Clinical effects of N-acetylcysteine in ICU patients with respiratory disease: a systematic review and meta-analysis

Amiri, Mehrnaz; Cheraghi, Mahdis; Khalili, Farima; D’Ambrosio, Lia; Centis, Rosella; Dinh-Xuan, Anh Tuan; Venketaraman, Vishwanath; Nasiri, Mohammad Javad; Migliori, Giovanni Battista

doi:10.36416/1806-3756/e20250438

SYSTEMATIC REVIEW AND META-ANALYSIS • Respir. Res. & Clin. Pract. 52 (1) • 2026 • https://doi.org/10.36416/1806-3756/e20250438 linkcopy

Clinical effects of N-acetylcysteine in ICU patients with respiratory disease: a systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective: Critically ill patients with respiratory disease often experience impaired airway clearance, which contributes to adverse clinical outcomes. N-acetylcysteine (NAC) has mucolytic and antioxidant properties, and may have therapeutic potential in this setting. This study evaluated the impact of NAC on clinical outcomes in ICU patients with underlying respiratory disease.

Methods: A systematic literature search was conducted in PubMed/MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Scopus, and Web of Science from January of 2000 to July of 2025 in order to identify randomized controlled trials evaluating NAC in ICU patients with respiratory conditions. Primary outcomes included hospital mortality, duration of mechanical ventilation, ICU length of stay (LOS), and hospital LOS. Data were synthesized using fixed- or random-effects models based on heterogeneity. Subgroup analyses were performed based on the route of NAC administration.

Results: Five randomized controlled trials comprising 340 patients were included. Hospital mortality was 44.76% in the NAC group and 47.61% in the control group (OR = 0.87; 95% CI: 0.49-1.53). No significant differences were observed in ventilation duration (mean difference [MD] = 0.79 days; 95% CI: −2.87 to 4.44) or ICU LOS (MD = 0.21 days; 95% CI: −3.75 to 4.17). However, NAC was associated with a shorter hospital stay (MD = −3.84 days; 95% CI: −7.44 to −0.24). Subgroup analysis suggested variability in mortality outcomes based on administration route.

Conclusions: NAC may reduce hospital LOS in critically ill patients with respiratory disease, although its effects on mortality and ventilation duration remain inconclusive. These findings may inform future research, particularly in patients with post-infectious lung damage such as that seen in COVID-19 or tuberculosis.

Keywords:
Acetylcysteine; Mucolytic agents; Intensive care units; Clinical study; Hospital mortality

Authors	Study Design	Country	Study period	Number of patients (case/control)	Mean age	No. of male patients	Underlying condition	APACHE II score	SOFA score	Baseline PaO₂/FiO₂	Prophylaxis/Treatment	Type of Mucolytic	Dose and Frequency	Route of administration	Duration of Treatment
Masoompour et al.²⁶	RCT	Iran	January of 2012 to June of 2012	40 (20/20)	55.15	19	hospitalized in the ICU (pneumonia, poisoning [carbon monoxide and drugs], and sepsis)	NM	NM	NM	T	NAC	2 mL of NAC 20% with 8 mL normal saline TDS	nebulizer	1 day
Sharafkhah et al.³⁷	RCT	Iran	March of 2014 to June of 2016	60 (30/30)	49.43 ± 18.7	43	At risk of VAP*	21.7 ± 7.5 (NAC), 22.7 ± 8.0 (control)	NM	NM	P	NAC	600 mg BD	p.o.	during the period of invasive mechanical ventilation
Ghorbi et al. ²⁹	RCT	Iran	2020	60 (30/30)	45.29 ± 15.91	32	hospitalized in the ICU (ARDS)	13.63 ± 2.42 (NAC), 14.16 ± 0.79 (control)	NM	123.66 ± 7.39 (NAC), 123.8 ± 7.04 (control)	T	NAC	150 mg/kg + 50 mg/kg	i.v.	150 mg/kg on day one and 50 mg/kg for 3 days
Gamarra-Morales et al. ²⁸	RCT	Spain	March of 2020 to June of 2020	140 (72/68)	61.8	106	hospitalized in the ICU with COVID-19	13.5 (NAC), 17.5 (control)	4.51 (NAC), 5.01 (control)	168.6 (NAC), 179 (control)	T	NAC	loading: 150 mg/kg + 50 mg/kg- maintenance: 50 mg/kg	i.v.	15 min + 4 h + 72 h
Rahimi et al. ²⁷	RCT	Iran	2020	40 (20/20)	58.52 ± 15.73	22	hospitalized in the ICU with a positive COVID-19 test	NM	NM	NM	T	NAC	300 mg/kg	i.v.	1 day

Authors	Random Sequence Generation	Allocation Concealment	Blinding of Participants	Blinding of Outcome Assessors	Incomplete Outcome Data	Selective Reporting	Other bias
Masoompour et al.²⁶	Low	Low	Low	Low	Low	Low	Low
Sharafkhah et al.³⁷	Low	Low	Low	Low	Low	Low	Low
Ghorbi et al.²⁹	Low	Low	Low	Low	Low	Low	Low
Gamarra-Morales et al.²⁸	Low	High	High	High	Low	Low	Low
Rahimi et al.²⁷	Low	Low	Low	Low	Low	Low	Low

Outcome	No. of participants	No. of studies	Effect Size % (95% Cl)
Ventilation duration	260	3	MD: 0.789 [−2.87 to 4.44]
ICU LOS	300	4	MD :0.21 [−3.75 to 4.17]
Hospital LOS	100	2	MD: −3.84 [−7.44 to −0.24]

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Sociedade Brasileira de Pneumologia e Tisiologia - SBPT SCS Quadra 01, Bloco K, Salas 203/204 Ed. Denasa, Brasília - DF CEP: 70.398-900, Fone/fax: 08000 61 6218, (61) 3245 1030 e (61) 3245 6218 - Brasília - DF - Brazil
E-mail: rrcp@sbpt.org.br

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[TFN1] RCT: randomized controlled trial; NM: not mentioned; T: treatment; BD: twice daily; NAC: n-acetylcysteine; TDS: three times a day; P: prophylaxis; and VAP: ventilator-associated-pneumonia. *Reasons for ICU admission included trauma, respiratory failure, and neurological (in most of the patients), heart, gastrointestinal, and endocrine conditions, as well as infection.