N-Acetylcysteine (NAC) for Hospitalized COVID-19 Patients
Based on the most recent and highest-quality evidence, N-acetylcysteine may reduce mortality in hospitalized COVID-19 patients by approximately 51%, but the evidence remains mixed and no major guideline currently recommends its routine use.
Current Guideline Position
The available COVID-19 treatment guidelines from major societies (American College of Chest Physicians, American Society of Hematology, Journal of Thrombosis and Haemostasis) do not include recommendations for or against NAC use in hospitalized COVID-19 patients 1. These guidelines focus primarily on antithrombotic therapy, anticoagulation, and immunomodulatory treatments rather than antioxidant adjunctive therapies 1.
Evidence from Randomized Controlled Trials
Most Recent Meta-Analysis (2025)
- A systematic review of 10 RCTs including 1,424 patients found that NAC reduced mortality with a pooled odds ratio of 0.49 (95% CI: 0.25-0.94), representing a 51% reduction in odds of death 2.
- The effect was most pronounced with higher doses or non-oral routes of administration 2.
- Heterogeneity was substantial (I² = 67%), indicating variability in treatment effects across studies 2.
Conflicting Evidence
- A 2023 meta-analysis of 4 studies with 355 patients found no significant benefit for NAC regarding intubation rate (OR 0.55,95% CI 0.16-1.89), mortality (OR 0.58,95% CI 0.23-1.45), ICU stay, or hospital stay 3.
- Trial sequential analysis in this meta-analysis suggested the evidence for mortality was conclusive for non-significance, though other outcomes required larger sample sizes 3.
Most Recent Individual RCT (2025)
- A propensity-score matched cohort study of mechanically ventilated COVID-19 patients (n=136, with 64 matched patients) found no significant difference in 28-day mortality, ventilator-free days, or length of stay with high-dose intravenous NAC (10g/day) 4.
- After propensity score matching and multivariable adjustment, NAC did not independently affect 28-day mortality 4.
Earlier Positive Observational Data (2021)
- A two-center retrospective cohort study (n=82) reported that oral NAC 600mg twice daily significantly reduced progression to severe respiratory failure (p<0.01) and decreased both 14-day and 28-day mortality (p<0.001 and p<0.01 respectively) 5.
- However, this was observational data with inherent selection bias limitations 5.
Clinical Recommendation Algorithm
For hospitalized COVID-19 patients without mechanical ventilation:
- NAC 600mg orally twice daily for 14 days may be considered as adjunctive therapy, particularly in patients with moderate-to-severe disease who have elevated inflammatory markers (CRP, D-dimers, LDH) 5, 2.
- This recommendation is based on potential mortality benefit from the 2025 meta-analysis, but clinicians should recognize the conflicting evidence 2, 3.
For mechanically ventilated COVID-19 patients:
- High-dose intravenous NAC (10g/day) is not recommended based on the most recent propensity-matched study showing no benefit in this critically ill population 4.
- Standard COVID-19 therapies (corticosteroids, immunomodulators, anticoagulation per guidelines) should take priority 1.
Monitoring if NAC is used:
- Baseline and serial inflammatory markers (CRP, D-dimers, LDH) to assess response 5.
- Oxygenation parameters (PaO2/FiO2 ratio) 5.
- No specific additional safety monitoring is required beyond standard COVID-19 care, as NAC has minimal side effects 6.
Important Caveats
- The 2025 meta-analysis showing mortality benefit had substantial heterogeneity (I²=67%), suggesting variable effects across different patient populations and NAC regimens 2.
- The most rigorous recent study in mechanically ventilated patients showed no benefit, suggesting NAC may not be effective in the most severely ill 4.
- NAC is not a substitute for proven COVID-19 therapies including corticosteroids for patients requiring supplemental oxygen, which have strong guideline support 1.
- Drug interactions are minimal, making NAC relatively safe to add to standard regimens 7.