On the possibility of using hyperbaric oxygenation in the treatment of sars-cov-2 infected patients

The article substantiates the feasibility of including Hyperbaric Oxygenation (HBO) in the treatment of patients infected with SARS-CoV-2. Possible mechanisms of therapeutic infl uence of hyperbaric oxygen on the course of the pathological process in the body of patients infected with SARS-CoV-2 are considered. The role of urea as a non-specifi c antioxidant adaptogen in the mechanisms of the therapeutic effect of HBO is considered. The important role of assessing the patient's condition at the time of oxygenation for the correct choice of modes and the number of HBO sessions is shown. It is concluded that it is appropriate to include in the therapy of SARS-CoV-2 infected patients with "soft" HBO regimens (1.3-2.0 ATA, isopression time 45-90 min), regardless of the degree and duration of hypoxemia. Against the background of the pandemic of a new coronavirus infection caused by SARS-CoV-2, which has engulfed our planet, the lack of an effective etiotropic method of treatment for this pathology has predetermined a high mortality rate among those infected. One of the leading causes in the pathogenesis of this infectious disease is the development of hypoxia in the patient's body. The formation of this pathological process in an organism infected with SARSCoV-2 follows several mechanisms. First, as a result of the development of an infl ammatory process in the lung tissue, leading to a violation of the diffusion of oxygen through the alveolocapillary membrane. Secondly, due to a violation of the oxygen transport function of hemoglobin, caused by exposure to viral proteins. Thirdly, it is a violation of microcirculation due to the formation of microthrombi in the capillaries. The combination of these factors explains the low effectiveness of normobaric oxygen therapy, including invasive lung’s ventilation, used for hypoxemia caused by COVID-associated pneumonia. Meanwhile, in the world of medical science, there has long been a method for effective treatment of severe hypoxic conditions, including those caused by pulmonary pathology. This is hyperbaric oxygenation (HBO), i.e. treatment with oxygen under high pressure. Why has there not been a proper place in the treatment of SARS-CoV-2 coronavirus infection? This is due to the fact that most doctors have an idea about the toxicity of high concentrations of oxygen to the cell [1,2], which is refl ected in the latest European Handbook to hyperbaric medicine [3]. This does not take into account the fact that in many studies, the ability of hyperbaric oxygen to activate free radical processes and lipid peroxidation, Deplete the body's antioxidant system, was found in HBO modes not used in the clinic [4,5]. This concerns the inadequacy of the time chosen by researchers to safely fi nd the body in hyperoxia, which negatively affects the antioxidant system of the lungs [6]. Experiments have shown that the use of HBO in a therapeutic mode (2 hours, 50 minutes), daily for 18 days does not cause depletion of the enzyme and metabolic links of the antioxidant system in the lungs of rats [7]. Similar data were obtained in the study of phylogenetically dissimilar structures of the rat brain after the course use of HBO in a similar mode [8]. It was found that a single application of HBO in a therapeutic mode (1.5 ATA, 60 min) signifi cantly increases the stability of the pulmonary alveoli, regardless of the age of the animal [10]. However, the research of P. I. Koshelev, et al. [9], which studied the infl uence of various modes of HBO course application on the structural organization of lung tissue in rabbits with experimental abscess, is of particular interest. The animals received a course of 8-13 sessions of HBO in the mode 2 ATA, 45 min. The difference was only in the number

Against the background of the pandemic of a new coronavirus infection caused by SARS-CoV-2, which has engulfed our planet, the lack of an effective etiotropic method of treatment for this pathology has predetermined a high mortality rate among those infected. One of the leading causes in the pathogenesis of this infectious disease is the development of hypoxia in the patient's body. The formation of this pathological process in an organism infected with SARS-CoV-2 follows several mechanisms. First, as a result of the development of an infl ammatory process in the lung tissue, leading to a violation of the diffusion of oxygen through the alveolocapillary membrane. Secondly, due to a violation of the oxygen transport function of hemoglobin, caused by exposure to viral proteins. Thirdly, it is a violation of microcirculation due to the formation of microthrombi in the capillaries. The combination of these factors explains the low effectiveness of normobaric oxygen therapy, including invasive lung's ventilation, used for hypoxemia caused by COVID-associated pneumonia.
Meanwhile, in the world of medical science, there has long been a method for effective treatment of severe hypoxic conditions, including those caused by pulmonary pathology. This is hyperbaric oxygenation (HBO), i.e. treatment with oxygen under high pressure. Why has there not been a proper place in the treatment of SARS-CoV-2 coronavirus infection? This is due to the fact that most doctors have an idea about the toxicity of high concentrations of oxygen to the cell [1,2], which is refl ected in the latest European Handbook to hyperbaric medicine [3]. This does not take into account the fact that in many studies, the ability of hyperbaric oxygen to activate free radical processes and lipid peroxidation, Deplete the body's antioxidant system, was found in HBO modes not used in the clinic [4,5]. This concerns the inadequacy of the time chosen by researchers to safely fi nd the body in hyperoxia, which negatively affects the antioxidant system of the lungs [6].
Experiments have shown that the use of HBO in a therapeutic mode (2 hours, 50 minutes), daily for 18 days does not cause depletion of the enzyme and metabolic links of the antioxidant system in the lungs of rats [7]. Similar data were obtained in the study of phylogenetically dissimilar structures of the rat brain after the course use of HBO in a similar mode [8]. It was found that a single application of HBO in a therapeutic mode (1.5 ATA, 60 min) signifi cantly increases the stability of the pulmonary alveoli, regardless of the age of the animal [10]. However, the research of P. I. Koshelev, et al. [9], which studied the infl uence of various modes of HBO course application on the structural organization of lung tissue in rabbits with experimental abscess, is of particular interest. of daily sessions: in the fi rst group-once a day, in the second group 2 times a day, in the third group-3 times a day. All the animals underwent HBO sessions satisfactorily. However, morphological research has established, hat the optimal mode that does not lead to destructive changes in the healthy part of the lung against the background of a pronounced therapeutic effect of HBO in the affected area of the lung is a course of 8 sessions of HBO in the mode of 2 hours, 30-45 minutes, 1 session per day. In other cases, HBO had a destructive effect on the lung tissue, the degree of which was directly dependent on the number of HBO sessions [9]. Experimental studies served as the basis for the successful use of HBO by Soviet doctors in patients with suppurative lung pathology [11][12][13]. Later it was shown that the addition of HBO (2.5). 90 min, twice a day, the average number of HBO sessions was (23 ± 11)  We should immediately note that the inclusion of HBO in the therapy of SARS-CoV-2 infected patients solely as a means of eliminating hypoxemia initially narrows our understanding of the possibilities of hyperbaric oxygen in this pathology. The fact is that hyperbaric oxygen, used for therapeutic purposes in conditions of pathology, acts not so much as an antihypoxic factor, but as an adaptogenic regulator of metabolic processes occurring in the patient's body [18]. At the same time, the mechanisms of adaptation to hyperoxia, fi xed in the process of evolution, are triggered, which is manifested by an increase in the sanogenic potential of the sick organism, leading to its recovery [18]. Due to this, the therapeutic effect of HBO is preserved in the post-hyperoxic period even in the conditions of " reversion " of hypoxia [19][20][21].
According to Leonov's doctrine of hyperoxic sanogenesis [22], oxygen, appearing millions of years ago in the atmosphere, acted as a pathogen for anaerobic life forms that existed at that reduces their permeability to lysosomal enzymes [28], thereby preventing cell autolysis. This is especially important in the post-hyperoxic period, when there may be a " reversion " of hypoxia. By inhibiting radical formation on iron-containing blood proteins, urea simultaneously increases its antioxidant potential [29]. Forming a complex compound with heparin, urea prolongs the physiological action of the latter [30].
f we add to this the ability of HBO to disaggregate platelets in experimental DIC-syndrom [31], there is every reason to expect a similar effect of HBO when it is included in the therapy of SARS-CoV-2 -infected patients, given the high risk of developing thrombotic complications in them. In mammals, urea is easily converted from a free state to a protein-and lipoprotein-bound state [27], which is activated in hyperoxia [28]. Therefore, it cannot be excluded that activation of this process by hyperbaric oxygen in epithelial cells, including pneumocytes, which are targets of SARS-CoV-2, will lead to certain changes in the physical and chemical properties of their membranes. This will manifest itself as an inhibition of exocytosis of the virus inside the cell, and a change in the conformation of the receptors located on its surface, which will lead to a decrease in their affi nity for the S1 SARS-CoV-2 spike Third, we should not discount the ability of hyperbaric oxygen to stimulate the t-cell link of the immune system, both by directly affecting the functional activity of lymphocytes [33] and by stimulating their formation [34]. The latter is important in the conditions of lymphopenia that develops with COVID infection. The experiment demonstrated the ability of HBO to increase the survival rate of mice with experimental tick-borne encephalitis [35].
The ability of HBO to change the pharmacodynamics and pharmacokinetics of drugs [36] does not exclude a reduction in the background of HBO therapy of side effects of antiviral drugs used in the treatment of COVID-19, as well as an increase in their antiviral action. It cannot be excluded that conformational changes in the hemoglobin molecule observed in HBO [22] will interfere with the effect of viral proteins on it, and adaptive morphogenetic changes occurring in the erythrocyte membrane in HBO [22] will determine the decrease in its permeability to the virus. The ability of HBO to increase the breadth of therapeutic action of antibiotics [37], have a bacteriostatic effect on Staphylococcus aureus, Proteus [38], increase the sensitivity of microbes to antibiotics and reduce the seeding of pathogenic microfl ora from the blood [39] this makes it possible to use HBO in the case of bacterial infection in patients with COVID-associated pneumonia.
Based on the above, we can conclude that it is appropriate to include in SARS-CoV-2 therapy infected patients in "soft" HBO regimens (in 1.6-2.0 ATA, isopression time 45-90 min), infection regardless of the degree and duration of hypoxemia. The latter should be taken into account only when choosing the atmospheric pressure of the pressure chamber and the time of isopression. The fact is that hyperoxia (as well as hypoxia) stimulates free radical processes in the body, which activate all three links of antioxidant protection, formed and fi xed in the process of evolutionary transformation of the atmosphere from an oxygen-free to an oxygen environment [22]. Therefore, the more severe hypoxemia, and therefore tissue hypoxia, at the time of oxygenation, the more likely the risk of depletion of one or all of the links of this system. This is especially important for patients with comorbidities (diabetes, heart failure), who already have "problems" with the body's antioxidant system. Therefore, the use in these conditions, automatic in "hard" mode or "soft", but a long time isopress (90 min), as well as unjustifi ed increase in the number of HBO sessions creates the risk of negative effects of hyperoxia on the patient's body.
In the end, this will lead to discrediting HBO as one of the components of COVID-associated pneumonia therapy. To avoid this, the use of HBO should occur only when the patient's body is "ready to perceive hyperbaric oxygen as a therapeutic factor" [16]. This implies an important role period before the beginning of HBO as in the assessment of the patient's condition at the moment of oxygenation in order to select modes HBO, as well as the decision on the use of oxygenated patients with prescribed medications and (or) medical procedures before or after hyperoxic exposure.