Hypothermia as a factor in enhancing the effect of antihypoxants



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Abstract

It is reported that selective hypothermia of organs and tissues reduces the intensity of biological combustion in mitochondria regardless of whether these organs and tissues are associated with the human body (in vivo) or completely isolated from it (in vitro). Therefore, local cooling of a selected part of the body reduces its oxygen demand and prolongs survival under hypoxia, i.e. it has a local antihypoxic effect. General hypothermia of warm-blooded animals and humans can both increase and decrease their survival rate under hypoxia conditions. This is due to the fact that in normal conditions external cooling effect on the organism of a warm-blooded animal increases oxygen-dependent thermogenesis in it. Therefore, in the norm, the process of general cooling of the human body does not contribute to the development of antihypoxic action in it. But oxygen-dependent thermogenesis can be turned off in the hospital setting with special hibernator drugs. Effectively shutting down thermogenesis in the patient's body before general cooling can provide the antihypoxic activity of general hypothermia. It is shown that at the beginning of the 21st century a group of oxygen-producing antihypoxants, the main ingredient of which is hydrogen peroxide, was discovered in Russia. A formulation of injectable hydrogen peroxide solution intended for local cooling of tissues at the injection site and providing them with oxygen is given. It is shown that injection of the invented cold solution of hydrogen peroxide into soft tissues (myocardium, brain, etc.) provides immediate local antihypoxic action, which develops due to local hypothermia of the tissue at the injection site by means of its physical cooling with cold solution and generation of oxygen gas in it by means of catalase cleavage of hydrogen peroxide into water and molecular oxygen. Since local hypothermia is an unrivaled way to preserve mitochondria during oxygen deprivation, and hydrogen peroxide is the leader among oxygen-producing antihypoxants, modernizing the administration of cold hydrogen peroxide solutions into the brain may in the future provide instant local cooling of the brain with simultaneous local oxygenation.

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  1. Introduction

The temperature of the human body and its individual parts changes daily under the influence of various factors of the external and internal environment [1-5]. It has been shown that the temperature in healthy men and women, as well as in patients with a wide variety of diseases and conditions, changes in a predictable and rhythmic manner, which is known as the circadian rhythm [6-10]. It has been found that the average daily fluctuations in adult body temperature are about 1.1 °C [7, 9]. At the same time, body temperature usually drops to the lowest values in the early morning between 4 and 6 o'clock and rises to the highest values in the evening between 16 and 18 o'clock [7, 11, 12]. At the same time, when evaluating the effect of temperature on the metabolism of biological objects, most researchers proceed from the fact that, according to the Arrhenius law, an increase in temperature by 10 ºC accelerates the rate of chemical reactions by 2 times [13-17]. From this it is concluded that the circadian rhythm, which changes the body temperature of people every day by an average of 1.1 ºC, can change the rate of chemical reactions occurring in their bodies by an average of 1.11 times [7].

Based on these calculations, it may seem that the change in body temperature is not a factor of significant influence on the metabolism of healthy and sick people, as well as on the effect of drugs. However, this is not the case. The fact is that the temperature of individual body parts can change more significantly and independently of the circadian rhythm. In particular, when inflammation occurs, the temperature of the inflamed part of the body and the whole organism may rise from the usual level of about +37 ºC to +41 ºC [18-21]. In some cases, the temperature of the selected body part can be increased even higher. This can be achieved by artificially warming it with a heat transfer medium. It is reported that the role of a heat carrier can be performed not only by a heating pad, but also by the drug itself, heated to +45 ºC [22-24]. On the other hand, in ischemia of the exposed parts of the body, their temperature may drop to ambient temperature, that is, to room temperature within +24 - +26 ºC, and sometimes below +20 ºC [25-27]. These facts indicate that during the treatment of diseases the temperature of some parts of the human body can change by more than 20 ºC. Consequently, based on Arrhenius' law, we can conclude that sometimes during treatment of patients in some parts of their body the rate of chemical reactions can change more than 4 times. 

In addition, the intensity of metabolism depends not only on the rate of simple chemical reactions, but also on the activity of enzymes that determine the rate of biochemical reactions. It is reported that in the human body, a temperature change of 10 ºC can change the activity of many enzymes by dozens of times or more.  Moreover, in case of excessively large temperature change, biochemical processes can be completely stopped [28-31]. 

These findings indicate that changes in the body temperature of patients and/or the drugs administered can have a significant impact on the state of tissues metabolism, which, in turn, can alter the effect of drugs when applied topically [32-35]. The fact is that the effect of drugs is inseparable from the biochemical and biophysical processes occurring in tissues [36, 37]. However, until recently, changes in tissue temperature, which change the intensity of metabolism and the effects of drugs, were not taken into account by most researchers [38].

The purpose of article is to consider and describe changes in local tissue temperature of human and warm-blooded animals, temperature dependence of metabolism and pharmacological activity of drugs at local application on the example of antihypoxants.

  1. MATERIALS AND METHODS

Methods and terminology

An unstructured literature review was conducted in the PubMed, Yandex, Google, E-library, CyberLeninka, РИНЦ, Scopus, Web of Science, MedLine, The Cochrane Library, EMBASE and Global Health databases using the search terms "temperature", “local temperature”, "hypothermia", “local hypothermia", "therapeutic hypothermia", “hibernation”, "targeted temperature management", “hyperthermia", "local hyperthermia", “cooling”, “heating”, "warming", "warm", "warm medicine", "drugs", "metabolism", "medicinal product", "medicinal solution", "injection", "pharmacological preparation", “antihypoxants”, “hydrogen peroxide”, “oxygen”, “oxygen content”, “oxygen tension”, “oxygen-producing antihypoxants”, “hypoxia”, “hypoxemia”, “lack of oxygen”, “ischemia” , and various combinations of the above-mentioned terms. No time limits were chosen for the research. All types of articles, dissertations, and descriptions of inventions in Russian and English were included. In addition, the information in the “References” section of the selected scientific articles was studied.

The information contained in the description of inventions was searched using the following databases: FIIP (RF), RUPTO, USPTO, Google Patents, EAPATIS, Espacenet, PATENTSCOPE, PatSearch, and DWPI. In addition, analogues and prototypes indicated in the selected inventions were studied.

The search for clinical studies was carried out by NU, AU, AR and AK, experimental studies were studied by AU, LF, AS, EF, and PS, while AB, SB, KM, EA, IH, ML,EM, IK and EN searched for theoretical, laboratory, biochemical and/or biophysical studies. The structured approach proved impractical due to the wide scope of the review, which included both the results obtained before the advent of temperature pharmacology and the advent of thermal imagers, and in the modern era, when monitoring the dynamics of local temperature using infrared thermography began to be widely implemented in laboratory, experimental research and clinical trials.

The article uses various terms to describe the temperature regimes of human body tissues, such as hypothermia, normothermia, hyperthermia, local hypothermia, local hyperthermia, hibernation, therapeutic hypothermia, cooling, heating, and lowering the temperature. At the same time, we assumed that "hypothermia" is a condition of human tissues with a temperature of less than 36.0°C. We have used the term "hypothermia" to describe any decrease in the general or local temperature of any part of the body below normal temperature. We also assumed that the temperature of all parts of the body changes cyclically, since there is a circadian rhythm and the dependence of local temperature on local metabolism and blood circulation. The article use the term "therapeutic hypothermia" to refer to an artificial lowering of body temperature or part of it to the maximum permissible safe level of 0 °C. At the same time, we used the term "normothermy" to refer to the active maintenance of a healthy person's body temperature in the range of daily fluctuations associated with the normal circadian rhythm. In addition, the article presents some data on the hibernation of animals such as ground squirrels, marmots, bears, hedgehogs, badgers and raccoons. This is due to the fact that, in our opinion, tissue protection from lack of oxygen can be improved in the future due to the achievements of local therapeutic hypothermia, since there are many similarities between natural hibernation and therapeutic hypothermia.

Warnings and side effects of therapeutic hypothermia

Although the review article highlights the benefits of preventing hypoxic cell damage by combining antihypoxants with refrigeration, there is very little direct clinical evidence for this (Munoz C, et al., 2024; Fisher EL, et al.,2024; Urakov AL, et al., 2024; Urakov AL, et al., 2025). Laboratory and experimental studies describing the potential mechanisms of action of local hypothermia have been conducted under various conditions. In vitro studies were performed using isolated myocardial mitochondria, human and animal blood portions, ring-shaped sections of blood vessels and animal myocardium. A significant number of studies on the effects of hypothermia on the pharmacokinetics and pharmacodynamics of drugs have been aimed at determining how the metabolism of isolated human and warm-blooded animal tissues and their response to drugs depend on cooling.  The potential antihypoxic effect of a combination of hypothermia with drugs was studied in an experimental biological model of acute limb ischemia in rats and in patients with acute and chronic arterial obstruction of the lower extremities in clinical settings.  Due to the lack of sufficient clinical data, it is necessary to take into account possible side effects, which are likely to occur with the use of general rather than local hypothermia. The fact is that general hypothermia can cause the development of colds. Therefore, it is necessary to monitor the dynamics of the patient's condition, with an emphasis on recording body temperature dynamics in anticipation of the likelihood of fever, which may be a symptom of a catarrhal disease. Local hypothermia of individual body areas, achieved by using a medical cooling package, is practically safe for all patients. When combining local hypothermia with antihypoxants, it should be assumed that the local effect of medicinal solutions is largely determined not only by their dose, but also by the concentration of dissolved ingredients, osmotic and acidic activity, as well as the duration of direct interaction with the tissue (Urakov AL, et al., 2014; Urakov AL, 2015; Urakov AL, 2016).

 

  1. RESULTS

Lack of oxygen in certain parts of the body caused by a decrease in their blood supply (ischemia) and/or a decrease in arterial blood oxygenation (hypoxemia) remains the main link in the pathogenesis of ischemic/hypoxic cell damage and tissue necrosis (infarction), regardless of people's age, their state of health and drug treatment, including the use of oxygen gas [41-45]. In humans and most warm-blooded animals, the brain has the least resistance to hypoxemia (ischemia) [46-50]. It is reported that with suffocation and/or cessation of blood supply to the brain, brain tissue cells usually die within a few minutes [51-54]. Within cells, mitochondrial damage is central to the pathogenesis of their hypoxic damage [55-58].

The central role of mitochondria in the pathogenesis of hypoxic brain cell damage is shown in Figure 1.

 

Figure 1. Schematic representation of the mitochondria in the center of the target, as the main subcellular organelle of the brain cell, with an arrow released by hypoxia and carrying death.

In a healthy person, the brain is the most oxygen-dependent part of the body. In brain tissue cells, almost all oxygen is used by mitochondria to produce ATP during oxidative phosphorylation [59-61]. Thus, for the onset of deadly hypoxic damage to the body, it is necessary to stop the supply of oxygen to the brain for just a few minutes. It is important to note that in the process of human evolution, an adaptive response to hypoxemia has formed in his body. It is reported that one of the long-known adaptive reactions is the redistribution of arterial blood in favor of the brain and to the detriment of blood supply to other parts of the body [62-66]. Another link in the adaptation to hypoxia is the availability of oxygen reserves and saving its consumption in the body [67-72]. It has long been noticed that not all blood circulates normally through the blood vessels, since a significant part of it is in the "depot", in particular, in the spleen and other internal organs. The reserve volume of blood is released from the depot and is included in the circulation only in a critical situation. It has also long been known that a decrease in the intensity of physical and mental work performed by the body, as well as a local decrease in the temperature of a selected part of the body, reduce the intensity of consumption of biological energy and oxygen reserves. It has been reported that sleep, as well as complete rest of skeletal muscles, increases the body's resistance to hypoxemia. Often this adaptation is manifested by limb ischemia, with the development of local hypothermia in the distal parts of the limbs [73-75].

It has been shown that in hypoxemia, localized hypothermia begins to form at the fingertips. This phenomenon was described more than 120 years ago as acrocyanosis and was explained by their ischemia [76]. Despite its apparent familiarity, acrocyanosis remains a poorly understood condition. Nevertheless, at the beginning of the 21st century, thanks to the widespread introduction of thermal imaging cameras into medical practice, it was found that acrocyanosis or local hypothermia of the fingers may be a manifestation of an adaptive decrease in blood supply to peripheral parts of the body [77-85]. Moreover, it has been shown that local hypothermia of the fingertips can be considered as a universal pattern not only of limb ischemia, but also of hypoxemia and cerebral hypoxia. The above data allowed inventing several ways to assess the degree of hypoxemia, cerebral hypoxia, human resistance to acute hypoxia, as well as the effectiveness of resuscitation measures under hypoxemic conditions [86-90].

Despite this, by now acrocyanosis is considered a pathologic condition and is an indication for the application of warming treatments [91-95]. Acrocyanosis is reported to be a functional peripheral vascular disease characterized by the development of local hypothermia and a bluish discoloration of the skin and mucous membranes due to decreased oxyhemoglobin.  However, the target temperature for the treatment of hypoxemia and cerebral hypoxia has not been definitively defined [96, 97]. In addition, the antihypoxic efficacy of oxygen and antihypoxants at different body temperatures in humans and animals has not been definitively established. But in recent years there have been reports that hypothermia can enhance the effect of antihypoxants, in particular, the oxygen-producing antihypoxant hydrogen peroxide [38, 98-101].

 

3.1. Targeted control of temperature and intensity of aerobic metabolism in tissues susceptible to hypoxia and ischemia as an unsolved problem of maintaining their viability

 

 

Body temperature is one of the most commonly used indicators of health status in humans. [102-108]. The temperature dynamics of various parts of the body using a thermal imager has been used since the early 1960s. Recent advances in the development of infrared cameras open up new possibilities in medicine [109-116]. The advantage of modern thermal imagers is that they provide high accuracy of non-contact temperature measurement of exposed areas of the body at a distance from the patient [117]. In recent years, it has been found that in many diseases, patients have fever, as the diseases are accompanied by inflammation [118]. At the same time, an increase in temperature is considered a pathology, therefore, it is considered correct in diseases to lower the temperature with the help of antipyretic drugs, in the role of which doctors use nonsteroidal anti-inflammatory drugs (NSAIDs) [119, 120].

However, since ancient times, people have been cooling inflamed areas of the body. Nowadays, it is recommended to use a cooling bag to lower body temperature in case of fever and heat stroke [121]. However, there is still no standard for regulating the body temperature of patients with many diseases, including many critical conditions [122-127]. Specific target temperatures are defined only for patients who are critically unconscious after cardiac arrest [128-133].

Surprisingly, the issue of targeted temperature management (TTM) has not yet been definitively resolved in medicine and pharmacology both in full health and with certain diseases [134-136]. No temperature standards have been set for patients in the intensive care unit (ICU) [137-140]. At the same time, there is no doubt that temperature is an important factor for human life, both in normal and in diseases [141, 142]. However, there are no generally accepted recommendations regarding the "correct" temperature of human organs and tissues for optimal treatment of a particular disease [143]. At the same time, the greatest threat to human life is not so much cardiac arrest, but the hypoxemia and hypoxic brain damage caused by it [7, 11, 37, 38, 46-48, 144-146]. At the same time, it has been known since ancient times that hypothermia (cooling) prolongs the life of biological objects in conditions of oxygen deficiency [106, 147-149]. The first areas of successful application of cold to protect biological objects from hypoxic damage were the extension of the period of preservation of organs and tissues for experimental study of the features of biochemical and biophysical processes occurring in them, as well as for subsequent transplantation into another organism [150-153]. A striking example of the protective effect of hypothermia is the technology that has become standard for preserving suspensions of mitochondria, donated blood, kidneys and heart at low temperatures [154-159]. However, in the treatment of a living person in the event of acute ischemia of any organ (or tissue), the standard of body temperature and the ischemic area has not yet been developed [160-162]. At the same time, it's no secret that the temperature of the human body changes every day, both in normal conditions and in diseases (including organ ischemia), as well as under the influence of medications [7, 11, 24, 33, 37, 39, 48, 77-80, 81, 83, 110, 111, 142, 149, 163]. Earlier it was reported that cooling of organs, tissues and parts of the human body (including during their ischemia) reduces their oxygen demand [164-169]. On the other hand, it has been shown that reducing the delivery of arterial blood to various parts of the body reduces their local temperature [77-84, 170-172]. This was especially evident in the fingers. Since this phenomenon was previously known as acrocyanosis, the development of which was attributed to vascular pathology, local hypothermia was not considered for a long time as an adaptive response to ischemia and hypoxemia [91, 173-176].

In addition, the formation of unambiguous and clear ideas about the correct (therapeutic) temperature of organs and tissues in their ischemia and hypoxia is hindered by reports that cooling of the human body in the cold and hypothermia stimulate aerobic metabolism in the body, which in these conditions is used to activate heat production [177-181]. It has been reported that the human body has a system for maintaining temperature homeostasis that prevents the body temperature from dropping in cold conditions [182, 183]. The ability of humans to generate heat by increasing metabolism in response to low ambient temperatures to maintain a stable body temperature was discovered as 1780 by Antoine Lavoisier and is known as known as cold-induced thermogenesis (CIT) [184-187]. That is why the general hypothermia of a person by placing his whole body in a bath with cold water does not reduce, but increases the intensity of aerobic metabolism and oxygen demand [188, 189]. At the same time, it was shown that during artificial therapeutic general hypothermia, the thermoregulation mechanism in the human body, preventing its cooling, stimulating aerobic metabolism and oxygen demand, can be switched off with the help of hibernator drugs [190].

It has been shown that local hypothermia of many parts of the body (for example, fingers) includes other thermoregulatory mechanisms that are not characteristic of general hypothermia. It has been reported that local hypothermia does not stimulate, but rather inhibits aerobic metabolism and tissue oxygen demand [191, 192]. In all likelihood, the lack of consensus on the correct temperature of tissues during their ischemia and hypoxia is explained by contradictory information about changes in the intensity of aerobic metabolism in conditions of general and local hypothermia. Therefore, we still have to thoroughly study these problems in the future, since the adaptation of organisms and their proteins to extreme conditions is a complex process. Each state has its own set of adaptations that make it uniquely stable in the environment [193]. Inspiring us to look for new and better solutions is that the possibility of hypothermic protection of brain tissue from hypoxic damage remains indisputable [194-197].

3.2. Нypothermia as a factor of intensity of aerobic metabolism, tissue resistance to hypoxia, and effectiveness of antihypoxants

 

Generally accepted ideas about the use of antihypoxants in hypoxia and anti-ischemic drugs in ischemia of organs and tissues are not based on the desired level of their temperature [5, 34, 36, 47, 48, 50]. At the same time, as early as the end of the 20th century, reports appeared in Russia proving that cooling organs and tissues lengthens and heating shortens the period of their viability in conditions of lack of oxygen (hypoxia) and/or arterial blood (ischemia) 191,192,198-200]. In particular, it was reported that in laboratory conditions, lowering the temperature from +37 to +4.0 °C increases, and heating from +37 to +42 °C decrease the viability period of a suspension of isolated myocardial mitochondria, portions of venous donor blood, portions of plasma, isolated ring–shaped segments of pig blood vessels, isolated segments of the myocardium and other organs and tissue of rats. Similar data were obtained in experiments using a model of acute intestinal loop ischemia in outbred dogs, acute hind limb ischemia in outbred white rats, as well as in clinical observations of the limb condition in adults with acute arterial insufficiency resulting from a traffic accident: lowering the temperature of the ischemic area of the body from +37 to +20 ºС prolonged the period of preservation of its viability more than 2 times. At the same time, in people injured in a traffic accident, local cooling of the extremities began not immediately, but several tens of minutes after the injury, because hypothermia was provided only from the moment of admission of the victims to the hospital. To cool the injured limb, the authors covered it with several cooling ice packs and/or wrapped the leg with a rubber hose through which cold tap water was continuously run at +18 to +20 ºC.

Russian researchers explained the protective effect of local hypothermia in ischemia and hypoxia by the fact that lowering the temperature reduces the intensity of aerobic metabolism in the mitochondria of skeletal muscle (and other tissues). Because of this, cooled tissues use oxygen more sparingly, and hypothermia reduces the mismatch between tissue oxygen demand and oxygen delivery to them. In other words, local hypothermia of tissues, organs and/or individual body parts of humans and animals plays the role of a natural antihypoxant.

The identified pattern formed the basis of 2 inventions: «A method for determining indications for reconstructive surgery and amputation in patients with limb ischemia» [201] and «Drug for pharmaco–cold therapy of chronic ischemic lesions of the lower extremities» [202].

A few years later, similar results confirming the anti-ischemic effect of local hypothermia in acute limb ischemia in experimental animals were obtained by researchers in Norway [165, 166].

 After 20 years, researchers from Sweden reported that encasing patients' ischemic limbs with six 4-liter plastic bags filled with snow increased survival of limb skeletal muscle in acute arterial insufficiency [168].

At the same time, researchers in Russia reported for the first time that the oxygen-producing antihypoxant hydrogen peroxide, administered at a therapeutic dose to water in which aquarium fish were swimming, increased the duration of their viability period inside a hermetically sealed container at different water temperatures. At the same time, lowering the temperature of water with fish potentiated the antihypoxic effect of hydrogen peroxide and lengthened the duration of the period of fish viability under conditions of cessation of air supply to the water with fish [98-101]. In other words, in experiments with aquarium fish, which are cold-blooded animals, it has been shown that general hypothermia increases the effectiveness of the antihypoxic action of hydrogen peroxide.

The discovered pattern was the basis for the invention of the «Method of maintenance of live fish during transportation and storage» [203]. 

Due to the results obtained in studies of fish resistance to general hypoxia under different temperature regimes, researchers in Russia proposed to study the role of hypothermia and anihypoxants not on warm-blooded animals, but on cold-blooded animals, in particular, on aquarium fish [38]. The point is that general hypothermia in warm-blooded animals is counteracted by the system of maintaining temperature homeostasis of their organism, which forces the organism of warm-blooded animals and humans to increase the intensity of heat dissipation due to intensification of aerobic metabolism. And this increases the intensity of oxygen consumption and provokes hypoxia. In this regard, the system of maintaining temperature homeostasis of warm-blooded animals and humans deprives global hypothermia of the potential for antihypoxic activity.

To date, the mechanism of action of the hydrogen peroxide solution, which underlies the antihypoxic activity of this drug, has been clarified [204-216]. It has been shown that many human and animal tissues contain catalase, which breaks down hydrogen peroxide into water and molecular oxygen. In this regard, it was proposed to convert hydrogen peroxide from antiseptics to oxygen-producing antihypoxant [215-218]. Moreover, the revealed mechanism of the antihypoxic activity of the hydrogen peroxide solution was enhanced due to the additional dissolution of oxygen gas in it under an excess pressure of 0.2 – 0.3 atm. This proposal formed the basis of such inventions as «Warm alkaline solution of hydrogen peroxide for intrapulmonary injection» and “Oxygenated warm alkaline solution of hydrogen peroxide for intrapulmonary injection” [219, 220].

Oxygen-carbonated solutions of hydrogen peroxide invented in Russia turned out to be the first oxygen-producing antihypoxants intended for intrapulmonary injection with the aim of immediate oxygenation of blood through the lungs. Thanks to these inventions, Russian researchers have been able to expand the generally accepted list of injections of medicinal solutions to include intrapulmonary injections.

By now, there is no doubt that therapeutic general (global) hypothermia of the human body can effectively prolong its life in case of cardiac arrest by protecting the brain from hypoxic damage [221]. However, the systemic side effects of general hypothermia significantly limit the clinical use of global hypothermia [222, 223]. Therefore, in order to reduce the systemic side effects caused by global hypothermia, global hypothermia began to be replaced by local hypothermia of the brain worldwide at the beginning of the 21st century [224-233]. In recent years, a method of cooling the brain using a transnasal flow of cold air has been used to cool the brain [234-236]. But brain resistance to hypoxia with the involvement of different factors continues to be studied  [237-240].

 

3.3. Local hypothermia as a quencher of "biological combustion" in mitochondria

 

The intensity of human air consumption ultimately reflects the intensity of oxygen consumption by mitochondria, since oxygen is the most consumed ingredient in inhaled air, and mitochondria are the main consumers of oxygen: up to 98% of oxygen entering the body is consumed in mitochondrial respiration [59, 60]. The basic ideas about the relationship between oxygen consumption in mitochondria and adaptation to stress were laid down more than half a century ago by Britton Chance, Maria Kondrashova and Ludmila Lukyanova [59, 60, 241-248]. The research of the founders of mitochondrial biophysics was mainly aimed at exploring the possibilities of activating rather than inhibiting mitochondrial oxygen use. Therefore, the results of their work fit well into high-speed mechanisms of adaptation to stress and temperature rise in humans and warm-blooded animals under the conditions of global exposure to cold. Their work was not aimed at increasing the resistance of mitochondria, cells and tissues to hypoxic damage. The fact is that these researchers did not aim to explain the antihypoxic effect of local hypothermia.

 However, we see that in laboratory studies, these and other researchers used local hypothermia to improve the preservation of isolated mitochondria: the process of isolating isolated mitochondria from organs and tissues was carried out under conditions of local hypothermia, namely at a temperature of 0 - +4 ° C. At the same time, they all proceeded from the fact that lowering the temperature of the mitochondrial suspension below +37 ° C progressively inhibits the process of biological combustion in them and increases the period of preservation of the viability of isolated mitochondria in conditions when the suspension rich in them was not saturated with oxygen.

In other words, in experiments conducted with isolated organs, tissues, and mitochondria in vitro, the founders of mitochondriology used local hypothermia as a very reliable antihypoxant!.

At the same time, their experiments showed that the subsequent increase in the temperature of the cold suspension in which isolated mitochondria were stored to the body temperature of warm-blooded animals immediately activates the process of "biological combustion" in them. Stimulation of biological combustion in mitochondria leads to a very rapid consumption of all oxygen dissolved in the suspension of mitochondria, after which the mitochondria die from hypoxic damage.

On the other hand, it has long been known about the successful long-term storage of erythrocytes and leukocytes in a portion of donated blood due to a combination of preservatives and cold. It should be added that several years ago this combination was successfully upgraded due to the fact that hydrogen peroxide was introduced into it. Russian inventors received a patent for the invention “Soikher's hyperoxygenated agent for venous oxygen saturation” [249].

In recent years, there has been a growing interest in research aimed at increasing the resistance of the brain to hypoxia through local hypothermia of the brain [47-50, 135, 136, 195-197, 228, 236].  It is reported that local hypothermia of the brain is by far the most powerful antihypoxant (neuroprotector). However, timely and safe delivery of localized hypothermia to the brain remains an unsolved clinical challenge. A special cooling helmet is proposed to facilitate this task [250]. The difficulty in targeting brain cooling in a patient using a cooling helmet is due to the fact that direct cooling of the head surface in an adult reduces brain temperature by approximately 0.12 °C after 60 min of hypothermia [251]. Previously, a medical cooling pack was used for local hypothermia of various body parts. However, it has been shown that it can reliably cool only superficial tissues, as local hyperthermia develops in deeper tissues [252].  In this regard, urgent effective selective reduction of local brain temperature in patients remains an unattainable task in the clinic. Therefore, the search for any other ways to protect the brain from hypoxic damage remains relevant.

At the same time, in 2016, a patent for the invention "Lympho-subsitute for local maintaining viability of organs and tissues in hypoxia and ischemia" was published in Russia (RU 2586292) [253]. Unfortunately, researchers around the world have not paid due attention to the cold solution of oxygen-producing antihypoxant for injection invented in Russia. The essence of this invention is that, for the first time, a cold solution of an oxygen-producing antihypoxant designed to be injected “in the right place” to immediately cool and provide a selected area of tissue with oxygen under conditions of hypoxia and/or ischemia in lieu of arterial blood has been invented. For this purpose, the invented solution included 0.88% sodium chloride, 0.06 - 0.1% glucose and 0.01- 0.02% hydrogen peroxide at pH 7.4 and osmotic activity of 280 mosmol/L water. An important distinguishing feature of the invented blood substitute was that the solution of oxygen-producing antihypoxant was not heated to a temperature of +37 ºC. Such a solution, like all other drug solutions, was room temperature, that is, it was cold.  On the one hand, this solution replaces arterial blood, so when injected directly into tissue (including brain tissue), this solution supplies it with oxygen because of the immediate catalase breakdown of hydrogen peroxide into water and molecular oxygen. On the other hand, this solution replaces the refrigerating agent, as the solution is not heated and is administered cold, usually at room temperature, i.e. at +24 - +26 ºC. Therefore, when injected into the tissue, the cold solution immediately lowers the tissue temperature from +37 ºC to +24 ºC, and sometimes even below this level. As a result of injection, the solution provides prolongation of tissue viability under conditions of hypoxia and ischemia.

Consequently, one of the ways to increase brain resistance to hypoxic damage is to develop a combination of local hypothermia with oxygen-producing antihypoxants. The rationale for the prospectivity of this line of research is the experience of successful storage of living isolated mitochondria, leukocytes and erythrocytes, as well as aquarium fish under conditions of limited oxygen content by lowering their temperature and introducing hydrogen peroxide. However, to date, there are insufficient data to draw a definitive conclusion about the unconditional efficacy of therapeutic hypothermia combined with hydrogen peroxide.

  1. Conclusion

Hypoxic brain cell damage that develops in patients minutes after the development of severe critical conditions associated with asphyxia and asphyxiation, including COVID-19, remains a heavy public health burden in many countries, including the USA. The development of ARDS in people around the world and the lack of available drugs and ways to urgently oxygenate blood through the lungs has forced scientists to search for and invent new anti-hypoxic drugs and ways to immediately cool the brain. Studying the possibilities of using catalase of various tissues as a new target during local application of aqueous solutions of hydrogen peroxide, which can be converted into water and molecular oxygen “in the right place” due to catalase cleavage, may open new opportunities for increasing the viability of mitochondria of any tissues, including the brain. In addition, there is hope for the rapid development of a method of selective local hypothermia of the brain, capable of lowering its temperature by several degrees in a few seconds. Since local hypothermia is an unrivaled way to conserve mitochondria during oxygen deprivation, and hydrogen peroxide is the leader among oxygen-producing antihypoxants, the modernization of injecting cold hydrogen peroxide solutions into the brain may provide in the future immediate cooling of the brain while providing oxygen. However, we are only at the very beginning of this journey. The fact is that selective hypothermic extinguishing of mitochondrial burning while preserving the process of oxidative phosphorylation of ADP inside the cells of organs and tissues of warm-blooded animals under hypoxia conditions still remains insufficiently studied.

Author contributions. All authors confirm that their authorship meets the ICMJE international criteria (all authors contributed substantially to the conceptualization, research and preparation of the article, read and approved the final version before publication).

Conflict of interest. The authors declare that they have no apparent and potential conflicts of interest related to the publication of this article.

Funding source. The authors state that there was no external funding in the conduct of the study.

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About the authors

Natalya A. Urakova

Izhevsk State Medical Academy

Email: urakovanatal@mail.ru
ORCID iD: 0000-0002-4233-9550
SPIN-code: 4858-1896

Cand. Sci. (Medicine), Assistant Professor

Russian Federation, Izhevsk, Kommunarov street, 281. Russia, 426034

Aleksandr L. Urakov

Izhevsk State Medical Academy, Izhevsk

Author for correspondence.
Email: alurakova@bk.ru
ORCID iD: 0000-0002-9829-9463

Dr. Sci. (Med.), Professor, Head of the Department

Russian Federation

Alexey P. Reshetnikov

Dental Clinic ReSto

Email: areshetnikov@list.ru
ORCID iD: 0000-0002-8710-9724
SPIN-code: 4115-4167
Russian Federation

Lubov V. Fedoseeva

Izhevsk State Medical Academy

Email: lvlfedoseeva@yandex.ru
ORCID iD: 0009-0003-7472-2153

Senior Lecturer at the Department of General and Clinical Pharmacology

Russian Federation

Evgeniy L. Fisher

Email: ELFischer@mail.ru
ORCID iD: 0000-0001-7319-9872
Russian Federation

Albina A. Shchemeleva

Email: Redbild@mail.ru
ORCID iD: 0000-0001-7771-8772
Russian Federation

Alexey A. Korepanov

Email: iamkorepanov@gmail.com
ORCID iD: 0009-0009-3245-2750
Russian Federation

Anastasiya A. Burkova

Email: anasteziamestnaya3000@gmail.com
ORCID iD: 0009-0004-0507-6335

Sofia A. Bondarenko

Email: bondarenkosophia0606@gmail.com
ORCID iD: 0009-0000-4256-1680

Kristina V. Mikryukova

Email: mikryukovakristina98@gmail.com
ORCID iD: 0009-0003-1121-8806

Elina A. Aslyamova

Email: alsuminullina57@gmail.com
ORCID iD: 0009-0001-2444-3047

Ilshat I Habibullin

Email: burkova.anastescha@yandex.ru
ORCID iD: 0009-0005-0845-8723

Margarita A. Lisovskaya

Email: l1sOvska@mail.ru
ORCID iD: 0009-0001-8876-769X

Elizaveta Yu. Matrosova

Email: eliza83245@gmail.com
ORCID iD: 0009-0000-5381-3812

Ilya P. Kolesnikov

Email: ilyabatur@mail.ru
ORCID iD: 0009-0002-9432-0939

Elvira I. Nazimova

Email: Elvira-nizamova-2000@mail.ru
ORCID iD: 0009-0003-2527-8615

Petr D. Shabanov

Institute of Experimental Medicine; Kirov Military Medical Academy

Email: pdshabanov@mail.ru
ORCID iD: 0000-0003-1464-1127
SPIN-code: 8974-7477

MD, Dr. Sci. (Medicine), Professor

Russian Federation, 12, Akademika Pavlova st., Saint Petersburg, 197022; 6, Akademika Lebedeva st., Saint Petersburg, 194044

References

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