4. Discussion
critically ill, non-septic, hypoxia, MOF, organ damage, septic shock, sepsis, septic
PCT, SARS-COV-2 INFECTION, CRITICALLY ILL, HYPOXIA, MOF, DYSFUNCTION, SEPTIC SHOCK, SEPSIS, PATHOGENESIS, INFLAMMATORY RESPONSE
The participation of OS in septic shock and MOF has been previously reported [In this study, we found that patients with septic shock had a high SOFA score on admission to the ICU. They had high PCT and CRP levels, elevated LPO and carbonylation, and decreased TAC. These variables were compensated by the treatment with antioxidants.The patients who received treatment with vitamin C and vitamin E had a decrease in LPO levels and although the difference did not reach a statistical significance, we can interpret that there is a tendency of six to seven times greater decrease with the use of this therapy. Our findings resemble those previously reported in an animal model where Vit C decreased LPO [Vit C is an enzymatic cofactor with an antioxidant function derived from its ability to act as an electron donor. It reduces LPO and carbonylation, OIn addition, LPO was blocked by Vit E treatment in our series of patients. This vitamin binds to the cell membrane and decreases the polyunsaturated fatty acid oxidation due to its lipophilic characteristics. The oxidation of these fatty acids is increased in proinflammatory states. Therefore, supplementation with this vitamin in patients with sepsis may modulate the excessive inflammatory response coordinated by macrophages [Protein oxidation can be estimated by carbonylation, which results from the direct oxidation of amino acid side chains and from oxidative cleavage of protein. Carbonyls are difficult to induce and therefore may indicate a more severe state of OS [At present, there are still controversies regarding the complementary use of Vit C in the general therapy of patients with septic shock. In a systematic review with a meta-analysis that included 16 randomized clinical trials, it was concluded that Vit C does not help improve clinical outcomes in patients [In the group treated with Vit C, the levels of ecSOD were decreased. This effect may be due to the fact that this enzyme regulates the ORegarding the findings associated with the clinical part, the use of Vit C did not decrease the number of days of hospital stay, but its use was related to a lower percentage of the employment of inotropes and invasive mechanical ventilation, which was observed in all patients that received antioxidant therapy. In the treated groups, the percentage of inotropic use was 15.6% and mechanical ventilation was necessary in 11%, while in the untreated groups, it was of 31% and 19%, respectively. However, the difference did not reach a statistical significance.A more recent meta-analysis reported that Vit C showed no evident clinical improvement and therefore effectiveness of the therapy was not recommended [One of the main objectives to be evaluated in this study was whether the use of antioxidants decreased organ damage. We found that with the early use of Vit C, patients had a decrease in organ damage measured through the SOFA score and that this occurred since the beginning (first day of therapy with this antioxidant), showing a 37.5% reduction. On the fifth day, the decrease reached 63%. This finding confirmed the effects seen in a previous study, in which a decrease in the SOFA score in patients who received MT and Vit C was observed in a smaller number of patients [In this study, this same effect was achieved with the use of NAC, which also reduces mortality [Other antioxidants such as MT could also be useful in patients with septic shock. We have found that it reduces the SOFA score and the LPO in SARS-CoV-2 infection. The reproducibility of the findings reinforces what was recently published in a pilot group, where evidence of its effect on reducing organ damage was found [In in vitro and in vivo studies, MT scavenges ROS, thus protecting cell membrane lipids, cytosol proteins, and nuclear and mitochondrial DNA. It preserves the permeability of the membrane, increasing its fluidity [In this study, we found that in patients treated with MT, the Se levels were maintained, ecSOD was decreased, and TAC and GPx were increased. Therefore, it is feasible that the therapeutic effect on other enzymes such as the one observed in the decrease in ecSOD may be beneficial to control the OS in sepsis.On the other hand, Se is used by GPx as cofactor and is decreased in septic shock [The possible benefits of therapy with trace elements such as Se, Cu, Zn and Mn in critically ill patients have been investigated without clear results. With the results obtained in this study, Se levels are maintained, which supports the role of this metal in the regulation of OS. Multiple studies have evaluated the effect of Se supplementation in critically ill patients. However, there are still controversies regarding the path of administration (enteral vs. parenteral), the dose (high vs. low), the use of loading doses, the selection of patients (septic vs. non-septic) and the supplementation of other antioxidants (mono therapy vs. cocktails), [On the other hand, the study of thiols in this series of patients was included since thiols are molecules that contain a hydrogen sulfide group in the side chain (SH) which may act as an antioxidant by stabilizing and reducing the bridge between proteins caused by free radicals by accepting an unpaired electron. This process is also regulated by TxrR, another selenoenzyme which was decreased in these patients. However, the antioxidant therapy increased the activity of this enzyme. Our results suggest that the increase in thiols can participate with a synergic effect with the Vit E and decrease the OS damage mechanism on protein carbonylation in patients with septic shock. Vit E and thiols may act together preventing and blocking LPO, carbonylation and increasing TAC [This study confirms the effect of antioxidants on the reduction of MOF measured by the SOFA score, which occurs from the second day of treatment on. Studies to follow should consider an adequate evaluation of the nutritional status and the participation of OS, and its consequences such as cytopathic hypoxia. This condition could explain the failure of different strategies used in the clinical management of septic shock, since when the mitochondrial machinery is blocked, many therapies result in unsuccessful efforts aimed at improving tissue oxygenation by increasing systemic oxygen supply and/or optimizing cardiovascular function.Specific pharmacological treatments to modulate or block components of the inflammatory process have not achieved the expected success. The participation of OS in the pathways of damage in patients with septic shock constitutes a solid foundation to propose an adjuvant antioxidant therapy for sepsis and septic shock. This therapy may improve these conditions by regulating enzymatic and non-enzymatic pathways as previously observed in animal models. Studies are needed to substantiate the interaction and participation of nitrosative stress, OS and the interaction of cytokines in the pathogenesis of sepsis. Nevertheless, the antioxidant therapy modulates the over-synthesis of NO and nitrosative stress, reducing organic dysfunction.These results raise new expectations for antioxidant treatment in MOF caused by sepsis. There are still gaps that need to be solved and these constitute areas of opportunity to explore in the future. The exact doses, the time of use and synergistic effects of combined use of several simultaneous antioxidants still remain unexplored.