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. 2020 Mar;32(1):108-114.
doi: 10.5935/0103-507x.20200016. Epub 2020 May 8.

Stratification to predict the response to antioxidant

[Article in English, Portuguese]
Cristiane Ritter  1 , Larissa Constantino  1 , Monique Michels  1 , Renata Casagrande Gonçalves  1 , Cassiana Fraga  1 , Danusa Damásio  2 , Felipe Dal-Pizzol  1
Affiliations

Stratification to predict the response to antioxidant

[Article in English, Portuguese]
Cristiane Ritter et al. Rev Bras Ter Intensiva. 2020 Mar.

Abstract
in English, Portuguese

Objective: To examine the effectiveness of stratification to identify and target antioxidant therapy for animal models of lethal sepsis and in patients who develop sustained hypotension.

Methods: Rats were subjected to sepsis induced by cecal ligation and puncture. Animals were divided into two groups: those with high and low plasma levels of interleukin-6. Following stratification, N-acetylcysteine plus deferoxamine or saline was administered to animals starting 3 and 12 hours after surgery. N-Acetylcysteine plus deferoxamine or placebo was administered within 12 hours of meeting the inclusion criteria in hypotensive patients.

Results: N-Acetylcysteine plus deferoxamine increased survival in the cecal ligation and puncture model when administered 3 and 12 hours after sepsis induction. When dividing animals that received antioxidants using plasma interleukin-6 levels, the protective effect was observed only in those animals with high IL-6 levels. The antioxidant effect of N-acetylcysteine + deferoxamine was similar in the two groups, but a significant decrease in plasma interleukin-6 levels was observed in the high-interleukin-6-level group. Compared with patients treated with antioxidants in the low-interleukin-6 subgroup, those in the high-interleukin-6 subgroup had a lower incidence of acute kidney injury but were not different in terms of acute kidney injury severity or intensive care unit mortality.

Conclusion: Targeting antioxidant therapy to a high inflammatory phenotype would select a responsive population.

Objetivo: Avaliar a efetividade da estratificação para identificar e escolher alvos para terapia antioxidante em um modelo de sepse letal em animais e pacientes que desenvolveram hipotensão prolongada.

Métodos: Submeteu-se um grupo de ratos à sepse induzida por ligadura e punção do ceco. Os animais foram divididos em dois grupos: os com níveis plasmáticos altos e os com níveis plasmáticos baixos de interleucina-6. Após a estratificação, administrou-se aos animais N-acetilcisteína mais desferroxamina ou soro fisiológico a partir de 3 e 12 horas após a cirurgia. Em pacientes hipotensos, N-acetilcisteína mais desferroxamina ou placebo foram administrados dentro de 12 horas após o cumprimento dos critérios para inclusão.

Resultados: O uso de N-acetilcisteína mais desferroxamina aumentou a sobrevivência no modelo com ligadura mais punção do ceco quando a administração ocorreu 3 e 12 horas após indução da sepse. Ao utilizar os níveis de interleucina-6 para separar os animais que receberam antioxidantes, o efeito protetor só foi observado nos animais que tinham níveis elevados de interleucina-6. O efeito antioxidante de N-acetilcisteína mais desferroxamina foi similar nos dois grupos, porém observou-se diminuição significante dos níveis plasmáticos de interleucina-6 no grupo que apresentava elevado nível de interleucina-6. Em comparação com pacientes tratados com antioxidantes no subgrupo que tinha baixos níveis plasmáticos de interleucina-6, aqueles que tinham níveis elevados de interleucina-6 tiveram menor incidência de lesão renal aguda, porém não foram diferentes em termos de severidade da lesão renal aguda ou da mortalidade na unidade de terapia intensiva.

Conclusão: Direcionar a terapia antioxidante para um elevado fenótipo inflamatório selecionaria uma população responsiva.

PubMed Disclaimer

Conflict of interest statement

Responsible editor: Luciano César Pontes de Azevedo

Figures

Figure 1
Figure 1
Effects of antioxidant administration three hours after sepsis induction in an animal model. (A) Mortality rate comparing the use of antibiotics with antibiotics plus antioxidants. (B) Mortality rate comparing the use of antibiotics plus antioxidants in animals in the high- and low-interleukin-6-level groups. Plasma levels of (C) thiobarbituric acid reactive species, (D) protein carbonyls, and (e) interleukin-6 in antibiotics, low interleukin-6 and high interleukin-6 antibiotics plus antioxidants groups. ATB - antibiotics; ATX - antibiotics plus antioxidants; IL - interleukin; MDA - malondialdehyde. # Different from baseline, same group; * different from the lowinterleukin- 6 group, same time. p < 0.05.
Figure 2
Figure 2
Effects of antioxidant administration twelve hours after sepsis induction in an animal model. (A) Mortality rate comparing the use of antibiotics with the use of antibiotics plus antioxidants. (B) Mortality rate comparing the use of antibiotics plus antioxidants in animals in the high- and low-interleukin- 6-level groups. Plasma levels of (C) thiobarbituric acid reactive species, (D) protein carbonyls, and (E) interleukin-6 in antibiotics, low interleukin-6 and high interleukin-6 antibiotics plus antioxidants groups. ATB - antibiotics; ATX - antibiotics plus antioxidants; IL - interleukin; MDA - malondialdehyde. # Different from baseline, same group; * different from the low-interleukin-6 group, same time. p < 0.05.
Figure 3
Figure 3
A retrospective stratification of patients by interleukin-6 plasma levels suggests beneficial effects of antioxidants for patients with high baseline circulating interleukin-6 levels. IL-6 - interleukin-6.
See this image and copyright information in PMC

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