Intravenous N-acetylcysteine compared to placebo for treatment of systemic inflammatory response syndrome and sepsis in seriously ill adults

Systemic inflammatory response syndrome (SIRS) is a complex response to an insult such as major surgery or trauma. It is called sepsis syndrome, or simply sepsis, when infection is present. The generalized inflammatory reaction involves activation of leukocytes and endothelial cells and the release of inflammatory mediators and toxic oxygen free radicals. Diffuse microthrombosis can result in localized tissue perfusion abnormalities and low oxygenation (hypoxia). Both SIRS and sepsis can be difficult to treat and are major causes of multiple organ failure and the death of patients in the intensive care unit. SIRS and sepsis both lead to a drop in the level of antioxidants normally present in the body.

N-acetylcysteine is an antioxidant with strong anti-inflammatory effects that is used in treating endotoxaemia and overdoses of acetaminophen. This Cochrane review of 41 randomized controlled trials with 2768 critically ill adult patients found no evidence to support the theory that N-acetylcysteine might reduce the risk of death in adults with SIRS or sepsis. Intravenous N-acetylcysteine did not affect the length of stay in the intensive care unit, duration of mechanical ventilation, duration of support for the cardiovascular system or incidence of new organ failure. There is currently insufficient evidence to support the use of N-acetylcysteine in SIRS or sepsis. We also found that when N-acetylcysteine was administered more than 24 hours after the development of clinical signs of SIRS or sepsis it may even be harmful, by causing cardiovascular depression.

Twenty of the trials used N-acetylcysteine in patients around the time of surgery, including cardiac, vascular and major abdominal surgery, and liver transplantation. Eight studies evaluated N-acetylcysteine in patients with severe sepsis or septic shock associated with the medical conditions acute respiratory distress syndrome (ARDS), multiple organ failure, liver failure, malaria or burns. The dosing of N-acetylcysteine, timing and duration of treatment, from a single intravenous dose to infusions up to seven days, varied. Twenty papers had a low risk of bias.

Authors' conclusions: 

Overall, this meta-analysis puts doubt on the safety and utility of intravenous N-acetylcysteine as an adjuvant therapy in SIRS and sepsis. At best, N-acetylcysteine is ineffective in reducing mortality and complications in this patient population. At worst, it can be harmful, especially when administered later than 24 hours after the onset of symptoms, by causing cardiovascular depression. Unless future RCTs provide evidence of treatment effect, clinicians should not routinely use intravenous N-acetylcysteine in SIRS or sepsis and academics should not promote its use.

Read the full abstract...

Death is common in systemic inflammatory response syndrome (SIRS) or sepsis-induced multisystem organ failure and it has been thought that antioxidants such as N-acetylcysteine could be beneficial.


We assessed the clinical effectiveness of intravenous N-acetylcysteine for the treatment of patients with SIRS or sepsis.

Search strategy: 

We searched the following databases: Cochrane Central Register of Clinical Trials (CENTRAL) (The Cochrane Library 2011, Issue 12); MEDLINE (January 1950 to January 2012); EMBASE (January 1980 to January 2012); CINAHL (1982 to January 2012); the NHS Trusts Clinical Trials Register and Current Controlled Trials (; LILACS; KoreaMED; MEDCARIB; INDMED; PANTELEIMON; Ingenta; ISI Web of Knowledge and the National Trials Register to identify all relevant randomized controlled trials available for review.

Selection criteria: 

We included only randomized controlled trials (RCTs) in the meta-analysis.

Data collection and analysis: 

We independently performed study selection, quality assessment and data extraction. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I2 statistic.

Main results: 

We included 41 fully published studies (2768 patients). Mortality was similar in the N-acetylcysteine group and the placebo group (RR 1.06, 95% CI 0.79 to 1.42; I2 = 0%). Neither did N-acetylcysteine show any significant effect on length of stay, duration of mechanical ventilation or incidence of new organ failure. Early application of N-acetylcysteine to prevent the development of an oxidato-inflammatory response did not affect the outcome, nor did late application that is after 24 hours of developing symptoms. Late application was associated with cardiovascular instability.