O impacto da n-acetilcisteína na morbimortalidade em cirurgias cardíacas valvares e de revascularização do miocárdio: revisão sistemática e metanálise
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Data
2018-12-07
Autores
Pereira, José Eduardo Guimarães [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
Cirurgias cardíacas são procedimentos muito eficientes para tratar os sintomas do infarto miocárdico, e para realizar trocas e plastias valvares. Contudo, problemas clínicos ocorrem ao realizar-se tais procedimentos em razão da lesão de isquemia-reperfusão e estresse oxidativo. Ambos, a cirurgia e a circulação extracorpórea (CEC) causam liberação de citocinas inflamatórias (TNF-α, IL-6, IL-10) e ativação de espécies reativas de oxigênio (O2-, H2O2-). Glutationa peroxidase (GPO) é uma enzima antioxidante que exerce papel importante no equilíbrio oxidativo e tem sua atividade limitada pela depleção das reservas de glutationa (GSH). N-acetilcisteína (NAC) é um resíduo acetilado do composto cisteína, e é necessária à ressíntese da glutationa (GSH). Estudos têm demonstrado a ação antioxidante da NAC, e seus efeitos na proteção da função dos pulmões, rins e coração, com resultados conflitantes. Sendo assim, este estudo avaliou o papel da n-acetilcisteína na redução da morbimortalidade de pacientes submetidos a cirurgias cardíacas. Foi realizada uma revisão sistemática e metanálise de ensaios clínicos randomizados (ECRs) e quase-ECRs, sem restrições quanto a línguas. ECRs foram pesquisadas nas seguintes bases de dados: MEDLINE, EMBASE, CENTRAL e LILACS, e a última busca ocorreu em 10 de outubro de 2018. Dois revisores independentes (JEGP, RED) selecionaram e extraíram os dados dos estudos, e a abordagem GRADE foi utilizada para classificar a certeza das evidências para os desfechos avaliados. Vinte e nove ECRs includindo 2.486 participantes mostraram-se elegíveis. Os resultados dessa metanálise demonstraram que a adição de NAC não resultou em uma redução significante da mortalidade (Risco Relativo (RR) 0,71; 95% Intervalo de Confiança (IC) 0,40 a 1,25; n=1.737; p = 0,23), insuficiência renal (RR 0,92; 95% IC 0,79 a 1,09; n = 1.711; p = 0,34), insuficiência cardíaca (RR 0,77; 95% IC 0,44 a 1,38; n = 1.149; p = 0,38), tempo de internação hospitalar (Diferença da Média (DM) -0,21, 95% IC -0,64 a 0,23; n = 1.650; p = 0,35), tempo de internação em CTI (DM -0,04, 95% IC -0,29 a 0,20; n = 1.512; p = 0,73), arritmia (RR 0,79; 95% IC 0,52 a 1,20; n = 886; p=0,27), e infarto agudo do miocárdio (RR 0,84; 95% IC 0,48 a 1,48; n = 1.178; p = 0,55). Após avaliação dos subgrupos, encontrou-se uma redução estatísticamente significante no tempo de internação em CTI (p<0.00001) (DM -0,63 dias, 95% IC -0,88 a -0,38; quatro estudos, n = 162) quando NAC foi administrado aos pacientes via solução de cardioplegia versus pacientes que receberam solução de cardioplegia sem NAC. Após análise de sensibilidade foi encontrada redução estatísticamente significante na incidência de arritmias quando NAC foi administrada intravenosamente em pacientes que não receberam aprotinina (RR 0,41; 95% IC 0,23 a 0,72; n = 404; p = 0,002). Conclusão: As análises primárias desta revisão sugerem uma tendência a favor da adição de NAC na redução de riscos dos desfechos clínicos em pacientes submetidos a cirurgias cardíacas valvares e de revascularização do miocárdio, entretanto sem significância estatística. Já resultados de análises de subgrupo indicam, de forma estatisticamente significante, que a adição de NAC à solução de cardioplegia reduz o tempo de internação em centros de terapia intensiva, e que a administração de NAC intravenosa reduz a incidência de arritmias nos pacientes que não receberam aprotinina quando comparados àqueles que receberam tratamento padrão. Ensaios clínicos robustos são necessários para definitivamente confirmar ou refutar os achados desta revisão.
Cardiac surgeries are very efficient procedures to treat acute myocardial infarction symptoms, and to perform heart valve repair or replacement. Nervertheless, clinical issues arise upon performing such procedures, like isquemia-reperfusion injury and oxidative stress. Both, surgery and the cardiopulmonary by-pass (CPB) cause liberation of inflammatory cytokines (TNF-α, IL-6, IL-10) and activation of reactive oxygen species (O2-, H2O2-). Glutathione peroxidase (GPO) is an enzymatic antioxidant and plays a major role on the oxidative balance, and its activity is limited due to glutathione (GSH) reserve depletion. N-acetylcysteine (NAC) is an acetylated residue of the cysteine compound, and is necessary for glutathione (GSH) resynthesis. Studies have demonstrated the antioxidant action of NAC, and its effects on the protection of lung, kidney and heart functions, although with conflicting results. Therefore, this study evaluated the role of NAC on the reduction of morbimortality of the patients submitted to cardiac surgeries. A Systematic review and metanalysis of randomized controlled trials (RCTs) and Quasi-RCTs, with no restrictions to languages, was performed. RCTs were searched from the following databases: MEDLINE, EMBASE, CENTRAL and LILACS, and the last search date was October 10th, 2018. Two independent reviewers have selected and extracted the data from the studies, and the GRADE approach was utilized to classify the certainty of the evidences for the outcomes assessed. Twenty-nine RCTs including 2,486 participants proved eligible. The results from this meta-analysis demonstrate that the addition of NAC did not result in a significant reduction of mortality (Risk Ratio (RR) 0.71; 95% Confidence Interval (CI) 0.40 to 1.25; n=1,737; p = 0.23), acute renal insufficiency (ARI) (RR 0.92; 95% CI 0.79 to 1.09; n = 1,711; p = 0.34), acute cardiac insufficiency (ACI) (RR 0.77; 95% CI 0.44 to 1.38; n = 1,149; p = 0.38), hospital length of stay (HLoS) (Mean Difference (MD) -0.21, 95% CI -0.64 to 0.23; n = 1,650; p = 0.35), intensive care unit length of stay (ICULoS) (MD -0.04, 95% CI -0.29 to 0.20; n = 1,512; p = 0.73), arrhythmia (RR 0.79; 95% CI 0.52 to 1.20; n = 886; p=0.27), and acute myocardial infarction (AMI) (RR 0.84; 95% CI 0.48 to 1.48; n = 1,178; p = 0.55). After assessing the a priori subgroups of interest using a test of interaction, there was a significant reduction in ICULoS (p<0.00001) (MD -0.63 days, 95% CI -0.88 to -0.38; four trials, n = 162) when NAC is administered to patients via cardioplegia solution versus patients receiving cardioplegia solution alone. After perfoming a sensitivity analysis there was a significant reduction reduction in the incidence of arrhythmias when NAC was administered intravenously in patients who did not receive aprotinin (RR 0,0,41; 95% IC 0,23 a 0,72; n = 404; p = 0,002). Conclusions: Results from the primary analyses from this review suggest a non-statistically significant trend towards risk reduction in clinical outcomes in patients submitted to cardiac valve and revascularization surgeries. Results from subgroup analyses indicate a statistically significant reduction in intensive care unity length of stay when NAC is added to the cardioplegia solution when compared to standard of care, and a statistically significant reduction on the incidence of arrhythmias when NAC is administered intravenously to patients who did not receive aprotinin when compared to standard of care. Larger robust clinical trials are needed to confirm or refute our findings.
Cardiac surgeries are very efficient procedures to treat acute myocardial infarction symptoms, and to perform heart valve repair or replacement. Nervertheless, clinical issues arise upon performing such procedures, like isquemia-reperfusion injury and oxidative stress. Both, surgery and the cardiopulmonary by-pass (CPB) cause liberation of inflammatory cytokines (TNF-α, IL-6, IL-10) and activation of reactive oxygen species (O2-, H2O2-). Glutathione peroxidase (GPO) is an enzymatic antioxidant and plays a major role on the oxidative balance, and its activity is limited due to glutathione (GSH) reserve depletion. N-acetylcysteine (NAC) is an acetylated residue of the cysteine compound, and is necessary for glutathione (GSH) resynthesis. Studies have demonstrated the antioxidant action of NAC, and its effects on the protection of lung, kidney and heart functions, although with conflicting results. Therefore, this study evaluated the role of NAC on the reduction of morbimortality of the patients submitted to cardiac surgeries. A Systematic review and metanalysis of randomized controlled trials (RCTs) and Quasi-RCTs, with no restrictions to languages, was performed. RCTs were searched from the following databases: MEDLINE, EMBASE, CENTRAL and LILACS, and the last search date was October 10th, 2018. Two independent reviewers have selected and extracted the data from the studies, and the GRADE approach was utilized to classify the certainty of the evidences for the outcomes assessed. Twenty-nine RCTs including 2,486 participants proved eligible. The results from this meta-analysis demonstrate that the addition of NAC did not result in a significant reduction of mortality (Risk Ratio (RR) 0.71; 95% Confidence Interval (CI) 0.40 to 1.25; n=1,737; p = 0.23), acute renal insufficiency (ARI) (RR 0.92; 95% CI 0.79 to 1.09; n = 1,711; p = 0.34), acute cardiac insufficiency (ACI) (RR 0.77; 95% CI 0.44 to 1.38; n = 1,149; p = 0.38), hospital length of stay (HLoS) (Mean Difference (MD) -0.21, 95% CI -0.64 to 0.23; n = 1,650; p = 0.35), intensive care unit length of stay (ICULoS) (MD -0.04, 95% CI -0.29 to 0.20; n = 1,512; p = 0.73), arrhythmia (RR 0.79; 95% CI 0.52 to 1.20; n = 886; p=0.27), and acute myocardial infarction (AMI) (RR 0.84; 95% CI 0.48 to 1.48; n = 1,178; p = 0.55). After assessing the a priori subgroups of interest using a test of interaction, there was a significant reduction in ICULoS (p<0.00001) (MD -0.63 days, 95% CI -0.88 to -0.38; four trials, n = 162) when NAC is administered to patients via cardioplegia solution versus patients receiving cardioplegia solution alone. After perfoming a sensitivity analysis there was a significant reduction reduction in the incidence of arrhythmias when NAC was administered intravenously in patients who did not receive aprotinin (RR 0,0,41; 95% IC 0,23 a 0,72; n = 404; p = 0,002). Conclusions: Results from the primary analyses from this review suggest a non-statistically significant trend towards risk reduction in clinical outcomes in patients submitted to cardiac valve and revascularization surgeries. Results from subgroup analyses indicate a statistically significant reduction in intensive care unity length of stay when NAC is added to the cardioplegia solution when compared to standard of care, and a statistically significant reduction on the incidence of arrhythmias when NAC is administered intravenously to patients who did not receive aprotinin when compared to standard of care. Larger robust clinical trials are needed to confirm or refute our findings.
Descrição
Palavras-chave
acetilcisteína, cirurgia torácica, cirurgia cardíaca, circulação extracorpórea, CEC, revisão sistemática, metanálises, n-acetylcysteine, acetylcysteine, thoracic surgery, myocardial revascularization, coronary artery bypass, metanalysis