Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects.

Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1ß, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFß), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO3- and NO2-), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls (p = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects.

Antioxidants and pentoxifylline as coadjuvant measures to standard therapy to improve prognosis of patients with pneumonia by COVID-19.

The type 2 coronavirus causes severe acute respiratory syndrome (SARS-CoV-2) and produces pneumonia with pulmonary alveolar collapse. In some cases it also causes sepsis and septic shock. There is no specific treatment for coronavirus disease 2019 (COVID-19). Vitamin C (Vit C), Vitamin E (Vit E), N-acetylcysteine (NAC) and Melatonin (MT) increase the intracellular content of GSH, kidnap free radicals and protect DNA, proteins in the cytosol and lipids in cell membranes. Pentoxifylline (Px) has anti-inflammatory activities. Here we evaluate the effect of Vit C, Vit E, NAC, and MT plus Px in COVID-19 patients with moderate and severe pneumonia. 110 patients of either sex were included. They were divided into five groups with 22 patients each. Group 1 received Vit C + Px, group 2 Vit E + Px, group 3 NAC + Px, group 4 MT + Px, and group 5 only Px. Oxidative stress (OS) markers such as lipid peroxidation (LPO) levels, total antioxidant capacity (TAC) and nitrites (NO2 -) were evaluated in plasma. The antioxidant therapy improved the survival scores including the Sequential Organ Failure Assessment (SOFA), the Acute Physiology and chronic Health Evaluation II (Apache II), the Simplified Acute Physiology Score II (SAPS II), the Critical Illness Risk Score, Launched during COVID-19 crisis (COVIDGRAM) and the Glasgow Coma Scale (GCS). We found that LPO (p≤0.04) and inflammation markers such as interleukin-6 (IL-6, p≤ 0.01), C reactive protein (CRP, p ≤ 0.01) and procalcitonin (PCT, p ≤ 0.05) were elevated. TAC (p ≤ 0.03) and NO2 - (p ≤ 0.04) found themselves diminished in diminished in COVID-19 patients upon admission to the hospital. The different antioxidants reversed this alteration at the end of the treatment. The treatment with antioxidant supplements such as Vit C, E, NAC, and MT plus Px could decelerate the aggressive and lethal development of COVID-19. Antioxidant therapy can be effective in this pandemia since it improves the survival scores including SOFA, Apache II, SAPS II, COVIDGRAM, GCS by lowering the LPO, IL-6, CRP, PCT and increasing systemic TAC and NO2 -.

Alteration in the Lipid Profile and the Desaturases Activity in Patients With Severe Pneumonia by SARS-CoV-2.

The kidnapping of the lipid metabolism of the host's cells by severe acute respiratory syndrome (SARS-CoV-2) allows the virus to transform the cells into optimal machines for its assembly and replication. Here we evaluated changes in the fatty acid (FA) profile and the participation of the activity of the desaturases, in plasma of patients with severe pneumonia by SARS-CoV-2. We found that SARS-CoV-2 alters the FA metabolism in the cells of the host. Changes are characterized by variations in the desaturases that lead to a decrease in total fatty acid (TFA), phospholipids (PL) and non-esterified fatty acids (NEFAs). These alterations include a decrease in palmitic and stearic acids (p ≤ 0.009) which could be used for the formation of the viral membranes and for the reparation of the host's own membrane. There is also an increase in oleic acid (OA; p = 0.001) which could modulate the inflammatory process, the cytokine release, apoptosis, necrosis, oxidative stress (OS). An increase in linoleic acid (LA) in TFA (p = 0.03) and a decreased in PL (p = 0.001) was also present. They result from damage of the internal mitochondrial membrane. The arachidonic acid (AA) percentage was elevated (p = 0.02) in the TFA and this can be participated in the inflammatory process. EPA was decreased (p = 0.001) and this may decrease of pro-resolving mediators with increase in the inflammatory process. The total of NEFAs (p = 0.03), PL (p = 0.001), cholesterol, HDL and LDL were decreased, and triglycerides were increased in plasma of the COVID-19 patients. Therefore, SARS-CoV-2 alters the FA metabolism, the changes are characterized by alterations in the desaturases that lead to variations in the TFA, PL, and NEFAs profiles. These changes may favor the replication of the virus but, at the same time, they are part of the defense system provided by the host cell metabolism in its eagerness to repair damage caused by the virus to cell membranes.

Asociación de marcadores inflamatorios en COVID-19 severo al ingreso con mortalidad y disfunción orgánica / Association of severe COVID-19 inflammatory markers at hospitalization with mortality and organic dysfunction / Associação de marcadores inflamatórios em COVID-19 grave na admissão com mortalidade e disfunção orgânica

Resumen: Introducción: se ha demostrado que los niveles iniciales de marcadores inflamatorios involucrados en COVID-19 (ej. ferritina, proteína C reactiva, procalcitonina, dímero D e interleucina-6) se relacionan con la mortalidad, sin encontrar resultados similares en pacientes con COVID-19 severo o quienes se encuentran bajo ventilación mecánica invasiva. Objetivo: determinar el nivel sérico con mayor sensibilidad y especificidad en los marcadores inflamatorios con relación a la mortalidad y gravedad de la disfunción orgánica en pacientes con COVID-19 severo usuarios de ventilación mecánica invasiva en las primeras 48 horas tras el ingreso hospitalario. Material y métodos: se realizó un estudio descriptivo de tipo cohorte retrospectiva y longitudinal en pacientes con diagnóstico de COVID-19 severo que fueran intubados antes de 48 horas tras el ingreso hospitalario por falla respiratoria aguda de enero de 2021 a agosto de 2021. Se determinó la relación entre los niveles de estos marcadores con las escalas pronósticas (SOFA, APACHE-II y SAPS-II), días de estancia hospitalaria, días en la Unidad de Terapia Intensiva Respiratoria, días de ventilación mecánica invasiva y las características de la mecánica ventilatoria inicial. Se agruparon los marcadores en niveles elevados y bajos para determinar su papel individual y en conjunto con los desenlaces. Resultados: se estudió una N = 218, con predominio de género masculino (77.5%) con media de edad de 60.3 ± 12.8 años. La hipertensión arterial sistémica y la diabetes mellitus tipo 2 fueron las comorbilidades más prevalentes (50.5% y 26.1%, respectivamente). La mediana de la relación PaO2/FiO2 fue de 128 mmHg (83.3-204.2), con una mortalidad total de 24.8%. Los niveles de biomarcadores con mayor sensibilidad para mortalidad y disfunción orgánica fueron: proteína C reactiva: ≥ 16 mg/dL, procalcitonina: ≥ 0.83 ng/mL, dímero D: ≥ 1,290 ng/mL, ferritina: ≥ 1,450 ng/mL e interleucina-6: ≥ 195 pg/mL. La procalcitonina y la interleucina-6 de manera aislada demostraron mayor riesgo de mortalidad y peor disfunción orgánica. Los marcadores inflamatorios se relacionaron a peor desenlace con respecto a las características del sistema respiratorio y el grado de alteración en gases arteriales. De forma conjunta (≥ 3 altos), los marcadores inflamatorios se relacionaron a mayor número de días de estancia hospitalaria, días en la Unidad de Terapia Intensiva Respiratoria y de días de ventilación mecánica invasiva. La proteína C reactiva, procalcitonina e interleucina-6 se asociaron a mayor riesgo de peor grado de disfunción orgánica por SOFA y peor pronóstico por APACHE-II y SAPS-II. Conclusión: la medición individual y conjunta de marcadores inflamatorios al ingreso hospitalario puede identificar a pacientes con mayor riesgo de estancia hospitalaria prolongada, así como ventilación mecánica invasiva, con mayor riesgo de mortalidad en el caso de procalcitonina e interleucina-6.

Abstract: Introduction: it has being demonstrated that the initial levels of inflammatory markers involved in COVID-19 (eg. C-reactive protein, procalcitonin, D-dimer, ferritin and interleukine-6) have an association with mortality, in different degree on severe COVID-19 patients or in those on invasive mechanical ventilation secondary to COVID-19 related acute respiratory distress syndrome. Objective: to determine the serum levels of these markers with the greatest sensibility and specificity for mortality and worst organ dysfunction in patients under invasive mechanical ventilation within the first 48 hours of hospitalization. Material and methods: in a retrospective and longitudinal cohort of severe COVID-19 patients on invasive mechanical ventilation within first 48 hours of hospitalization due to respiratory failure through January 2021 to August 2021, we determined the relation of inflammatory markers with prognostic scores (SOFA, APACHE-II and SAPS-II), hospital length-of-stay (LOS), intensive care LOS, invasive ventilation's days and initial ventilatory mechanics. We divided markers in high and low levels to identify the relation between each one and by groups with the outcomes. Results: we studied a N = 218, with male predominance (77.5%) and mean age of 60.3 ± 12.8 years. Arterial hypertension and diabetes mellitus type 2 were the most prevalent co-comorbidities (50.5% y 26.1%, respectively). The median initial PaO2/FiO2 was 128 mmHg (83.3-204.2), with a total mortality rate of 24.8%. Inflammatory markers levels with the highest sensibility for mortality were: C-reactive protein: ≥ 16 mg/dL, procalcitonin: ≥ 0.83 ng/mL, D-dimer: ≥ 1,290 ng/mL, ferritin: ≥ 1,450 ng/mL and interleukin-6: ≥ 195 pg/mL. Procalcitonin and interleukin-6 were associated to higher risk of mortality and worst organ dysfunction. The inflammatory markers were related with worst outcome in relation to respiratory mechanics and the amount of arterial-blood gases' alteration. Having ≥ 3 inflammatory markers within high levels was associated with prolonged LOS, more intensive care LOS and more days under invasive mechanical ventilation. The c-reactive protein, procalcitonin and interleukin-6 had higher organic dysfunction defined by SOFA and worst outcome defined by APACHE-II and SAPS-II. Conclusion: individual and joint measurement of inflammatory markers at hospitalization can identify patients with greater risk of longer hospital LOS, intensive care LOS and longer mechanical ventilation's days, with greater risk of mortality with higher procalcitonin and interleukine-6 serum levels.

Resumo: Introdução: demonstrou-se que os níveis iniciais de marcadores inflamatórios envolvidos no COVID-19 (por exemplo, ferritina, proteína C reativa, procalcitonina, D-dímero e interleucina-6) estão relacionados à mortalidade, sem encontrar resultados semelhantes em pacientes com COVID-19 grave ou que estejam sob ventilação mecânica invasiva. Objetivos: nosso objetivo foi determinar o nível sérico com maior sensibilidade e especificidade em marcadores inflamatórios em relação à mortalidade e gravidade da disfunção orgânica em pacientes com COVID-19 grave que usaram ventilação mecânica invasiva nas primeiras 48 horas após a admissão hospitalar. Material e métodos: realizou-se um estudo descritivo do tipo coorte retrospectivo e longitudinal em pacientes diagnosticados com COVID-19 grave que foram intubados nas primeiras 48 horas após a internação hospitalar por insuficiência respiratória aguda no período de janeiro de 2021 a agosto de 2021. A relação entre os níveis desses marcadores com as escalas de prognóstico (SOFA, APACHE-II e SAPS-II), dias de internação, dias na unidade de terapia intensiva respiratória, dias de ventilação mecânica invasiva e as características da ventilação mecânica inicial. Agrupou-se marcadores em níveis altos e baixos para determinar seu papel individualmente e em conjunto com os resultados. Resultados: estudou-se uma N = 218, com predominância do sexo masculino (77.5%) com idade média de 60.3 ± 12.8 anos. A hipertensão arterial sistêmica e a diabetes mellitus tipo 2 foram as comorbidades mais prevalentes (50.5% e 26.1%, respectivamente). A mediana da relação PaO2/FiO2 foi de 128 mmHg (83.3-204.2), com mortalidade total de 24.8%. Os níveis de biomarcadores com maior sensibilidade para mortalidade e disfunção orgânica foram: proteína C reativa: ≥ 16 mg/dL, procalcitonina: ≥ 0.83 ng/mL, dímero: ≥ 1.290 ng/mL, ferritina: ≥ 1.450 ng/mL, e interleucina-6: ≥ 195 pg/mL. A procalcitonina e a interleucina-6 sozinhas demonstraram maior risco de mortalidade e pior disfunção orgânica. Os marcadores inflamatórios foram relacionados a pior evolução quanto às características do sistema respiratório e ao grau de alteração dos gases arteriais. Juntos (≥ 3 altos), os marcadores inflamatórios foram relacionados a um maior número de dias de internação, dias na unidade de terapia intensiva respiratória e dias de ventilação mecânica invasiva. A proteína C-reativa, procalcitonina e interleucina-6 foram associadas a maior risco de pior grau de disfunção orgânica pelo SOFA e pior prognóstico pelo APACHE-II e SAPS-II. Conclusão: a medida individual e conjunta de marcadores inflamatórios na admissão hospitalar pode identificar pacientes com maior risco de internação prolongada e ventilação mecânica invasiva, com maior risco de mortalidade no caso da procalcitonina e interleucina-6.