Double-blind, Randomized, Placebo-controlled Trial With N-acetylcysteine for Treatment of Severe Acute Respiratory Syndrome Caused by Coronavirus Disease 2019 (COVID-19)
Julio Cesar Garcia De Alencar, Claudia De Lucena Moreira, Alicia Dudy Müller, Cleuber Esteves Chaves, Marina Akemi Fukuhara, Elizabeth Aparecida Da Silva, Maria De Fátima Silva Miyamoto, Vanusa Barbosa Pinto, Cauê Gasparotto Bueno, Felippe Lazar Neto, Luz Marina Gomez Gomez, Maria Clara Saad Menezes, Julio Flavio Meirelles Marchini, Lucas Oliveira Marino, Rodrigo Antônio Brandão Neto, Heraldo Possolo Souza, Fernando Salvetti Valente, Hassan Rahhal, Juliana Batista Rodrigues Pereira, Eduardo Messias Hirano Padrão, Annelise Passos Bispos Wanderley, Bruno Marques, Luz Marina Gomez Gomez, Edwin Albert D’souza, Arthur Petrillo Bellintani, Rodrigo Cezar Miléo, Rodrigo Werner Toccoli, Fernanda Máximo Fonseca E Silva, João Martelleto Baptista, Marcelo De Oliveira Silva, Giovanna Babikian Costa, Rafael Berenguer Luna, Henrique Tibucheski Dos Santos, Mariana Mendes Gonçalves Cimatti De Calasans, Marcelo Petrof Sanches, Diego Juniti Takamune, Luiza Boscolo, Pedro Antonio Araújo Simões, Manuela Cristina Adsuara Pandolfi, Beatriz Larios Fantinatti, Gabriel Travessini, Matheus Finardi Lima De Faria, Ligia Trombetta Lima, Bianca Ruiz Nicolao, Gabriel De Paula Maroni Escudeiro, João Pedro Afonso Nascimento, Bruna Tolentino Caldeira, Laura De Góes Campos, Vitor Macedo Brito Medeiros, Tales Cabral Monsalvarga, Isabela Harumi Omori, Diogo Visconti Guidotte, Alexandre Lemos Bortolotto, Rodrigo De Souza Abreu, Nilo Arthur Bezerra Martins, Carlos Eduardo Umehara Juck, Lucas De Oliveira Utiyama, Felipe Mouzo Bortoleto, Renan Dourado Tinel, Gabriel Martinez Andreola, Natalia Paula Cardoso, Osvaldo Santistevan Claure, João Vitor Ziroldo Lopes, Sabrina Correa Da Costa Ribeiro
Clinical Infectious Diseases, doi:10.1093/cid/ciaa1443
Background. A local increase in angiotensin 2 after inactivation of angiotensin-converting enzyme 2 by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may induce a redox imbalance in alveolar epithelium cells, causing apoptosis, increased inflammation and, consequently, impaired gas exchange. We hypothesized that N-acetylcysteine (NAC) administration could restore this redox homeostasis and suppress unfavorable evolution in patients with coronavirus disease 2019 . Methods. This was a double-blind, randomized, placebo-controlled, single-center trial conducted at the Emergency Department of Hospital das Clínicas, São Paulo, Brazil, to determine whether NAC in high doses can avoid respiratory failure in patients with COVID-19. We enrolled 135 patients with severe COVID-19 (confirmed or suspected), with an oxyhemoglobin saturation <94% or respiratory rate >24 breaths/minute. Patients were randomized to receive NAC 21 g (~300 mg/kg) for 20 hours or dextrose 5%. The primary endpoint was the need for mechanical ventilation. Secondary endpoints were time of mechanical ventilation, admission to the intensive care unit (ICU), time in ICU, and mortality. Results. Baseline characteristics were similar between the 2 groups, with no significant differences in age, sex, comorbidities, medicines taken, and disease severity. Also, groups were similar in laboratory tests and chest computed tomography scan findings. Sixteen patients (23.9%) in the placebo group received endotracheal intubation and mechanical ventilation, compared with 14 patients (20.6%) in the NAC group (P = .675). No difference was observed in secondary endpoints. Conclusions. Administration of NAC in high doses did not affect the evolution of severe COVID-19. clinical Trials Registration. Brazilian Registry of Clinical Trials (REBEC): U1111-1250-356 (http://www.ensaiosclinicos.gov. br/rg/RBR-8969zg/).
References
Alnahdi, John, Raza, N-acetyl cysteine attenuates oxidative stress and glutathione-dependent redox imbalance caused by high glucose/high palmitic acid treatment in pancreatic Rin-5F cells, PLoS One
Atkuri, Mantovani, Herzenberg, Herzenberg, N-Acetylcysteine-a safe antidote for cysteine/glutathione deficiency, Curr Opin Pharmacol
Bunyavanich, Do, Vicencio, Nasal gene expression of angiotensinconverting enzyme 2 in children and adults, JAMA
Cao, Wang, Wen, A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19, N Engl J Med
Cazzola, Calzetta, Page, Rogliani, Matera, Thiol-based drugs in pulmonary medicine: much more than mucolytics, Trends Pharmacol Sci
Diamond, The renin-angiotensin system: an integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications, J Exp Med
Dikalov, Nazarewicz, Angiotensin II-induced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease, Antioxid Redox Signal
Docherty, Harrison, Green, Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study, BMJ
Ehre, Rushton, Wang, An improved inhaled mucolytic to treat airway muco-obstructive diseases, Am J Respir Crit Care Med
Ershad, Wermuth, Vearrier, N acetylcysteine
Felice, Nardin, Tanna, Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives, Am J Hypertens,
doi:10.1093/ajh/hpaa096Fiorentini, Falzano, Rivabene, Fabbri, Malorni, N-acetylcysteine protects epithelial cells against the oxidative imbalance due to Clostridium difficile toxins, FEBS Lett
Fisher, Curry, Evaluation and treatment of acetaminophen toxicity, Adv Pharmacol
Grasselli, Zangrillo, Zanella, Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy, JAMA
Gurwitz, Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics, Drug Dev Res,
doi:10.1002/ddr.21656Harrison, Wendon, Gimson, Alexander, Williams, Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure, N Engl J Med
Hoffmann, Kleine-Weber, Schroeder, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell
Lanza, Perez, Costa, Covid-19: the renin-angiotensin system imbalance hypothesis, Clin Sci
Laurindo, De Souza, Mde, Janiszewski, Redox aspects of vascular response to injury, Methods Enzymol
Lee, Hynan, Rossaro, Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure, Gastroenterology
Merad, Martin, Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages, Nat Rev Immunol
Oliveira, Laurindo, Implications of plasma thiol redox in disease, Clin Sci (Lond)
Pirola, Sookoian, Estimation of renin-angiotensin-aldosterone-system (RAAS)-inhibitor effect on COVID-19 outcome: a meta-analysis, J Infect
Redza-Dutordoir, Da, Activation of apoptosis signalling pathways by reactive oxygen species, Biochim Biophys Acta
Richardson, Hirsch, Narasimhan, Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area, JAMA
Smilkstein, Knapp, Kulig, Rumack, Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the national multicenter study (1976 to 1985), N Engl J Med
Souza, Frediani, Cobra, Angiotensin II modulates CD40 expression in vascular smooth muscle cells, Clin Sci (Lond)
Tay, Poh, Rénia, Macary, Ng, The trinity of COVID-19: immunity, inflammation and intervention, Nat Rev Immunol
Touyz, Li, Delles, ACE2 the Janus-faced protein-from cardiovascular protection to severe acute respiratory syndrome-coronavirus and COVID-19, Clin Sci
Wang, Zhang, Bai, An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients, Int J Cardiol
Wong, Graudins, Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions, Clin Toxicol (Phila)
Wu, Hu, Zhang, Ren, Yu et al., Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients, Crit Care
Wu, Leung, Bushman, Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China, Nat Med
Zhang, Wang, Ni, COVID-19: melatonin as a potential adjuvant treatment, Life Sci
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'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:sec>\n'
' <jats:title>Background</jats:title>\n'
' <jats:p>A local increase in angiotensin 2 after inactivation of '
'angiotensin-converting enzyme 2 by severe acute respiratory syndrome coronavirus 2 '
'(SARS-CoV-2) may induce a redox imbalance in alveolar epithelium cells, causing apoptosis, '
'increased inflammation and, consequently, impaired gas exchange. We hypothesized that '
'N-acetylcysteine (NAC) administration could restore this redox homeostasis and suppress '
'unfavorable evolution in patients with coronavirus disease 2019 (COVID-19).</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Methods</jats:title>\n'
' <jats:p>This was a double-blind, randomized, placebo-controlled, '
'single-center trial conducted at the Emergency Department of Hospital das Clínicas, São '
'Paulo, Brazil, to determine whether NAC in high doses can avoid respiratory failure in '
'patients with COVID-19. We enrolled 135 patients with severe COVID-19 (confirmed or '
'suspected), with an oxyhemoglobin saturation &lt;94% or respiratory rate &gt;24 '
'breaths/minute. Patients were randomized to receive NAC 21 g (~300 mg/kg) for 20 hours or '
'dextrose 5%. The primary endpoint was the need for mechanical ventilation. Secondary '
'endpoints were time of mechanical ventilation, admission to the intensive care unit (ICU), '
'time in ICU, and mortality.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Results</jats:title>\n'
' <jats:p>Baseline characteristics were similar between the 2 groups, with no '
'significant differences in age, sex, comorbidities, medicines taken, and disease severity. '
'Also, groups were similar in laboratory tests and chest computed tomography scan findings. '
'Sixteen patients (23.9%) in the placebo group received endotracheal intubation and mechanical '
'ventilation, compared with 14 patients (20.6%) in the NAC group (P\u2005=\u2005.675). No '
'difference was observed in secondary endpoints.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Conclusions</jats:title>\n'
' <jats:p>Administration of NAC in high doses did not affect the evolution of '
'severe COVID-19.</jats:p>\n'
' </jats:sec>\n'
' <jats:sec>\n'
' <jats:title>Clinical Trials Registration</jats:title>\n'
' <jats:p>Brazilian Registry of Clinical Trials (REBEC): U1111-1250-356 '
'(http://www.ensaiosclinicos.gov.br/rg/RBR-8969zg/).</jats:p>\n'
' </jats:sec>',
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'volume': '40',
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'year': '2019',
'journal-title': 'Trends Pharmacol Sci'},
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'regimen for paracetamol poisoning results in a lower incidence of '
'adverse drug reactions',
'volume': '54',
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'author': 'Cao',
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'volume': '217',
'author': 'Diamond',
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'volume': '20',
'author': 'Sturrock',
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'first-page': '355',
'DOI': '10.1016/j.coph.2007.04.005',
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'volume': '7',
'author': 'Atkuri',
'year': '2007',
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'redox imbalance caused by high glucose/high palmitic acid treatment in '
'pancreatic Rin-5F cells',
'volume': '14',
'author': 'Alnahdi',
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'first-page': '124',
'DOI': '10.1016/S0014-5793(99)00706-1',
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'imbalance due to Clostridium difficile toxins',
'volume': '453',
'author': 'Fiorentini',
'year': '1999',
'journal-title': 'FEBS Lett'},
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'doi-asserted-by': 'crossref',
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'DOI': '10.1056/NEJM199106273242604',
'article-title': 'Improvement by acetylcysteine of hemodynamics and oxygen transport in '
'fulminant hepatic failure',
'volume': '324',
'author': 'Harrison',
'year': '1991',
'journal-title': 'N Engl J Med'},
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'first-page': '319',
'article-title': 'Efficacy of oral N-acetylcysteine in the treatment of acetaminophen '
'overdose: analysis of the national multicenter study (1976 to 1985)',
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'doi-asserted-by': 'crossref',
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'DOI': '10.1038/s41577-020-0331-4',
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'author': 'Merad',
'year': '2020',
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