Specific Features of Compensatory and Adaptive Metabolic Reactions under Different Variants of Hypothermic Protection of the Body

The dissertation focuses on a comparative study of compensatory and adaptive metabolic reactions in patients with congenital heart defects who underwent surgical correction under hypothermic perfusion or no-perfusion hypothermia. It addresses carbohydrate and lipid metabolism, the lipid peroxidation–antioxidant defense system, the thyroid response, and the effect of the duration of hypothermic perfusion or circulatory arrest on the severity of biochemical shifts.

Particular attention is paid to lipid peroxidation activation in artificial circulation, its relationship to the duration of hypothermic exposures, changes in carbohydrate metabolism and cholesterol levels, and the rationale for antioxidant therapy during prolonged cardiac surgical procedures.

Relevance of the topic. The potential of hypothermia as a factor that reduces the rate of metabolic processes and increases resistance to hypoxia and stress (Novikov et al., 1998; Schneider, Salmina, 2004; Swain et al., 1991; Rebeyka, 1994) determines the wide use of hypothermic and hypometabolic strategies in medicine—and, above all—in cardiac surgery.

At the same time, during open-heart operations, in addition to cooling, the body is exposed to a large number of damaging factors of different origins, including anesthesia, surgical trauma, artificial perfusion, or interruption of blood flow through the major vessels. This leads to the development of a powerful response in the body, manifested in the activation of hormonal systems and a number of metabolic pathways (Meshalkin and Vereshchagin, 1985; Tsvetovskaya et al., 1990, 1995; Karaskov, 1999; Werb et al., 1989; Pesonen, 1995). These findings do not fit within the framework of concepts regarding hypometabolism under hypothermic conditions and rather indicate a nonspecific reorganization of metabolic processes characteristic of a stress response.

As is well known, any adaptive response becomes damaging if the intensity of the stimulus or the duration of its action exceeds the body's reserve capacities (Pshennikova, 2000). In this connection, a clear understanding of the nature of the compensatory reorganization of metabolism during cardiac surgery under controlled hypothermia is necessary to ensure reliable protection of the body from the factors of the surgical insult.

Changes in carbohydrate and lipid metabolism have been described both during artificial circulation (Meshcheryakov et al., 1989; Dementieva, 1995; Jakob et al., 2001) and during no-perfusion hypothermia (Litasova et al., 1988; Tsvetovskaya et al., 1994), but primary attention has been paid to questions of the adequacy of the hypothermic protection methods used; substrate support for compensatory and adaptive reactions has therefore been insufficiently studied. The response of the lipid peroxidation–antioxidant defense system under both forms of hypothermia has been studied without comparison with energy metabolism (Meshcheryakov et al., 1990; Dubikaitis et al., 1994; Tsvetovskaya et al., 1997; Karaskov, 1999; Kirsanova et al., 2002; Pesonen et al., 1995; Belboul et al., 2001). Although thyroid hormones play an important role in adaptation processes during cooling of the body, data on changes in their levels during cardiac surgical procedures, particularly in the postoperative period, are inconsistent (Tsvetovskaya et al., 1996; Uglyova, 1998; Karaskov and Lomivorotov, 2004; Ririe et al., 1998).

Given the continuing interest in hypothermia as a method of protecting the body during open-heart surgery, a comparative analysis of the metabolic response to hypothermic perfusion and no-perfusion hypothermia, as well as an assessment of the degree of biochemical changes at different durations of hypothermic perfusion and circulatory arrest, have acquired particular relevance. Studies aimed at investigating metabolic reactions make it possible to understand the nature of pathophysiological shifts that occur when the body is exposed to extreme factors specific to these hypothermic protection methods, identify risk factors for the transition of compensatory and adaptive reactions into damaging reactions, and develop approaches to preventing critical metabolic disturbances in the postoperative period.

The aim and objectives of the study. The aim of the present study was to identify the features of the response of carbohydrate and lipid metabolism, the lipid peroxidation–antioxidant defense system, and antioxidant defense in the human body during open-heart surgery performed under hypothermic perfusion and no-perfusion hypothermia.

The following objectives were set:

1. To study the dynamics of blood concentrations of substrates and metabolites of carbohydrate and lipid metabolism, products of lipid peroxidation, and the activity of antioxidant defense enzymes, as well as their contribution to supporting compensatory and adaptive metabolic reactions during surgical correction of congenital heart defects under hypothermic perfusion.

2. To study the dynamics of blood concentrations of substrates and metabolites of carbohydrate and lipid metabolism, products of lipid peroxidation, and the activity of antioxidant defense enzymes, as well as their contribution to supporting compensatory and adaptive metabolic reactions during surgical correction of congenital heart defects under no-perfusion hypothermia.

3. To assess the effect of the duration of hypothermic circulatory arrest and hypothermic perfusion on the severity of biochemical shifts in patients' bodies during surgical correction of congenital heart defects.

4. To study the reaction of the central and peripheral links of the thyroid system in patients with congenital heart defects to cardiac surgical procedures under no-perfusion hypothermia.

Scientific novelty. For the first time, in a comparative comprehensive analysis of the metabolic response to cardiac surgical procedures under hypothermic perfusion and hypothermic circulatory arrest, it was established that, despite differences in the dynamics and degree of biochemical changes, the compensatory and adaptive reorganization of metabolism under these exposures is of the same type and is implemented as a stress response.

For the first time, it was shown that artificial circulation makes the greatest contribution to the activation of lipid peroxidation during cardiac surgical procedures. The duration of hypothermic perfusion and blood-flow arrest is a risk factor for hyperactivation of lipid peroxidation. Under both methods of hypothermic protection, peroxidation processes are involved in the reorganization of carbohydrate metabolism and the development of hypocholesterolemia; under hypothermic perfusion, more pronounced activation of lipid peroxidation is accompanied by more prolonged maintenance of hyperglycemia in the postoperative period.

It was shown that, as the duration of hypothermic circulatory arrest increases, the rise in glucose levels and glycolysis products is associated with impaired utilization.

It was established that functional activity of the thyroid gland increased on the third postoperative day, indicating the involvement of thyroid hormones in readaptation and restoration of homeostasis after surgical correction of congenital heart defects.

Scientific and practical significance. The studies made it possible to determine the direction of metabolic reactions at the main stages of cardiac surgical procedures under controlled hypothermia and to identify the dependence of a number of biochemical indicators, including malondialdehyde, catalase, cholesterol, lactate, and pyruvate, on the duration of hypothermic perfusion or circulatory arrest. This makes it possible to substantiate approaches to preventing the transition of compensatory and adaptive reactions into damaging reactions. The rationale for using these indicators to predict critical conditions after correction of congenital heart defects was formulated in a guide for physicians approved by the Educational and Methodological Council of the Ministry of Health of the Russian Federation for cardiovascular surgery (Protocol No. 3 of 15 November 2000) and was reflected in an act on implementation in the practical activities of the E. N. Meshalkin National Research Institute of Preventive and Clinical Medicine dated 2 September 2004.

The results obtained substantiate the need to use antioxidant therapy during prolonged cardiac surgical procedures, especially in artificial circulation, with the therapy directed toward enhancing anti-radical activity, beginning during the operation and continuing into the postoperative period through the tenth day.

Provisions put forward for defense:

1. The compensatory and adaptive reorganization of metabolism during cardiac surgical procedures under controlled hypothermia is characterized by activation of glycogenolysis, lipolysis, glycolysis, and lipid peroxidation; a decrease in blood cholesterol; and increased functional activity of the pituitary–thyroid system, and it is implemented as a stress response. During no-perfusion hypothermia, glycolysis makes a greater contribution to maintaining energy homeostasis at the operative stages; during hypothermic perfusion, fatty acid oxidation does.

2. During correction of congenital heart defects under hypothermic protection, marked activation of lipid peroxidation occurs, with artificial circulation making the greatest contribution to this response. Intensification of lipid peroxidation under no-perfusion hypothermia and hypothermic perfusion is accompanied by a compensatory increase in catalase activity dependent on the levels of peroxidation products and a decrease in ceruloplasmin. Intensification of lipid peroxidation processes affects the reorganization of carbohydrate metabolism and the development of hypocholesterolemia under both methods of hypothermic protection of the body.

3. The degree of glucose metabolism disturbance, intensification of lipid peroxidation, and activation of antiperoxidative defense depends on the duration of hypothermic perfusion and hypothermic circulatory arrest. Restoration of carbohydrate metabolism indicators and levels of lipid peroxidation products after heart surgery following prolonged hypothermic perfusions or occlusions, unlike shorter exposures, occurs at a later stage.

The study was conducted within the framework of research work at the E. N. Meshalkin National Research Institute of Preventive and Clinical Medicine of the Ministry of Health of the Russian Federation under Contract 008(29)002, “Development and Improvement of Technologies for the Surgical Treatment of Diseases of the Heart and Blood Vessels,” State Registration No. 01.200.112900.

Approval of the study. The main findings of the study were presented and discussed at the I All-Russian Congress on Extracorporeal Technologies (Novosibirsk, 1997), the III International Conference “Hypoxia in Medicine” (Moscow, 1998), the V All-Russian Congress of Cardiovascular Surgeons (Novosibirsk, 1999), and the IV Congress of Physiologists of Siberia (Novosibirsk, 2002).

Publications. The main findings of the dissertation are presented in 21 published works, including 6 articles in peer-reviewed journals and a guide for physicians.