Prophylaxis of encephalopathies and risk factors of atherogenesis development in the postresuscitation period in rats by means of succinic acid.

The effect of oral administration of succinic acid was studied in 66 rats exposed to 10 min cardiac arrest with further resuscitation. A total of 30 mg/kg of the drug were administered daily for 5 days starting with day 3 up to day 7 after resuscitation. The experiments have revealed that treatment with succinic acid caused normalization of the orienting behavior in an 'open field' test, decrease of the intensity of response to electric shock, normalization of free radical formation in the brain and serum and reduced cerebral morphological changes. The succinic acid prevented the increase of cholesterol, triglyceride and low density lipoproteins in the blood. The data suggested that after additional trials the succinic acid could be used to prevent development of postresuscitation encephalopathies (3 months after reanimation).

Postresuscitation changes in brain free radical-mediated processes and nitric oxide synthase activity in rats: effects of individual behavior in "emotional resonance" test.

Effects of 7-min cardiac arrest and individual behavior on free radical-mediated processes and nitric oxide synthase (NOS) activity was evaluated in brains of male Wistar rats one hour and one week after resuscitation. "Emotional resonance" test was used for the behavioral selection of rats. The test includes factors of significance for rats: the choice between large and lighted or small and dark space as well as signals of pain of another rat. Free radical generation (using chemiluminescence method), superoxide scavenging/generating activity, substances reacting with 2-thiobarbituric acid and NOS activity (by measuring mononitrosyl iron complex of NO with diethyl dithiocarbamate and endogenous brain Fe2+ by electron spin resonance spectroscopy) were determined in cerebral cortex, cerebellum and hippocampus. Cardiac arrest induced oxidative stress accompanied by the loss of NOS activity, as well as compensatory changes of free radical-mediated processes in cerebral cortex. Oxidative stress was also evident in cerebellum and, to a lesser extent, in hippocampus. Most of neurochemical differences between behavioral groups were induced by cardiac arrest. These differences were global, related to a specific brain region or became apparent in cerebral lateralization of biochemical indices.

Cardiac arrest induces decrease of nitric oxide synthase activity and increase of free radical generation in rat brain regions.

Rats were subjected to 15 min cardiac arrest and sacrificed 1 h or 15-20 days after resuscitation. Homogenates of brain regions were assayed for nitric oxide synthase (NOS) activity (by measuring the mononitrosyl iron complex of NO with diethyl dithiocarbamate and endogenous brain Fe2+ using electron spin resonance spectroscopy) and generation of free radicals (FRG; by measuring H2O2-induced, luminol-dependent chemiluminescence). Cardiac arrest induced marked decrease of NOS activity and the increase of FRG, most prominent in cerebellum and less marked in cerebral cortex. Two groups of rats were revealed 15-20 days after cardiac arrest: with NOS activity significantly lower than control and not different from control. Positive linear inter-regional cross-correlations of both NOS activity and FRG (except of the group 1 h after resuscitation) as well as negative correlations between NOS and FRG were demonstrated.

Cerebral resuscitation from cardiac arrest: pathophysiologic mechanisms.

Both the period of total circulatory arrest to the brain and postischemic-anoxic encephalopathy (cerebral postresuscitation syndrome or disease), after normothermic cardiac arrests of between 5 and 20 mins (no-flow), contribute to complex physiologic and chemical derangements. The best documented derangements include the delayed protracted inhomogeneous cerebral hypoperfusion (despite controlled normotension), excitotoxicity as an explanation for selectively vulnerable brain regions and neurons, and free radical-triggered chemical cascades to lipid peroxidation of membranes. Protracted hypoxemia without cardiac arrest (e.g., very high altitude) can cause angiogenesis; the trigger of it, which lyses basement membranes, might be a factor in post-cardiac arrest encephalopathy. Questions to be explored include: What are the changes and effects on outcome of neurotransmitters (other than glutamate), of catecholamines, of vascular changes (microinfarcts seen after asphyxia), osmotic gradients, free-radical reactions, DNA cleavage, and transient extracerebral organ malfunction? For future mechanism-oriented studies of the brain after cardiac arrest and innovative cardiopulmonary-cerebral resuscitation, increasingly reproducible outcome models of temporary global brain ischemia in rats and dogs are now available. Disagreements exist between experienced investigative groups on the most informative method for quantitative evaluation of morphologic brain damage. There is agreement on the desirability of using not only functional deficit and chemical changes, but also morphologic damage as end points.

Post-resuscitation disease--a new nosological entity. Its reality and significance.

Experimental and clinical investigations of patients resuscitated after cardiac arrest or terminal states, testify to the fact that in the post-resuscitation period alongside processes of recovery and compensation, a number of new pathological phenomena develop. The latter differ substantially from those caused by ischemia and hypoxia. These post-resuscitation processes involve not only the CNS, but also the entire body and may lead to severe disability and even death of the seemingly successfully revived body. The data available suggests that this post-resuscitation pathology is a new nosological entity--a post-resuscitation disease. This disease has it own specific etiology, pathogenesis, variants of the clinical course (a number of syndromes) and the system of treatment and rehabilitation. In view of the ever wider use of resuscitation in clinical practice, it is expedient to organize an all-round study of this nosological entity, the optimum systems of its treatment, and to include this entity into International Classification of Diseases of WHO.

Experimental data on the nature of postresuscitation alpha frequency activity.

Synchronized activity of alpha frequency recorded from a number of dog brain formations in the initial stages of postischaemic (postresuscitation) restoration was studied. Using the methods of destruction and elimination it was shown that the amygdaloid nuclei were the main source of such activity. Analysis of the general and particular coherence functions at the frequencies of alpha-like activity has shown that subcortical formations (thalamus, nucleus caudatus) become secondarily active sources of the generation of the bursts and of their generalization in the brain. Investigations and available literature lay the basis for the hypothesis that the activity observed in experiments and the activity described during postresuscitation alpha-pattern coma in humans have similar mechanisms of development and are, probably, identical.

Correlation analysis of delta activity generated in cerebral hypoxia.

1. Differences in spatial and temporal characteristics between polymorphous delta activity (PDA) and "standard slow complexes" (SSCS) resulting from grave cerebral hypoxia have been demonstrated by means of digital correlation analysis and on line recording of correlograms. 2. PDA observed in the human EEG and the ECoG of dogs is characterized by the absence of periodic organization (high extinction indices of auto- and crosscorrelation functions) and absence of spatial synchronization when recorded from widely separated areas of the hemispheres (low correlation coefficients, significant and variable time shifts), with bilateral symmetry of slow waves being preserved. 3. Delta waves recorded from nucleus amygdalae, nucleus caudatus, thalamus, hypothalamus and midbrain in the dog differ from cortical PDA by a more synchronous and rhythmically arranged process. 4. During the establishment of SSC activity correlograms show a synchronous process common to all cortical aand subcortical areas characteized by very high values of correlation coefficients. 5. It is suggested that the unorganized slow wave PDA process could arise under conditions of hypoxic dysfunction of distant cortico-cortical relationships, accompanied by weak subcortical pacemaker influences. The process reflects local coexcitation of relatively limited cortical areas. The particular statistical characteristics of SSCs generated during further increase in oxygen deficit can be accounted for by simultaneous generation of responses in some subcortical areas to single volleys of impulses from a hypothetical pacemaker, accompanied by a passive wave propagation towards a cortex completetly depressed by hypoxia

Types of hypoxic and posthypoxic delta activity in animals and man.

1. Two types of hypoxic delta activity were observed in ECoG records of dogs subjected to exsanguination, sudden cardiac arrest resulting from ventricular fibrillation or mechanical asphyxiation, as well as during post-hypoxic recovery. They were polymorphous delta activity (PDA) and "standard slow complexes" (SSCs). 2. These two types of delta activity were found to differ from each other as to the shape of the potentials; their amplitude in monopolar and bipolar leads; the cortical areas in which the activity exhibited the highest amplitude; the degree of manifestation in the cortex and subcortical structures; their relation to activating influences; their dependence on the stage and character of hypoxia. 3. Analysis of EEG records of patients during and after hypoxia made it possible to distinguish both PDA and a type of delta activity similar to the SSCs observed in experimental animals. 4. It is suggested that the appearance of SSCs is determined by the activity of a pacemaker situated in the diencephalon and responding to pO2 changes, and that the mechanism of SSC generation is closer to that of monorhythmic, bilataerally synchronous delta waves observed in primary irritative or epileptogenic processes in the diencephalon.

The immune response in stationary suspension cultures containing different numbers of cells. The surface density effect.

Correlation between the number of dissociated spleen cells, incubated with antigen in a modified Mishell and Dutton system, and the number of antibody-forming cells (AFC) produced as a result of incubation has been studies in mice of C57Bl/6 strain. It has been shown that when suspension densities are increased 2- to 4-fold, the number of AFC formed is very often reduced 10- to 100-fold, although the percentage of viable cells recovered at the end of incubation is not significantly diminished. The observed reduction of AFC formation in cultures containing increased numbers of cells, designated here the surface density effect, was found to be expressed more by spleen cells of unimmunized than of immunized mice. Inhibition was dependent on the thickness of the cell layer formed on the bottom of the incubation vessel (cells per square centimeter), rather than on the cell: volume ratio of cultures. The effect was not due to a deficit of antigen or nutrition and could not be reproduced by adding of incubation media conditioned by dense cultures. It was determined not by impairment of clone induction but by inhibition of subsequent proliferation. This suppression is reversible and can be reversed by decreasing the cell density, even after 3 days of culture.