General Patterns, Pathogenetic Significance, and Correction of Early Postresuscitative Changes in Cerebral Blood Flow (Experimental Study)

The dissertation is devoted to the investigation of general patterns, pathogenetic significance, and correction of early postresuscitative changes in cerebral blood flow. The study was conducted on experimental models of clinical death in animals induced by hemorrhage, carbon monoxide inhalation, and compression of the thorax. The dynamics of cerebral and systemic hemodynamics in the postresuscitation period are investigated, and the relationship between changes in cerebral blood flow and parameters of systemic circulation is established. Special attention is given to the substantiation of pathogenetic principles for correction of reperfusion disturbances of the brain in order to increase the efficiency of resuscitative measures.

Relevance of the problem. The most important issue in modern resuscitology is the development of effective methods for the prevention and correction of postresuscitative disorders of the central nervous system (CNS), which constitute the primary cause of high mortality and disability following a transferred terminal state [49, 78, 160, 449, 485].

The pathogenesis of postresuscitative CNS disorders is presented by various factors, the relative contribution of each of which to the development of neurological impairments is difficult to determine [5, 58, 61, 193, 242, 293]. Despite the multiplicity of pathogenetic factors, it is unquestionable that the completeness and speed of restoration of CNS functions are determined, first and foremost, by the adequacy of cerebral reperfusion [44, 101, 107, 216, 368, 381]. With the resumption of circulation in the resuscitated organism, blood flow increases in many organs and tissues, which, in the opinion of many authors, has adaptive significance — rapid elimination of the consequences of ischemic metabolic disturbances [31, 272, 413]. Despite numerous experimental and clinical investigations, at present there is no representation of the patterns and pathogenetic significance of postresuscitative changes in cerebral blood flow. This impedes the development of pathogenetically grounded methods for assessment and correction of reperfusion changes in cerebral circulation.

The relationship between early postresuscitative changes in cerebral blood flow and the dynamics of systemic circulation of the resuscitated organism remains unclear, at a time when many central and peripheral autoregulatory mechanisms are disrupted [68, 139, 151, 271, 487]. In particular, it has been established that the intensity of reperfusion after a transferred terminal state substantially varies not only in different organs but also in different regions of the same organ, and is not always analogous to the intensity of systemic hemodynamics, which, in the authors' opinion, is due to impaired and uneven restoration of vascular tone [69, 124, 255, 382]. However, targeted investigations of early postresuscitative changes in blood flow in functionally distinct regions of the cerebral cortex in relation to changes in systemic hemodynamics and assessment of their significance for processes of restoration of vital activity have not been conducted to date.

The totality of these circumstances determined the goal and objectives of this investigation.

Goal of the investigation: to establish general patterns and pathogenetic significance of early postresuscitative changes in cerebral blood flow in relation to changes in systemic hemodynamics, and to substantiate pathogenetic principles of their correction.

Objectives of the investigation:

1. To study, in a comparative aspect, early postresuscitative changes in cerebral blood flow and systemic hemodynamics in animals that underwent 5-minute clinical death from hemorrhage of varying duration; hemorrhage combined with carbon monoxide inhalation; compression of the thorax.

2. To establish general patterns of restoration of cerebral blood flow after undergone 5-minute clinical death.

3. To assess the dependence of early postresuscitative changes in cerebral blood flow on systemic hemodynamics.

4. To evaluate the pathogenetic significance of early postresuscitative changes in cerebral blood flow for processes of restoration of vital activity.

5. To develop pathogenetically grounded principles of correction of early postresuscitative changes in cerebral blood flow.

Scientific novelty

It has been demonstrated that regardless of the cause and duration of death, early postresuscitative changes in cerebral blood flow have a general pattern characteristic of changes in systemic hemodynamics — initial transient hyperperfusion is replaced by relative normalization of blood flow with subsequent development of hypoperfusion.

For the first time, it has been established that early postresuscitative hyperperfusion of the brain is due to increased cardiac output and its redistribution in favor of the supra-diaphragmatic segment of the body.

For the first time, it has been shown that the negative effect on the completeness and speed of restoration of CNS functions after a transferred terminal state is caused not only by insufficient cerebral hemoperfusion but also by excessive hyperperfusion in terms of intensity and duration, which develops as a result of centralization of circulation in conditions of hypervolemia and increased cardiac output.

It has been proven that there exists an adaptive range of early postresuscitative hyperperfusion of the brain, within the limits of which maintenance of cerebral blood flow allows improvement of the course of restorative processes in the CNS and increase survival after a transferred terminal state.

Theoretical and practical significance

New data have been obtained that testify to general patterns of early postresuscitative changes in cerebral blood flow and their relationship with the systemic hemodynamics of the resuscitated organism.

The obtained data constitute a theoretical foundation for the development of pathogenetically grounded methods for assessment and correction of early reperfusion changes in cerebral circulation in extreme and terminal states, which will allow increasing the efficiency of resuscitative measures and, ultimately, reducing mortality and disability following acute disturbances of cerebral circulation.

It has been proven that one of the most physiological, sufficiently accessible, and controllable methods of modulation of cerebral circulation of the resuscitated organism is management of cardiac output and its distribution.

The results of the investigation, together with the developed models of terminal states, constitute an experimental basis for further investigations into the mechanisms of development of postresuscitative disease.

Main provisions to be defended

1. In the postresuscitation period, regardless of the cause and duration of the terminal state, early reperfusion changes in cerebral blood flow have a lawful phased character. Initially developing hyperperfusion is replaced by gradual decrease in blood flow and development of hypoperfusion. With increasing duration of death, the duration of early postresuscitative hyperperfusion increases, whereas its intensity does not reliably change.

2. Phased changes in cerebral blood flow in the early postresuscitation period are associated with changes in systemic hemodynamics and are due to initial increase in cardiac output and its redistribution in favor of the supra-diaphragmatic segment of the body. Subsequent progressive decrease in cerebral blood flow and development of cerebral hypoperfusion are associated with decrease in cardiac output and its supra-diaphragmatic fraction.

3. Both insufficient and excessive, in terms of intensity and duration, hyperperfusion of the brain of the resuscitated organism are accompanied by worsening of processes of restoration of vital activity and increase in lethality after a transferred terminal state. The adaptive range of early postresuscitative hyperperfusion of the brain for 5-minute clinical death is an increase in cerebral blood flow of no less than 30% and no more than 60% from the baseline, lasting from 5 to 10 minutes.

4. One of the promising methods of increasing the efficiency of resuscitative measures is modulation of early postresuscitative reperfusion of the brain through management of systemic hemodynamics of the resuscitated organism.

Presentation of dissertation materials

The materials of the dissertation were reported and discussed at: scientific-practical conference "Priority Questions of Anesthesiology and Intensive Care" (Novokuznetsk, 2004); All-Russian scientific-practical conference "Critical States in Miners with Diseases and Technological Disasters" (Novokuznetsk, 2005); XII Russian National Congress "Man and Medicine" (Moscow, 2005); scientific conference "Fundamental and Applied Aspects of Basic and Clinical Pathophysiology" (Omsk, 2005); II scientific-practical conference "State Medicine: Science and Practice" (Kemerovo, 2005); interregional scientific-practical conference "Actual Problems of Clinical and Experimental Medicine, Medical Science and Education" (Kemerovo, 2005); second scientific session of the branch of GU SO RAMN - KNTC (Kemerovo, 2005); III interregional scientific-practical conference "Modern Aspects of Anesthesiology and Intensive Care" (Novosibirsk, 2006); meetings of problem commissions of RAMN: "Hypoxia of Critical States" and "Extreme and Terminal States" (Moscow, 2006); All-Russian scientific conference with international participation "Resuscitology - Science of Critical States" (Moscow, 2006); scientific conference with international participation "Critical and Terminal States, Postresuscitative Disease (Pathogenesis, Clinical Course, Treatment)" (Moscow, 2007).

Publications

32 printed works have been published on the dissertation topic, including 6 articles in journals recommended by VAK RF for publication of dissertation materials for the degree of Doctor of Sciences.

Volume and structure of the dissertation

The dissertation is presented on 226 pages of typed text and consists of the following sections: introduction, literature review, description of material and methods of investigation, four chapters of original research results, discussion of results and conclusion, conclusions, list of cited literature including 249 domestic and 243 foreign sources. The work is illustrated with 33 tables and 28 figures.

Personal contribution of the author

Analysis of literary data on the research topic, development of terminal state models, all experiments, statistical processing of obtained data, their analysis and interpretation, and writing of the dissertation were performed personally by the author.