in reanimated animals. It was found that, during the first day, all these indices of non-specific immunity except the absorbent function of neutrophils, were activated at various moments.
The increase in bactericidal and complementary activity was preceded by a phase of the lowering of these indices, the length of which depended on the gravity of the course of the restorative period and was more marked in animals that had suffered lengthy hypotension prior to clinical death. In the last case a regular lowering of the absorbent activity of neutrophils was observed during the first day. There is no doubt that evaluation of the pathophysiological importance of the changes observed in natural immunological mechanisms calls for further study, but we can already suggest that the activation of certain immunological mechanisms during the postreanimation period is a defence reaction of the organism, needed to restore impaired homeostasis.
It is supported by the fact that the activation of these mechanisms was observed in all surviving animals. Numerous investigations have shown moreover, that the resistance of animals to such serious states of hypoxia as shock and haemorrhagic hypotension depends on the absorbent activity of the RES, which is closely related in turn to the activity of the other factors of non-specific immunity.
Without denying a certain importance of a bacterial endotoxin in the pathogenesis of resuscitation of the organism, it seems unlikely that it can be considered the main ‘critical’ factor determining the irreversibility of terminal states, as some authors suggest. Many researchers have been unable to confirm the importance of this factor in the pathogenesis of terminal states.
Several toxic substances of a non-bacterial nature have been described in recent years that are considered to be of great importance in the impairment of haemodynamics in various states of shock, independently of their cause. These substances include MDF (myocardial depressant factor), RDC (reticuloendothelial depressant factor), lysosomic enzymes, and others, coming from internal organs and entering the blood stream either directly or through the lymphatic system, depending on their molecular weight.
A search for methods for the most rapid elimination or neutralization of toxic products from the organism during the restorative period has been carried on in our Laboratory for many years. Administration of a sodium bicarbonate solution after the restoration of cardiac activity had a noticeable effect in experiments on dogs, and is now widely used in clinical practice to compensate metabolic acidosis.
Complete or partial substitution of blood and plasmaphaeresis have been found very useful detoxicating measure.
Shikunova’s research showed that complete 200 per cent substitution of the blood of the reanimated animal by fresh donor blood by Glozman and Kasatkina’s technique, when done during the early restorative period helped normalize haemodynamics, respiration, and certain metabolic parameters. The content of organic acids reached the initial level by the end of the first hour of the restorative period. The degree of survival of the animals studied was raised considerably — after ten minutes of circulatory arrest by as much as 100 per cent, and after 12 minutes by up to 80 per cent.
On the other hand blood substitution carried out an hour after resuscitation, when the EEG showed signs indicating a negative prognosis, was no longer of any help in improving the restoration of the organism’s vital activity, which is indirect confirmation that posthypoxic metabolic disorders and secondary hypoxia still exert their harmful effect in the earliest stages of the restorative period.
The search for methods by which the most rapid excretion of toxic products can be achieved led to a detailed examination of plasmaphaeresis. This technique promotes elimination of blood plasma in which the toxic products are mainly concentrated, and rapid introduction of washed formed blood elements.
In carrying out plasmaphaeresis the test animals were first bled with subsequent partial making up of the volume of circulating blood. The blood, collected in plastic bags, was centrifuged, the plasma being discarded and the erythrocytes reintroduced into the blood stream. In dogs that had been seven minutes in clinical death as a result of blood loss and ten to fifteen minutes of circulatory arrest caused by ventricular fibrillation due to an electric current, reinfusion of their own erythrocytes led to an increase in oxygen saturation of the blood, in the quantity of haemoglobin and in the haematocrit index, and to a lowering of the total concentration of organic acids in the plasma. Plasmaphaeresis had a positive effect on the duration and character of the restoration of the central nervous functions, as was evidenced by the earlier appearance of electrical activity in the brain than in controls and its more rapid normalization.
It was also established that plasmaphaeresis permitted lengthening of the period of complete circulatory arrest after which complete functional restoration of the central nervous system could be achieved. Thus, in experiments in which plasmaphaeresis was not employed, 30 per cent of the dogs survived 12 minutes of cardiac arrest due to ventricular fibrillation; when it was employed 66 per cent of the dogs survived 14 or 15 minutes of cardiac arrest. When plasmaphaeresis was employed after seven minutes of clinical death provoked by massive bleeding 58 per cent of the dogs survived but when detoxication therapy was not used only 20 per cent survived.
Two animals that had been in clinical death for 14 or 15 minutes were used in experiments mounted to study functional restoration of the cerebral cortex and the possibility of compensating it, which was done by studying their conditioned reflex activity by means of the acid-defensive technique. The formation of conditioned reflexes, both positive and negative, was rapid in the reanimated dogs, the positive reflexes being stable and marked, which indicated adequate strength of the stimulant process. Inhibition was fairly strong and well concentrated, judging from the results of the elaboration of differentiation and from the animals’ behaviour during the experiments.
Histological study of the brain established that plasmaphaeresis and blood substitution had a distinct positive effect on preservation of the brain’s morphologic structure. Thus the morphologic changes in the brains of animals that had suffered 12 to 15 minutes of cardiac arrest with subsequent plasmaphaeresis were no greater than those found in the brains of animals that had suffered only seven or eight minutes of cardiac arrest but had not been treated by plasmaphaeresis.
It can be supposed that use of this technique in clinical practice to treat terminal states would enable hypoxia and acidosis to be eliminated more rapidly and the conditions of the compensatory functions of the central nervous system to be improved in the postreanimation period. Thus the experiments carried out indicated that blood substitution and plasmaphaeresis were highly effective in detoxicating the organism.
The method of cross circulation should also be considered promising. The certain experience accumulated in experiments and clinical practice confirms its value in the postreanimation period. Some authors, it should be noted, have succeeded in obtaining restoration of vital functions in dogs after 20 minutes of clinical death by using cross circulation.
Other methods of detoxication also deserve attention.
Detoxication methods cannot, of course, be considered universal methods suitable in all cases of irreversibility. The mainstay of the treatment of terminal states is and always has been the pathogenetic approach, but the metabolic disorders underlying the pathological shifts which occur in the early restorative period, and the accumulation of toxic products in the reanimated organism, always call for the use of detoxicating therapy.
There can be no doubt that, in order to resolve the problem of the effect of bacterial detoxication on the course of postreanimation disease the research into the latter periods of the postreanimation period already begun must be continued, and also the search for direct proof of the role of bacterial toxins in the intoxication that develops in animals that have experienced clinical death.